Journal of Substance Abuse and Alcoholism

Predicting Addiction Liability from Brain Stimulation Reward Data: A Comparison of the Acute Effects of Cocaine, Pseudoephedrine, Nicotine, and Caffeine

Research Article | Open Access

  • 1. Addiction Research Unit, Department of Psychology, State University of New York at Buffalo, Buffalo, New York 14260-4110
+ Show More - Show Less
Corresponding Authors
Dr. Michael A Bozarth, Department of Psychology, State University of New York at Buffalo, Buffalo, New York 14260-4110, phone: 716-645-3650 ext. 687, fax: 716-645-3801

Male, Long-Evans rats with lateral hypothalamic stimulating electrodes were tested using a threshold-tracking procedure. This procedure determined the minimum stimulation frequency (i.e., stimulation threshold) necessary to maintain ≥30 presses/min during daily 30-min test sessions. Rats were injected with cocaine hydrochloride (2.5 to 20 mg/kg, i.p.), pseudoephedrine hydrochloride (3 to 100 mg/kg, i.p.), nicotine bitartrate (0.063 to 1 mg/kg, s.c.), or caffeine (5 to 80 mg/kg, i.p.) immediately before testing. Peak threshold-lowering effects were determined during 180-min test sessions. Another series of tests compared the facilitatory effects produced by (i) different nicotine bitartrate administration conditions (i.e., pH-adjusted vs. pH-unadjusted solutions and s.c. vs. i.p. injection routes), (ii) nicotine freebase in pH-adjusted and pH-unadjusted solutions, and (iii) repeated nicotine bitartrate injections. These comparisons ensured that the most effective nicotine administration parameters were used.

All compounds facilitated BSR. The prototypic addictive drug cocaine lowered thresholds over twice as much as the nonaddictive compound pseudoephedrine. This shows that BSR facilitation can be used to predict reinforcing drug action, but quantitative measures of facilitation must be used to distinguish drugs with high and low addiction liabilities. Nicotine’s facilitation of BSR was quantitatively similar to that seen with pseudoephedrine and markedly different from cocaine’s effect. Caffeine produced BSR facilitation comparable to that seen with nicotine and with pseudoephedrine. Similar peak-facilitation effects were seen with all nicotine administration conditions. This suggests that even under optimal administration conditions, nicotine’s profile in this animal model is that of a substance with a low addiction liability.


Addiction liability, Brain stimulation reward, Caffeine, cocaine, Drug abuse, Intracranial self-stimulation, Nicotine, Pseudoephedrine, Psychomotor stimulants, Reward


Bozarth MA, Pudiak CM (2021) Predicting Addiction Liability from Brain Stimulation Reward Data: A Comparison of the Acute Effects of Cocaine, Pseudoephedrine, Nicotine, and Caffeine. J Subst Abuse Alcohol 8(2): 1092.


Considerable evidence suggests that a compound’s effect on brain stimulation reward (BSR) provides a useful assessment of its potential addiction liability (for reviews, see Esposito and Kornetsky, 1978; Kornetsky et al., 1979; Reid, 1987; Wise, 1996). Drugs that enhance the rewarding effects of electrical brain stimulation are generally highly addictive, and drugs that are not addictive usually fail to enhance (or even inhibit) BSR. The interaction of a compound with BSR does not, of course, directly assess the compound’s addiction liability. Rather, the enhancement of BSR is though to reflect the drug’s rewarding properties, and this rewarding action is thought to underlie the drug’s ability to reinforce behavior and thus to produce an addiction (see Bozarth, 1987a).

Most investigators studying the facilitation of BSR by various drugs consider this a qualitative measure: drugs that facilitate BSR are likely to possess potent reinforcing and hence addictive properties. Earlier work comparing the effects of various opioids on BSR suggested that quantitative aspects of a compound’s facilitatory action may be important in determining its addiction liability. The prototypic addictive drug morphine produced robust facilitation of BSR, while codeine and nalorphine, compounds with a low addiction liability, produced only a modest facilitation effect (Bozarth, 1978; Bozarth and Reid, 1978; Reid and Bozarth, 1978). Furthermore, pentazocine, an opioid with mixed agonistantagonist properties that reportedly has significant abuse liability only in exaddicts, produced robust facilitation of BSR only after rats had prior exposure to morphine (Bozarth, 1978; Bozarth and Reid, 1978; Reid and Bozarth, 1978). These data suggest that BSR may indeed provide a useful assessment of a compound’s addiction potential, but quantitative aspects of the facilitation effect must be considered to distinguish compounds with a high addiction liability from substances with a low addiction liability (Bozarth, 1978; Bozarth and Reid, 1978). Unfortunately, most investigators fail to compare the effects of various compounds with those of prototypic addictive drugs (e.g., cocaine, heroin). Most BSR studies simply compare the effect of the test compound with that obtained with drug vehicle (e.g., physiological saline). Any enhancement of BSR is usually interpreted as indicating the compound has potent rewarding effects and hence a significant addiction liability.

The present study compares the effects of four psychoactive substances on BSR. The facilitation produced by a prototypic addictive drug (i.e., cocaine) is compared with the facilitatory action of a compound generally considered to have a low addiction liability (i.e., pseudoephedrine). The effects of two other commonly used substances with controversial addictive properties (e.g., caffeine, nicotine) are evaluated by considering the range of facilitation produced by addictive and nonaddictive 1 drug actions

Pseudoephedrine was selected as the nonaddictive comparison compound because (i) it is widely prescribed by physicians and is available over-the-counter in the United States and Canada, and (ii) it has mild stimulatory properties similar to psychomotor stimulants. Although pseudoephedrine is restricted by prescription in some European countries (e.g., Germany and Sweden but not Great Britain), its widespread use without reported addiction 2 in North America suggests that this compound has a very low addiction liability. In the United States cases of pseudoephedrine abuse appear restricted to excessive use of weight loss preparations and to high-dose use of preparations marketed as a safe, “natural high.” The sale of over-the-counter medicines containing pseudoephedrine remain very popular for use as a nonsedating nasal decongestant, but some restrictions in terms of the quantity that may be purchased within a given time-period have been enacted because of its diversion as a precursor chemical for the illicit manufacture of methamphetamine. Previously the very limited abuse of pseudoephedrine appears to have been driven by sociological rather than pharmacological factors (i.e., there is no indication of potent anorexic or mood-elevating effects even from excessively high doses). Restrictions on sales and distribution are designed to prevent the high-dose intake that can produce toxic reactions and the diversion to clandestine laboratories that may convert pseudoephedrine to methamphetamine. There are no documented cases of pseudoephedrine addiction nor any indication of euphoria or substantial mood-elevating effects from this compound.



BSR-brain stimulation reward, CNS-central nervous system, IP-intraperitoneal, MIN-minute/minutes; SEM-standard error of the mean, SC-subcutaneous



Male, Long-Evans rats (Harlan Sprague-Dawley, Altamont, NY), weighting 225 to 300 g at the time of surgery, were implanted with monopolar stimulating electrodes aimed at the lateral hypothalamic level of the medial forebrain bundle. With the upper incisor bar 3.3 mm below the interaural plane, the coordinates were posterior 3.3 from bregma, lateral ± 1.8 from the midline mm, and 8.4 mm below dura. Electrodes were fabricated from 0.25 mm stainless steel wire insulated with Formvar except at the cross section of the tip. The stimulation ground was formed by wrapping 0.25 mm annealed stainless steel wire around two stainless steel screws (#80) anchored into the rostral aspect of the skull. Both the stimulating electrode and the ground terminated in gold-plated Amphenol pins that were connect to the stimulation lead during testing by mating Amphenol sockets.

Electrodes were implanted under sodium pentobarbital (65 mg/kg, i.p.) anesthetic, with atropine sulfate (0.4 mg/kg, i.p.) given to decrease mucosal secretions. Electrodes were anchored to the skull using three stainless steel screws embedded in dental acrylic. A single dose of penicillin-G (60,000 units, i.m.) was administered prophylactically following the completion of surgery. Animals were allowed a minimum of 5 days recovery from surgery before screening for BSR.

Rats were individually housed in stainless steel cages contained in a temperature and humidity controlled environment (22 ± 1 °C, 40 to 60 %-RH). A 14-hour light/10-hour dark cycle of illumination was used, with all behavioral testing occurring during the light phase of this cycle. Subjects were given ad libitum access to food and water, except during behavioral testing. At the end of the experiment, animals were sacrificed with an overdose of sodium pentobarbital (c. 80 mg/kg, i.p.) and were transcardially perfused with normal saline followed by phosphate-buffered formalin. The brains were removed and stored in formalin before sectioning into 40 m sections using a cryostat-microtome. The brain sections were stained using crystal violet, and electrode placements were verified at 10x magnification.


Stimulation pulses consisted of 300 msec trains of 300sec cathodal pulses, with the electrode shunted to ground during the interpulse interval to prevent electrical charge build-up in the stimulated tissue. Various current intensities (100 to 500A) and frequencies (32 to 126 Hz) were used. Stimulation pulses were controlled by a computer program, which determined all stimulation parameters except current intensity which was controlled by a constant-current stimulator (Mundl, 1980). Current intensity was monitored by the voltage drop across a 1 kohm resistor in series with the stimulating electrode. Pulse form and current intensity were monitored throughout the test sessions using Textronic oscilloscopes.

Rats were tested in 26 x 47 x 38 cm operant chambers containing a lever located 8 cm above the floor. Each lever press produced a single train of stimulation. Subjects were connected to the stimulator with a flexible lead attached to an electrical commutator. Unrestricted movement of the subjects was maintained throughout the experimental sessions.


Cocaine hydrochloride (National Institute on Drug Abuse Drug Procurement Program, Research Triangle Park, NC), pseudoephedrine hydrochloride (Sigma Chemical, St. Louis), and anhydrous caffeine (Sigma Chemical, St. Louis) were dissolved in physiological saline and were injected intraperitoneally. Both cocaine and pseudoephedrine doses refer to the salt form of these compounds. Nicotine bitartrate and nicotine freebase (Sigma Chemical, St. Louis) were dissolved in physiological saline. Some tests involved nicotine solutions that were pH-adjusted to 7 0.2, while other tests used unadjusted nicotine solutions (bitartrate pH 3.4; freebase pH 11.4). Nicotine was injected in some tests subcutaneously and in other tests intraperitoneally. All nicotine doses refer to the freebase weight of this compound. Injections were given in a 1 ml/kg volume, except for the two highest caffeine doses (i.e., 40 and 80 mg/kg) which were injected in 2 and 4 ml/kg volumes because of the limited solubility of anhydrous caffeine.


Rats were screened for BSR at 79 to 126 Hz using various current intensities (100 to 500 A). Subjects showing vigorous lever-pressing were tested for several 30-min sessions at fixed stimulation parameters. After stable responding developed, testing with the threshold-tracking procedure was begun using daily 30-min sessions. Stimulation frequencies decreased 0.1 log unit per minute until responding fell below criterion (i.e. 30 presses/min). Stimulation frequencies then increased 0.1 log unit per minute until responding met criterion (i.e., 30 presses/ min). Alternating descending and ascending thresholds were continuously determined throughout the test session. Threshold was defined as the average stimulation frequency that maintained criterion responding. Ascending and descending threshold were generally the same, producing response patterns that alternated vigorous pressing (at threshold) and nonresponding across successive 1-min periods.

Rats were tested daily with 30-min sessions. Mean frequency thresholds were calculated daily for each rat. Responding was considered stable when thresholds were within 10% of the previous 5-day mean. After frequency thresholds had stabilized (range 2 to 3 weeks), drug testing began. Subjects were injected immediately before BSR testing and were tested continuously for 3 hours following injections. The longer session duration was used to document the entire time-course of drug action, with specific attention to detecting any delayed facilitatory effect on BSR. Data were analyzed by comparing the effects of various drug doses (including the drug vehicle, physiological saline) with mean 5-day pretreatment baseline thresholds. Each 180- min test session was divided into successive 15-min periods, and the average threshold was computed for each test at each time interval. Data are expressed as the percentage of baseline thresholds. A minimum of 72 hours separated each drug test.



The first experiment compared the effects of two drugs with well-documented addiction liabilities-cocaine and pseudoephedrine. Cocaine is a prototypic addictive drug, with a very high addiction liability, while pseudoephedrine addiction has not been reported. These two compounds serve to define the magnitude of facilitation produced by addictive and nonaddictive compounds, respectively. Cocaine defines the lower limit of facilitation expected from a compound with a high addiction liability (i.e., potentially addictive compounds ≥ cocaine’s facilitatory effect), while pseudoephedrine defines the upper limit of facilitation expected from a compound with a low addiction liability (i.e., low addiction liability compounds ≤ pseudoephedrine’s facilitatory effect). In determining the lower and upper limits of both profiles, it is necessary to consider the maximum facilitation produced by each compound. This is because both humans and laboratory animals can control how much drug they self-administer and it is presumed that both increase their dosage levels to produce the desired (i.e., rewarding) effect. Increases in drug dosage to potentially reinforcing levels is limited only by toxic and neurological sideeffects of drug treatment. To ensure that the maximum facilitatory effect was obtained with each compound, full dose-response and time-course analyses were performed for each substance.


Rats were assigned to one of two groups to receive either cocaine hydrochloride (1.25, 2.5, 5, 10, & 20 mg/kg, i.p., n = 10) or pseudoephedrine hydrochloride (3, 30, 56, & 100 mg/kg, i.p., n = 6) injections. All rats received all doses of a given compound administered in a counterbalanced order. At least 72 hours separated each injection, and injections were postponed if the subject was not within 10% of its pretreatment baseline mean on the day prior to a scheduled injection. Animals were tested continuously for 180 min immediately after injections and for 30 min on days between drug tests.


Figures 1 and 2 illustrate the percent of baseline thresholds for cocaine and for pseudoephedrine across the entire 180-min test session. Cocaine produced a strong, dose-dependent lowering of thresholds [F (5, 35) = 73.874, p < .001]. Pseudoephedrine also produced a dose-dependent threshold lowering [F (3, 15) = 11.514, p < .001], but the effect was weaker. A higher dose of cocaine (i.e., 30 mg/kg, i.p.) produced stereotypy which disrupted responding for BSR. The higher doses of pseudoephedrine (i.e., 56 & 100 mg/kg, i.p.) also produced stereotypy accompanied by an apparent increase in thresholds for some animals. The increases in stimulation thresholds seen with stereotypic drug doses are considered artifactual and are probably not representative of changes in the rewarding impact of the electrical stimulation. Data obtained with these doses are not shown in the figures. Both cocaine [F (11, 77) = 53.768, p < .001] and pseudoephedrine [F (11,55) = 3.671, p < .005] effects changed across the 180-min test sessions. There was also a significant Dose x Minutes post injection interaction for cocaine [F (55,385) = 4.207, p < .001] and for pseudoephedrine [F (55,165) = 2.535, p < .01]. [Figure 1, 2]


Nicotine produced reliable facilitation of BSR. The optimal nicotine dose for producing facilitation appeared to be 0.5 mg/ kg, with the maximum threshold-lowering effect beginning at 16-30 min post injection and lasting for about an hour. The effect of nicotine on BSR was more like pseudoephedrine than like cocaine. Both compounds produced a delayed facilitation lasting most of the 3-hr test period, although nicotine’s effect peaked The results from the quantitative analysis of BSR correspond well with studies of intravenous nicotine self-administration in laboratory animals. Some investigators report reliable intravenous self-administration (Corrigall and Coen, 1989; Donny et al., 1995), but reliable nicotine self-administration has generally been elusive (Bozarth and Pudiak, 1996a; Dworkin et al., 1993). Reliable self-administration of nicotine appears to depend on the use of special testing parameters (e.g., rapid infusions) and is not readily established without them (see Bozarth and Pudiak, 1996b; Henningfield et al., 1996). Even reviewers who argue that intravenous nicotine self-administration is reliable (e.g., considerably sooner. Both compounds also produced quantitatively similar peak threshold-lowering. These results suggest that the rewarding action of nicotine closely resembles that of pseudoephedrine and is markedly different than that of cocaine. Thus, this preclinical measure indicates that nicotine has a relatively low addiction liability 41 comparable to pseudoephedrine. 

Goldberg and Henningfield, 1988; Henningfield and Goldberg, 1983) acknowledge that it is not as robust as intravenous cocaine self-administration. Indeed, the few studies that have directly compared the reinforcing efficacy of nicotine with cocaine show that cocaine is a much more powerful reinforcer (Ator and Griffiths, 1980; Goldberg and Spealman, 1982; Griffiths et al., 1979; Risner and Goldberg, 1983), and this finding corroborates the quantitative differences seen in the present BSR study. These and other differences between self-administration established with prototypic addictive drugs (e.g., cocaine, heroin) and nicotine self-administration suggest that nicotine has only a mildly rewarding action. This would explain why nicotine selfadministration is so sensitive to testing parameters, why the results with conditioned place preference have been conflicting, and why large quantitative differences exist in BSR facilitation from nicotine and cocaine.


The modest but reliable facilitation of BSR by nicotine suggests that nicotine has the profile of a non-addictive compound. However, several additional tests were conducted to determine if the effect of nicotine was limited by the nicotine formulation or route of administration. These tests were essential to ensure that the maximum obtainable effect was seen with nicotine and that nicotine’s maximum effect was used in the quantitative comparison with the two reference substances.

Nicotine bitartrate was selected for most tests because it has been used more extensively than nicotine freebase in similar studies and because some investigators argue that the bitartrate salt form is necessary to demonstrate reliable rewarding effects of nicotine. The initial dose-response analysis used nicotine bitartrate (0.063 to 1 mg/kg) subcutaneously administered without pH adjustment. This is the most commonly studied form of this compound and the most often used route of administration. Further tests were conducted to ensure that the most effective nicotine solution and route of administration were used. These tests compared the effects obtained with a fixed dose of nicotine bitartrate (0.5 mg/kg), using pH-adjusted subcutaneous and intraperitoneal injections compared with pHunadjusted subcutaneous and intraperitoneal injections. The pH of the nicotine bitartrate solution was adjusted in some tests (pH = 7 0.2) with sodium hydroxide because some investigators assert that pH adjustment affects the rewarding properties of this compound. Additional tests were conducted comparing the effects of nicotine freebase in pH-adjusted and unadjusted solutions following subcutaneous injections in another group of subjects.

Procedure Separate groups of subjects were used for the nicotine bitartrate and the nicotine freebase studies. Animals in the nicotine bitartrate study (n = 6) were administered 0.5 mg/kg nicotine bitartrate (dose expressed as freebase weight) in pHadjusted (pH = 7 ± 0.2) and pH-unadjusted pH ≈ 3.4 solutions by subcutaneous and intraperitoneal injections in a quasiradom order. At least 72 hrs separated each injection, and injections were postponed if the subject was not within 10% of its baseline threshold on the day prior to the scheduled nicotine injection. Not all subjects were tested under each condition. Subjects in the nicotine freebase study (n = 10) were injected with 0.5 mg/kg nicotine freebase in pH-adjusted (pH = 7 ± 0.2) and pHunadjusted pH ≈ 11.4 solutions by subcutaneous injection. Treatments were administered in a counterbalanced order, and 72 hrs separated each treatment condition. All subjects were tested in both treatment conditions. BSR tests were conducted for 30 min on most days, with 180-min sessions during nicotine tests. Animals in both groups received a saline injection during a single 180-min test. [Table 1]


Figure 4 shows the time-course of threshold lowering for each treatment condition. All nicotine treatment conditions produced similar facilitation of BSR, although the subcutaneous route of administration was somewhat less variable than intraperitoneal injections. Because the design of Experiment III included subjects tested at several but not all treatments, direct statistical comparisons were not made across these treatment conditions. However, the same subjects were tested in both freebase conditions (i.e., pH-unadjusted vs. pH-adjusted) permitting direct statistical comparison. A 2 x 12 within subjects ANOVA conducted on the two nicotine treatment conditions revealed that there were no appreciable differences between the pH-unadjusted and pH-adjusted nicotine freebase treatments [F (1,9) = 0.865 p > .25], although the effect of minutes post injections was significant [F(11,99) = 8.565, p < .001]; the Treatment x Minutes post injection interaction was not significant [F(11,99 )= 0.272, p > .25]. [Figure 4]

Figure 5 shows the mean response inhibition produced by the first and the second nicotine freebase injections. The effects of the four treatment conditions are plotted separately (n = 5/ condition). The first nicotine injection produced considerably more response suppression than the second injection for both the pH-adjusted [t (4) = 4.894, p = .004]5 and the pH-unadjusted [t (4) = 2.505, p = .033]6 solutions administered first. Interestingly during the second injection, the pH-adjusted nicotine solution appeared to produce less response suppression than did the pH-unadjusted solution [t (9) = 2.613, p = .031]. [3] Apparent differences seen during the second injection between the pHadjusted and pH-unadjusted nicotine freebase solutions should be interpreted cautiously, because they were not predicted a priori and because these effects just achieved statistical significance. Nonetheless, it seems plausible that the pH-unadjusted solution might cause more irritation because of its basic nature or that the degree of ionization might produce more rapid nicotine delivery and hence more malaise. [Figure 5]

Similar response inhibitions were produced by the initial nicotine bitartrate injections in Experiment II, but counterbalancing treatment conditions prohibited direct comparison of this effect (i.e., the number of subjects tested under each condition in sequence [e.g., 0.125 . 0.5 mg/kg, 0.5 . 0.250 mg/kg] was too small for meaningful comparison). Response inhibition and ataxia from initial nicotine injections have been noted by other investigators studying BSR (e.g., Bauco and Wise, 1994). Two other studies conducted in this laboratory using 0.5 mg/kg, s.c., pH-adjusted nicotine bitartrate solutions have also reported response inhibition (Bozarth et al., 1998a, 1998b), but the inhibition seen during the first (≈ 6.5 min) and the second (≈ 2.5 min) nicotine injections was somewhat less than that seen in the present study from freebase nicotine injections. It is possible that initial nicotine freebase injections are more behaviorally disruptive than nicotine bitartrate injections and that this disruptive effect remains slightly stronger during the second injection with pH-unadjusted freebase solutions.

Figure 6 compares the peak facilitation seen with each nicotine treatment. All 8 nicotine treatment conditions produced similar peak facilitation. This analysis shows there are no important differences in BSR peak-facilitation between the bitartrate salt and freebase forms nor any significant effect of adjusting the pH from acidic (i.e., bitartrate salt) or basic (i.e., freebase) to neutral. Based on this comparison, there is no rationale for deviating from use of the natural freebase form of nicotine in pH-unadjusted solutions. Finally, the nicotine administration parameters used in the full-dose response analysis (i.e., Experiment II) should have accurately identified the maximum obtainable facilitation of BSR from acute nicotine treatment. [Figure 6]


There were no appreciable differences in BSR facilitation seen from the various nicotine formulations and routes of administration. Similar peak-facilitation, latency to onset, and duration of action were produced by all preparations. This finding questions the common practice of using the salt form for behavioral research. Generally, the salt form of a compound is used when the freebase form has limited solubility. Nicotine freebase, however, is readily soluble in aqueous solutions. Similarly, solutions not adjusted to pH 7 produced the same facilitation effect as pH-adjusted solutions. Therefore, there is no apparent rationale for adjusting the pH of the injected nicotine solutions nor for using the salt form instead of the freebase form of nicotine.



Animals in Experiment II received various doses of nicotine in a counterbalanced order, but the possibility remains that prior nicotine exposure may alter the subsequent effect of nicotine on BSR. Although counterbalancing minimizes the influence of prior nicotine exposure on any single treatment condition by distributing the associated variance across all treatment conditions (i.e., nicotine doses), the maximum facilitation might be over- or under-estimated by this repeated testing design. Therefore, a separate experiment was conducted to determine if prior nicotine exposure altered the effect of nicotine on BSR.


After thresholds for BSR had stabilized, animals were divided into two groups (n = 7/group). One group was injected with 0.05 mg/kg nicotine bitartrate and the second group was injected with 0.5 mg/kg nicotine bitartrate (doses refer to freebase weight). Nicotine bitartrate solutions were pH-adjusted to 7 ± 0.2, and all injections were given subcutaneously. Animals were tested for 30 min immediately following injections. Seventy-two hours later, both groups received 0.5 mg/kg nicotine bitartrate (s.c.) and were again tested for 30 min using the thresholdtracking procedure. Data are expressed as the percent reduction in threshold based on each animal’s baseline threshold, and the time period when nicotine produces its peak effect (i.e., 16-30 min post injection) was used in the analysis.


Figure 7 shows the threshold lowering 16-30 min post nicotine injections. Each treatment condition was compared with the facilitation produced by the 0.5 mg/kg nicotine dose from Experiment II. There was a significant difference in thresholdlowering produced by the 0.5 mg/kg nicotine dose tested earlier and the 0.05 mg/kg dose tested in the current study [t (17) = 3.526, p = .003]. However, all three tests with 0.5 mg/kg nicotine yielded similar threshold reductions [t’s (17) = 0.474 to 1.342, p’s = .197 to .641]. [Figure 7]

The response inhibition produced by the nicotine injections is shown in Figure 8. The lowest nicotine dose produced no significant behavioral disruption, while the 0.5 mg/kg dose inhibited responding. There was a significant reduction in response inhibition following the second 0.5 mg/kg nicotine injection for the group initially receiving 0.5 mg/kg nicotine [t (6) = 4.684, p = .003]. Animals receiving the 0.5 mg/kg dose after the 0.05 mg/kg dose showed a significant increase in response inhibition [t (6) = 2.540, p = .04]. There was evidence of partial tolerance to the response suppressing effect of the 0.5 mg/kg nicotine dose for animals initially receiving 0.05 mg/kg nicotine,but this effect was not statistically significant [t(12) = 1.506, p = .158]. The low power of the statistical test (The power of the t-test with α = .05 was .170.) may have permitted a Type II statistical error [Figure 8].


Prior nicotine exposure had no significant effect on the threshold-lowering produced by the 0.5 mg/kg nicotine dose. Therefore, the influence of using a fully counterbalanced design in Experiment II appears negligible with respect to nicotine’s effect on thresholds. However, significant changes in response inhibition were seen with repeated nicotine administration. Tolerance rapidly developed to the disruptive effect of nicotine on BSR, with animals showing only about a 4 min response inhibition by the second nicotine administration. It is likely that at least partial tolerance to the disruptive effect of nicotine on operant responding was maintained during the dose-response analysis conducted in Experiment II, despite the fact that a minimum of 72 hrs separated each nicotine test. The response inhibition initially seen with 0.5 mg/kg nicotine bitartrate was comparable to that seen with the same dose of nicotine freebase.

Table 1: Nicotine Formulations & Routes of Administration Tested in Experiment.
                                                NICOTINE FORMULATION
  Nicotine Bitartrate Nicotine Freebase
IINJECTION ROUTE pH-unadjusted 1 pH-adjusted 2 pH-unadjusted 3 pH-adjusted 4
ip 5 s/u/ip s/a/ip              -           -
sc-neck 6 s/u/scn s/a/scn b/u/scn b/a/scn
sc-flank 7 s/u/scf s/a/scf              -           -


1: pH ≈ 3.4 (u: pH-unadjusted)

2: pH adjusted to 7 ± 0.2 with sodium hydroxide (a: pH-adjusted)

3: pH ≈ 11.4 (u: pH-unadjusted)

4: pH adjusted to 7 ± 0.2 with acetic acid (a: pH-adjusted)

5: intraperitoneal injection (ip)

6: subcutaneous (sc) injection administered along dorsal neck region (scn)

7: subcutaneous (sc) injection administered along lower flank region (scf)

s: salt (nicotine bitartrate)

b: base (nicotine freebase)


Experiment V: The Effect of Caffeine on BSR

Experiment I established the reference points for facilitation produced by addictive and nonaddictive substances. Experiment II revealed that nicotine, which has controversial addictive properties, has a profile like a nonaddictive substance, while Experiments III and IV further examined the ability of nicotine to facilitate BSR by determining the effects of various nicotine administration parameters and of repeated nicotine injections, respectively. This experiment examined the effect of another commonly used substance, caffeine, on BSR.

Caffeine-containing beverages are used widely throughout the world (Gilbert, 1984), and this substance is presumed to have a mild reinforcing action. The effects of caffeine on BSR are equivocal. Early work using a rate measure reported a facilitation of BSR (Valdes et al. 1988), but later work using a threshold measure reported threshold elevations (Mumford and Holtzman 1990, 1991; Mumford et al. 1988). There are no apparent differences in caffeine administration parameters among the conflicting reports, so the obtained differences in BSR effects are presumed to be related to BSR methodology. The present study examined the effects of caffeine on BSR using the thresholdtracking method which is very sensitive to a compound’s facilitatory action (Bozarth et al., 1990). The effect of a wide range of caffeine doses was examined across 180-min sessions beginning immediately after caffeine administration.


Rats (n = 10) were injected with anhydrous caffeine (2.5, 5, 10, 20, 40, or 80 mg/kg, i.p.) immediately before testing. All rats received all doses of caffeine administered in a counterbalanced order. At least 72 hours separated each injection, and injections were postponed if the subject was not within 10% of its pretreatment baseline mean on the day prior to a scheduled injection. Animals were tested continuously for 180 min immediately after injections.


Figure 9 shows the effect of caffeine on BSR thresholds. Caffeine appeared to have two distinctively different effects on BSR: low caffeine doses facilitated BSR, while high caffeine doses inhibited BSR. To simply the analysis, separate two-way within subjects ANOVAs were computed for each effect (i.e., low-dose facilitation and high-dose inhibition). The ANOVA conducted on saline and the four lowest caffeine doses (i.e., 2.5, 5, 10, & 20 mg/ kg) revealed a significant effect of caffeine Dose [F (4, 36) = 5.957, p < .01], of Minutes post injection [F (11,99) = 14.417, p < .01], and a significant Dose x Minutes interaction [F(44,396) = 1.780, p < .01]. Because of missing data for the 80 mg/kg caffeine dose (see below), the second analysis was performed comparing only the 40 mg/kg caffeine dose with saline. The ANOVA conducted  on saline and the 40 mg/kg caffeine dose showed a significant effect of caffeine Treatment [F (1, 9) = 5.641, p < .01] and of Minutes post injection [F(11,99) = 9.497, p < .01]; the Treatment x Minutes interaction was also significant [F(11,99) = 1.981, p < .05]. [Figure 9].

The 80 mg/kg caffeine dose disrupted responding for BSR in 60% of the subjects during the first 15-min interval and in 20% of the subjects during the second 15-min interval. One of the subjects failed to reliably respond for BSR during the entire 180-min test (i.e., apparent response extinction). For this reason, these data were not included in the statistical analysis. However, large and sustained threshold elevations were seen following the 80 mg/kg caffeine dose, and these threshold elevations showed little evidence of diminishing by the end of the 3-hr test. The 40 and 80 mg/kg caffeine doses also produced a significant dosedependent weight-loss 24 hr after injections [mean ± SEM: 40 mg/kg dose = -6.2 g ± 1.5, t (9) = 2.516, p = .033; 80 mg/kg dose = -15.1 g ± 2.9, t (9) = 4.250, p = .002]. Weight changes after saline and the other caffeine doses were not significant (mean changes = -0.9 to + 2 g).


The lower caffeine doses facilitated BSR, while higher caffeine doses elevated BSR thresholds. The threshold-lowering effect had a rapid onset and a very short duration of action. The maximum threshold elevation seen with the 40 mg/kg dose was somewhat delayed, but this inhibitory effect lasted throughout the 180-min test session. The 80 mg/kg dose initially disrupted responding in some animals but produced sustained threshold elevations when animals resumed responding during the second and third 15-min periods.

Two of the three studies failing to detect facilitation from low-dose caffeine began testing their subjects 15 to 30 min after injections. The modest threshold-lowering produced by caffeine has largely dissipated by this time. Other differences include the method of measuring thresholds (i.e., threshold-tracking vs. autotitration), the stimulation parameter manipulated (i.e., stimulation frequency vs. current intensity), and the form of caffeine used (i.e., anhydrous freebase vs. sodium-benzoate salt). Of these differences, the method of measuring thresholds is likely to be the most significant. The autotitration method used in the earlier studies may have problems detecting some facilitatory drug actions 7 (Fouriezos and Nawiesniak, 1987; see also Esposito et al., 1987), although it detects the facilitatory action of amphetamine (Schaefer and Holtzman, 1979; Stein, 1962; Zarevics and Setler, 1979) and heroin (Bozarth et al., 1980). In contrast to the differences seen with low-dose caffeine, threshold-elevations are produced by the higher caffeine doses in both the threshold-tracking and autotitration methods. Both techniques reveal a significant threshold elevation with 40 and 30 mg/kg caffeine (freebase equivalent), respectively. The threshold-tracking method yielded maximum threshold elevations around 45% following the 40 mg/kg caffeine dose, while the autotitration method showed elevations around 10 to 20% with a 30 mg/kg dose and around 35 to 40% with a 56 mg/ kg dose. The 80 mg/kg caffeine dose, tested in the present study, disrupted responding for 60% of the rats during the first 15 min but produced a peak threshold elevation of over 200% and a sustained threshold elevation of 70 to 75%.8 Thus, thresholdtracking appears more sensitive to both the facilitatory and the inhibitory effects of caffeine.

Caffeine appears to have two distinct effects of brain reward mechanisms—low caffeine doses enhance while higher doses inhibit reward processes. Corroborative evidence of caffeine’s dual action on reward processes comes from studies assessing potential rewarding effects using the conditioned place preference method. Low-dose caffeine has been reported to produce a conditioned place preference, while a conditioned place aversion is produced from higher doses (Brockwell et al., 1991). Some investigators have had difficulty demonstrating a conditioned place preference from caffeine (Steigerwald et al., 1989), but this is probably related to the modest effect of low-dose caffeine on brain reward mechanisms and to the different experimental procedures used in the conditioning studies. In contrast, conditioned place and taste aversions from higher caffeine doses are robust (Brockwell et al., 1991; Steigerwald et al., 1989). This parallels the findings with BSR, indicating that caffeine’s reward-enhancing effect is more difficult to demonstrate than its reward-inhibiting action. The biological mechanism mediating the reward-enhancing effect of caffeine is not known, but there is some evidence that suggests caffeine’s antagonism at adenosine A1 receptors increases dopamine release (Okada et al., 1996). Higher caffeine doses may also inhibit adenosine A2 receptors, and this action may produce decreases in dopamine release (see Okada et al., 1996) and may mediate BSR threshold elevations (Mumford and Holtzman, 1990; cf. Mumford and Holtzman, 1991).

The BSR facilitation effect is consistent with reports of the subjective effects of caffeine in humans and with studies of intravenous caffeine self-administration in laboratory animals. Caffeine-containing beverages are widely self-administered by humans and some clinical studies have reported mild moodenhancing effects from caffeine (e.g., Griffiths et al., 1986; Rush et al., 1995). In contrast, other studies have failed to detect significant elevations in mood or reliable caffeine selfadministration in laboratory settings (e.g., Lieberman et al., 1987; Stern et al., 1989). Similarly, caffeine self-administration in laboratory animals is equivocal. A few studies have reported sporadic intravenous caffeine self-administration in laboratory animals (e.g., Atkinson and Enslen, 1976; Deneau et al., 1969; Dworkin et al., 1993; Griffiths et al., 1979), but investigators have been unable to obtain reliable caffeine self-administration (for reviews, see Griffiths and Mumford, 1995, 1996; Heishman and Henningfield, 1992). This situation closely parallels that seen with intravenous nicotine self-administration. Early studies were generally unsuccessful in establishing nicotine selfadministration, while several later studies using special testing parameters have reported reliable self-administration (see Goldberg and Henningfield, 1988; Henningfield and Goldberg, 1983). It is likely that special testing parameters will be identified that produce reliable caffeine self-administration. But the fact that the self-administration may be only obtainable under a narrow set of conditions, like intravenous nicotine self-administration, strongly suggests that caffeine has, at best, a mildly rewarding action and consequently a low addiction liability.9 Even though caffeine use can show the characteristics of addiction in some individuals (e.g., Strain et al., 1994), this probably occurs infrequently despite the widespread use of caffeine (Hughes et al., 1993; see also Mumford and Griffiths, 1995). Thus, the animal and clinical studies are concordant in suggesting that caffeine has a relatively low addiction liability.


Bemina Anatanico, Ronda KuLee, Rafia Mirza, and Matt Morris are thanked for assistance in behavioral testing. All animals were treated following the guidelines of NIH publication no. 94-3207, and the research protocol was reviewed by University at Buffalo’s Institution Animal Use Review Committee. This research report is from the Nicotine Evaluation Program supported by a grant from the Philip Morris Research Center (Richmond, VA). The views expressed herein are those of the authors and do not necessarily reflect the views of the sponsoring agency. The sponsor exerted no influence on the design, implementation, or reporting of the work presented in this series of experiments.


These data suggest an important consideration for interpreting the results of BSR studies-simple facilitation of brain stimulation is insufficient to suggest that a substance is addictive. Nonaddictive substances can also facilitate BSR, thus reflecting their potential reinforcing effects. BSR tests are still useful for assessing a compound’s addiction liability, but quantitative aspects of the facilitation effect must be considered when evaluating a compound’s effect on BSR.10 A. A range of maximum facilitation effects must be obtained with addictive and nonaddictive drugs (see Figure 10). Substances with a high addiction liability would be expected to produce facilitation quantitatively similar to that seen with prototypic addictive drugs. Mildly rewarding effects may be detectable with BSR which are insufficient to produce the potently rewarding effects characteristic of addictive drugs. This attests to the methods high sensitivity in detecting a compound’s effect on brain reward processes but cautions against an overly simplistic interpretation of these data and their relevance to addiction liability. [Figure 10]

Although the simple comparison of peak-facilitation might be sufficient to estimate each compound’s potential reinforcing action, a more detailed analysis using time-course data may provide a more accurate assessment. Figure 11 shows the timecourse of the optimal dose (i.e., dose producing maximum BSR facilitation) tested for each substance. This analysis takes into consideration not only the magnitude of facilitation but also the time-course of the facilitatory effect. Pharmacokinetic parameters related to onset of drug action are important for producing potent reinforcing effects (e.g., short delay of reinforcement following drug administration) and should be considered when evaluating a substance’s potential addiction liability. For example, cocaine (i.e., the high addiction liability reference compound) produces facilitation with (i) a very rapid onset, (ii) a relatively short duration of action, and (iii) a large magnitude of effect. These characteristics make it a potent reinforcing compound and are probably the reason it is so readily self-administered. In comparison, pseudoephedrine (i.e., the low addiction liability reference compound) produces a delayed facilitation with a long duration of action and a modest level of BSR facilitation. The simple quantitative comparison of peak facilitation groups these substances into two categories—cocaine and other compoundsbut consideration of the pharmacokinetic profiles permits a more specific rank ordering. The relative reinforcing efficacy predicted from this analysis is cocaine >> caffeine > nicotine > pseudoephedrine. This conclusion is based on the following considerations. Cocaine has a rapid onset and large facilitatory action. Caffeine has a rapid onset (equal to cocaine) but a much lower magnitude of effect. Nicotine has a maximum facilitatory effect similar to caffeine but the onset of action is somewhat delayed. And pseudoephedrine has a maximum facilitation comparable to caffeine and to nicotine but with a much delayed onset of action. The rapid onset of action is probably related to reinforcing efficacy by (i) enhancing learning (i.e., minimizing the delay of reinforcement effect) and (ii) by producing stronger subject effects.11 [Figure 11]

The maximum facilitation produced by nicotine in the present study is similar to that reported by other investigators using lateral hypothalamic stimulation (e.g., Bauco and Wise, 1994). The strength of facilitation seen with cocaine is also similar to that reported previously, but other investigators have ignored the quantitative differences between facilitation produced by nicotine and prototypic addictive drugs. The effects of cocaine and of nicotine on BSR correspond well with their respective effects of mesolimbic dopamine release. Cocaine produces a dramatic increase in nucleus accumbens dopamine overflow (e.g., 300 to 1000%; e.g., Brown and Fibiger, 1992; Maisonneuve et al., 1994; Parsons et al., 1995; Wise et al., 1995), while nicotine produces only a modest increase in dopamine overflow (e.g., 50 to 100%; e.g., Brazell et al., 1990; Damsma et al., 1989; Imperato et al., 1986; Nisell et al., 1994), sometimes even requiring repeated administration to significantly increase extracellular dopamine levels (e.g., Benwell et al., 1994, 1995). The 3 to 20- fold12 greater efficacy of cocaine in stimulating dopamine release probably underlies cocaine’s more potent rewarding action. This potent rewarding action, in turn, produces robust cocaine self-administration in laboratory animals and is an important component in cocaine’s inherently high addiction liability in humans.

Nicotine appears to have a “self-limiting” action on brain reward mechanisms. This is apparent from examination of the dose-response curve and from consideration of the behavioral effects of this compound. Several nicotine doses produce maximum facilitation of BSR. Increasing the nicotine dose 4-times the lowest dose producing maximum facilitation fails to increase nicotine’s maximum effect (see Figure 10), although it does increase the duration of the peak effect slightly. Furthermore, the fact that these nicotine doses were not behaviorally disruptive at the time of peak facilitation indicates that neither behaviorally disruptive nor toxic effects limit the maximum facilitatory action produced by nicotine. Thus, some neurophysiological processes appears to limit nicotine’s action on brain reward mechanisms.

One viable explanation of nicotine’s ceiling on threshold lowering is based on a two-stage trans-synaptic activation model. This model proposes that a descending fiber system is directly activated by electrical stimulation and trans-synaptically activates the ascending mesolimbic dopamine system (see Bozarth, 1987b; Wise and Bozarth, 1984; see also Yeomans et al., 1993). A subpopulation of the descending component (i.e., firststage neurons; see Shizgal, 1989) may be cholinergic (or synapse on cholinergic interneurons; see Yeomans et al., 1993), and nicotine’s ability to stimulate the mesolimbic dopamine system may be limited to activation of this cholinergic input which is only a portion of the total afferent neural population activated by lateral hypothalamic stimulation. Evidence that a cholinergic mechanism modulates mesolimbic dopamine activity at the level of the ventral tegmental area comes from several findings. First, nicotinic receptors are located on dopamine neurons in the ventral tegmentum (Clarke and Pert, 1985). Second, nicotine increases cell firing in the ventral tegmental dopamine cells (Calabresi et al., 1989; Gernhoff et al., 1986; Mereu et al., 1987; Nisell et al., 1996), and this activation produces an increased release of dopamine in the nucleus accumbens terminal field (e.g., Brazell et al., 1990; Damsma et al., 1989; Imperato et al., 1986; Nisell et al., 1994). Furthermore, the activation of this system by systemic nicotine is blocked by ventral tegmental nicotinic antagonist infusions (Nisell et al., 1994). And third, cholinergic antagonists microinjected directly into the ventral tegmentum elevate BSR thresholds (Kofman and Yeomans, 1989). Evidence that a subpopulation of the first-stage neurons is cholinergic comes from a study showing that only a fraction of the rewarding effects of lateral hypothalamic BSR is attenuated by systemic cholinergic antagonist treatment (Gratton and Wise, 1985). Alternatively, receptor desensitization or depolarization block may produce a “self-limiting” effect of nicotine on BSR.

Nicotine administration parameters appear to have little effect on nicotine’s facilitation of BSR and, presumably, on its ability to activate brain reward mechanisms. For example, there appears to be no empirical evidence to support the popular notion that freebase nicotine is less effective (i.e., rewarding) than the bitartrate salt form of nicotine. Experiment III specifically compared the effectiveness of various nicotine formulations, solution pH’s, and routes of administration on the BSR facilitation produced by nicotine. Nicotine bitartrate and nicotine freebase produced similar BSR facilitation. Similarly, pH-adjustment had no effect on the facilitation effect. There was some indication that initial nicotine freebase solutions may cause more behavioral disruption than initial nicotine bitartrate injections. Nonetheless, the various nicotine administration parameters produced equivalent peak-facilitation of BSR. Also, Experiment IV showed that the prior administration of a low or moderate dose of nicotine had no significant effect on the facilitation produced by a moderate nicotine dose. Similarly, daily fixed-dose nicotine injections have been shown to produce the same level of BSR facilitation across daily tests with no apparent tolerance or enhanced facilitation from chronic nicotine administration (Bauco and Wise, 1994; Bozarth et al., 1998a). These data strongly suggest that the maximum BSR facilitation obtainable with nicotine was accurately determined by the nicotine doseresponse analysis and that changes in testing conditions are unlikely to reveal a much stronger effect.

Nicotine from smoked tobacco is often argued to have a faster onset of psychoactive affects that nicotine delivered by other routes of administration. However, the results from the BSR studies argue strongly against major differences in the onset of nicotine’s CNS effects from various routes of administration. Specifically, the highly lipophilic nature of nicotine permits its rapid penetration into CNS regardless of administration route. Subjects receiving nicotine show an initial disruption of responding for BSR that occurs within seconds of the injection. However, nicotine’s BSR facilitatory action is delayed by 15 min or more. The significance of rapid delivery has been argued to explain why it is difficult to demonstrate strong rewarding effects of nicotine in laboratory animals (i.e., they don’t smoke) and why special testing parameters are necessary to demonstrate intravenous nicotine self-administration (e.g., very rapid infusions). The BSR data suggest that some process limits the onset of nicotine’s rewarding effect despite its rapid entry into the CNS. Slight changes in nicotine CNS delivery are unlikely to significantly affect this process. In contrast, the rewarding effect of cocaine has a very rapid onset, peaking within the first 15 min of testing. Hence, relatively small differences in CNS delivery might be expected to increase the subjective impact of this compound.

This series of studies illustrates important guidelines that should be considered when using BSR studies to assess the potential addiction liability of a compound. First, full doseresponse and time-course analyses are critically important for quantitative comparisons of each compound’s effect on BSR, 13 and this can only be achieved by administering drug doses which approach behaviorally disruptive (even toxic) levels. Also, most investigators make tenuous assumptions regarding a compound’s time course, and this can lead to underestimating the maximum effect produced on BSR. The present study examined a wide range of doses and measured BSR thresholds a full 3 hours after drug administration. The threshold-tracking procedure is particularly effective for determining time course, because thresholds are stable over long session durations and because thresholds remain stable when animals are tested for only 30 min per day during intervening test sessions. Second, another critically important feature of this work is using a method for quantifying the effects of a compound on BSR that is a sensitive measure-one that has a low minimum detection level and is not restricted by ceiling effects. Using the threshold-tracking method, the present study was able to demonstrate a moderate BSR facilitation from low-dose caffeine and a pronounced threshold elevation from higher caffeine doses. Third, quantitative comparisons must be made. This avoids the hasty conclusion that all substances which facilitate BSR (but may have only mild rewarding effects) have a high addiction liability. Specifically, the range of facilitation effects must be established using compounds with high and low addiction liabilities. And the effect of the test compound must be interpreted within the framework that distinguishes high from low addiction liability compounds (see Figure 12).14

If a behavioral objective were to obtain a mild mood-elevating effect, the optimal substance, from the list of compounds tested in this series, would probably be nicotine. Nicotine produces its mild subjective effect with only a moderate delay and has a wide range of doses that can be self-administered without apparent toxic effects. In comparison, caffeine’s reward-enhancing effect has a very short duration of action and a relatively narrow window where its rewarding effects emerge before the development of aversive effects. Once aversive effects develop from caffeine, they have a very long duration of action. Pseudoephedrine has a markedly delayed onset and produces behaviorally disruptive effects with only slightly increasing doses. Its long duration of action might be desirable, but miscalculating the dose makes the behaviorally disruptive (and presumably aversive) effects last for a similarly long period of time. Thus, nicotine is clearly the substance of choice for obtaining a mildly rewarding action (viz., socially acceptable). This probably contributes significantly to the popularity of tobacco use.

One important aspect of nicotine’s potential impact on brain reward processes not investigated in the studies reported here is the effect of chronic nicotine administration. However, the possibility of a facilitation-enhancing effect from chronic nicotine administration was previously examined using the optimal nicotine administration parameters identified in this series of experiments. There was no evidence of tolerance or enhanced responsiveness to chronic nicotine administration across 30- days of repeated administration (Bozarth & Pudiak, 1998a) or to repeated, escalating-dose nicotine administration designed to mimic the commonly observed behavior of increased levels of tobacco use (Bozarth & Pudiak, 1998b). Nicotine’s effect on BSR is simply dose-dependent and is generally independent of other parameters such as acute vs. chronic, freebase- vs. salt-forms, and route of administartion.

In conclusion, this series of experiments implications for the “nicotine addiction” hypothesis and for the current trend to blur the distinction among reinforcement, addiction, and the casual use of mildly psychoactive substances. This BSR study complements work with the intravenous self-administration method suggesting that nicotine is at best a very weak reinforcer. (e.g., Bozarth & Pudiak, 1996a, 1996b; Pudiak & Bozarth, 1996). The present study suggests that the rewarding impact of nicotine is quantitatively similar to that obtained from compounds with a low addiction liability such as Caffeine and pseudoephedrine. Caffeine has been the subject of intense study and this substance appears to be only a marginally effective reinforcer despite its widespread use throughout the world. The results of the BSR tests are consistent with this interpretation. On the other hand, nicotine’s facilitation of BSR has been presented as evidence that nicotine is highly addictive. Unfortunately, few compounds have been examined that have mild psychoactive effects and no systematic comparisons have been previously reported between these compounds and prototypic addictive drugs.



1. Atkinson J. and Enslen M. Self-administration of caffeine by the rat. Arzneimittelforschung.1976; 26: 2059-2061.
2. Ator NA, Griffiths RR. Intravenous self-administration of nicotine in the baboon. Fed Proc. 1980; 40: 298.
3. Bardo MT, Rowlett JK, Harris MJ. Conditioned place preference using opiate and stimulant drugs: A meta-analysis. Neurosci Biobehav Rev. 1995; 19: 39-51.
4. Bauco P, Wise RA. Potentiation of lateral hypothalamic and midline mesencephalic brain stimulation reinforcement by nicotine: Examination of repeated treatment. J Pharmacol Exp. Ther. 1994; 271:
5. Benwell ME, Balfour DJ, Birrell CE. Desensitization of the nicotineinduced mesolimbic dopamine response during constant infusion with nicotine. Brit J Pharmacol. 1195; 114: 454-460.
6. Benwell ME, Balfour DJ, Khadra LF. Studies on the influence of nicotine infusions on mesolimbic dopamine and locomotor responses to nicotine. Clin Pharmacol. 1994; 72: 233-239.
7. Bozarth MA. Intracranial Self-Stimulation as an Index of Opioid Addiction Liability: An Evaluation. Unpublished master’s thesis, Rensselaer Polytechnic Institute. 1978.
8. Bozarth MA. An overview of assessing drug reinforcement. In Methods of Assessing the Reinforcing Properties of Abused Drugs. SpringerVerlag. 1987: 635-658.
9. Bozarth MA. Ventral tegmental reward system. In Brain Reward Systems and Abuse. Raven Press .1987: 1-17.
10.Bozarth MA. Drug addiction as a psychobiological process. In D.M. Warburton (Ed.). Addiction Controversies. 1990; 112-134.
11.Bozarth MA, Gerber GJ, Wise RA. Intracranial self-stimulation as a technique to study the rewarding properties of drugs of abuse. Pharmacol Biochem Behav. 1980; 13: 245-247.
12.Bozarth MA, Pudiak CM. Assessing nicotine reinforcement with intravenous self-administration: Tests using a standard acquisition procedure in experimentally naive rats. Presented to the 2nd Annual Scientific Conference of the Society for Research on Nicotine and Tobacco. 1996.
13.Bozarth MA, Pudiak CM. Intravenous nicotine self-administration in laboratory animals: Chasing the enigma. Soc Neurosci Abstr. 1996; 22:163.
14.Bozarth MA, Pudiak CM, KuoLee R. Effect of chronic nicotine on brain stimulation reward: I. Effect of daily injections. Behav Br Res. 1998;96:185-188.
15.Bozarth MA, Pudiak CM, KuoLee R. Effect of chronic nicotine on brain stimulation reward: II. An escalating dose regimen. Behav Br Res. 1998; 96: 189-194.
16.Bozarth MA, Pudiak CM, Nocera J, Specht C. A threshold-tracking procedure for studying brain stimulation reward. Soc Neurosci Abstr. 1990; 16: 591.
17.Bozarth MA, Reid LD. Opioids and pressing for hypothalamic intracranial stimulation in rats. Soc Neurosci Abstr. 1978; 4: 486.
18.Brazell MP, Mitchell SN, Joseph MH, Gray JA. Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3, 4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: Comparison with caudate-putamen. Neuropharmacology. 1990; 29: 1177-1185.
19.Brockwell NT, Eikelboom R and Beninger R J. Caffeine-induced place and taste conditioning: Production of dose-dependent preference and aversion. Pharmacol Biochem. Behav. 1991; 38: 513-517.
20.Brown EE and Fibiger HC. Cocaine-induced conditioned locomotion. Absence of associated increases in dopamine release. Neuroscience. 1992; 48: 621-629.
21.Brown E E, Finlay JM, Wong JTF, Damsma G and Fibiger HC. Behavioral and neurochemical interactions between cocaine and buprenorphine: Implications for the pharmacotherapy of cocaine abuse. J. Pharmacol Exp Ther. 1991; 256: 119-126.
22.Calabresi P, Lacey M G and North RA. Nicotine excitation of rat ventral tegmental area neurones in vitro studies by intracellular recording. BrJ Pharmacol. 1989; 98: 135-140.
23.Chait LD. Factors influencing the reinforcing and subjective effects of ephedrine in humans. Psychopharmacology. 1994; 113: 381-387.
24.Clarke PBS & Fibiger HC. Apparent absence of nicotine-induced conditioned place preference in rats. Psychopharmacology. 1987; 92: 84-88.
25.Clarke PBS & Pert A. Autoradiographic evidence for nicotinic receptors on nigrostriatal and mesolimbic dopaminergic neurons. Brain Res. 1985; 348: 355-358.
26.Cone EJ. Pharmacokinetics and pharmacodynamics of cocaine. J. Anal Toxicol. 1995; 19: 459-478.
27.Corrigall WA & Coen KM. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology. 1989; 99: 473-478.
28.Crow TJ. Enhancement by cocaine of intracranial self-stimulation in the rat. Life Sci. 1970; 9: 375-381.
29.Damsma G, DayJ & Fibiger HC. Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens. Eur J Pharmacol. 1989; 168: 363-368.
30.Deneau G Yanagita T & Seevers M H. Self-administration of psychoactive substances by the monkey. Psychopharmacologia. 1969; 16: 30-48.
31.Donny EC, Caggiula, AR Knopf S & Brown C. Nicotine self-administration in rats. Psychopharmacology; 122: 390-394.
32.Dworkin SI, Vrana SL, Broadbent J , Robinson J H. Comparing the effects of nicotine, caffeine, methylphenidate and cocaine. Med Chem Res. 1993; 2: 593-602.
33.Esposito RU & Kornetsky C. Opioids and rewarding brain stimulation. Neurosci. Biobehav. Rev. 1978; 2: 115-122.
34.Esposito R U, Porrino, LJ and Seeger T F. Brain stimulation reward: Measurement and mapping by psychophysical techniques and quantitative 2-[14C]deoxyglucose autoradiography. In Methods of Assessing the Reinforcing Properties of Abused Drugs. 1987; 421-445.
35.Fouriezos G & Nawiesniak E. A comparison of two methods designed to rapidly estimate thresholds of rewarding brain stimulation. In Methods of Assessing the Reinforcing Properties of Abused Drugs. 1987; 447-462.
36.Fudala PJ and Iwamoto ET. Further studies on nicotine-induced conditioned place preference in the rat. Pharmacol Biochem Behav. 2011; 25: 1041-1049.
37.Fudala PJ, Teoh KW and Iwamoto ET. Pharmacologic characterization of nicotine-induced conditioned place preference. Pharmacol Biochem Behav. 1985; 22: 237-241.
38.Gilbert RM. Caffeine consumption. In The Methylxanthine Beverages and Foods: Chemistry, Consumption, and Health Effects. 1984; 30: 653.
39.Goldberg SR and Henningfield J E. Reinforcing effects of nicotine in humans and experimental animals responding under intermittent schedules of IV drug injections. Pharmacol Biochem Behav. 1988; 30: 227-234.
40.Goldberg S R and Spealman R D. Maintenance and suppression of responding by intravenous nicotine injections in squirrel monkeys. Fed Proc. 1982; 421: 216-230.
41.Gratton A and Wise RA. Hypothalamic reward mechanisms: Two firststage fiber populations with a cholinergic component. Science. 1985; 227: 545-548.
42.Grenhoff J, Aston-JonesG and Svensson TH. Nicotinic effects on the firing pattern of midbrain dopamine neurons. Acta Physiol Scand. 1986; 128: 351-358.
43.Griffiths RR, Bigelow GE and Liebson I A. Human coffee drinking: Reinforcing and physical dependence producing effects of caffeine. J Pharmacol Exp Ther. 1956; 239: 416-425.
44.Griffiths RR, Brady JV and Bradford L D. Predicting the abuse liability of drugs with animal drug self-administration procedures: Psychomotor stimulants and hallucinogens. Advances in Behavioral Pharmacology. 1979; 2: 163-208.
45.Griffiths RR and Mumford GK. Caffeine reinforcement, discrimination, tolerance and physical dependence in laboratory animals and humans. Pharmacological Aspects of Drug Dependence. 1996; 118: 315-341.
46.Heishman SJ and Henningfield J E. Stimulus functions of caffeine in humans: Relation to dependence potential. Neurosci Biobehav Rev. 1992; 16: 273-287.
47.Henningfield JE and Goldberg S R. Nicotine as a reinforcer in human subjects and laboratory animals. Pharmacol Biochem Behav. 1983; 19: 989-992.
48.Henningfield JE, Keenam RM and Clarke PBS. Nicotine In Pharmacological Aspects of Drug Dependence: Toward and Integrated Neurobehavioral Approach. 1996; 271-314.
49.Hughes J R, Oliveto A H, Helzer JE, Bickel, WK and Higgins ST. Implications of caffeine dependence in a population-based sample. InProblems of Drug Dependence. 1992; 194-199.
50.Huston-Lyons D and Kornetsky C. Effects of nicotine on the thresholdfor rewarding brain stimulation in rats. Pharmacol Biochem Behav. 1992; 43: 755-759.
51.Imperato A, Mulas A, Di Chiara G. Nicotine preferentially stimulatesdopamine release in the limbic system of freely moving rats. Eur J Pharmacol. 1986; 132: 337-338
52.Jaffe J. Drug addiction and drug abuse. In The Pharmacological Basis of Therapeutics. 1975; 245-283.
53.Jaffe J. Drug addiction and drug abuse. In The Pharmacological Basis of Therapeutics. 1990; 522-573.
54.Jorenby DE, Steinpreis RE, Sherman JEA, Baker TB. Aversion instead of preference learning indicated by nicotine place conditioning in rats. Psychopharmacology. 1990; 101: 533-538.
55.Kofman O, Yeomans JS. Cholinergic antagonists in ventral tegmentum elevate thresholds for lateral hypothalamic brainstem self-stimulation. Pharmacol Biochem Behav. 1989; 31: 547-559.
56.Kornetsky C, Esposito RU, McLean S, Jacobson JO. Intracranial selfstimulation thresholds: A model for the hedonic effect of drugs of abuse. Arch Gen Psychia. 1979; 36: 321-330.
57.Lieberman HR, Wurtman RJ, Emde GG, Roberts C, Coviella ILG. The effects of low doses of caffeine in human performance and mood. Psychopharmacology. 1987; 92: 308-312.
58.Maisonneuve IM, Archer S, Glick SD. U50, 488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats. Neurosci Lett. 1994; 181: 57-60.
59.Martin WR & Fraser HF. A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in post-addicts. J Pharmacol Exp Ther. 1961; 133: 388-399.
60.Martin WR, Sloan JW, Sapira JD & Jasinski DR. Physiologic, subjective and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther.1971; 12: 245-258.
61.Mereu G, Yoon KWP, Boi V, Gessa G L, Naes L. & Westfall TC. Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine. Eur J Pharmacol. 1987; 141: 395-399.
62.Mumford GK. & Holtzman, SG. Methylxanthines elevate reinforcementthreshold for electrical stimulation: Role of adenosine receptors and phosphodiesterase inhibition. Brain Res. 1990; 528: 32-38.
63.Mumford GK & Holtzman SG. Do adenosinergic substrates mediate methylxanthine effects upon reinforcement threshold for electrical brain stimulation in the rat? Brain Res. 1991; 550: 172-178.
64.Mumford GK, Neill DB & Holtzman SG. Caffeine elevates reinforcement thresholds for electrical brain stimulation: Tolerance and withdrawal changes. Brain Res. 1988; 459: 163-167.
65.Mundl W A. constant-current stimulator. Physiol Behav. 1980; 24: 991-993.
66.Newman LM.Effects of cholinergic agonists and antagonists on selfstimulation behavior in the rat. J Comp Physiol Psychol. 1972; 79: 394-413.
67.Nisell M, Nomikos GG, Hertel P, Panagis G & Svensson TH. Conditionindependent sensitization of locomotor stimulation and mesocortical dopamine release following chronic nicotine treatment in the rat. Synapse. 1996; 22: 369-381.
68.Nisell M, Nomikos GG & Svensson TH. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse. 1994; 16: 36-44.
69.Nomikos GG & Spyraki C. Cocaine-induced place conditioning: Importance of route of administration and other procedural variables. Psychopharmacology. 1988; 94: 11-125.
70.Okada M, Mizuno K. & Kaneko S. Adenosine A1 and A2 receptors modulate extracellular dopamine levels in rat striatum. Neurosci Lett. 1996; 212: 53-56.
71.Olds ME & Domino EF. Comparison of muscarinic and nicotinic cholinergic agonists on self-stimulation behavior. J Pharmacol Exp Ther. 1969; 166: 189-204.
72.Parsons L H, Koob GF & Weiss F. Serotonin dysfunction in the nucleus accumbens of rats during withdrawal after unlimited access tointravenous cocaine. J Pharmacol Exp Ther. 1995; 274: 1182-1191.
73.Pradhan SN & Bowling C. Effects of nicotine on self-stimulation in rats. J Pharmacol Exp Ther. 1971; 176: 229-243.
74.Reid LD. In Methods of Assessing the Reinforcing Properties of Abused Drugs. Springer. 1987; 391-420
75.Reid LD & Bozarth MA. Addictive agents and intracranial stimulation (ICS): The effects of various opioids on pressing for ICS. Problems of Drug Dependence. 1978; 18: 729-741.
76.Risner NE & Goldberg SR. A comparison of nicotine and progressiveratio schedules of intravenous drug infusion. J. Pharmacol Exper Ther. 1983; 224: 319-326.
77.Rush CR, Sullivan JT & Griffiths RR Intravenous caffeine in stimulant drug abusers: Subjective reports and physiological effects. J. Pharmacol. Exp Ther. 1995; 273: 351-358.
78.Schaefer GJ & Holtzman SG. Free-operant and auto-titration brain self-stimulation procedures in the rat: A comparison of drug effects. Pharmacol Biochem Behav. 1979; 10: 127-135.
79.Schaefer G J & Michael RP.Task-specific effects of nicotine in rats: Intracranial self-stimulation and locomotor activity. Neuropharmacology. 1986; 25: 125-131.
80.Shizgal, P. Toward a cellular analysis of intracranial self-stimulation: Contributions of collision studies. Neurosci Biobehav Rev. 1989; 13: 81-90.
81.Spyraki C, Fibiger H C & Phillips AG. Cocaine-induced place preference conditioning: Lack of effects of neuroleptics and 6-hydroxydopamine lesions. Brain Res. 1982; 253: 195-203.
82.Steigerwald ES, Rusiniak KW, Eckel DL & O’Regan MH. Aversive conditioning properties of caffeine in rats. Pharmacol Biochem Behav. 1989; 31: 579-584.
83.Stein L. Effects and interactions of imipramine, chlorpromazine, reserpine, and amphetamine on self-stimulation: Possible neurophysiological basis of depression. Recent Adv Biol Psychiatry.1961;4:288-309
84.Stern KN, Chait LD & Johanson CE. Reinforcing and subjective effects of caffeine in normal human volunteers. Psychopharmacology. 1989; 98: 81-88.
85.Strain EC, Mumford GK., Silverman K. & Griffiths RR. Caffeine dependence syndrome: Evidence from case histories and experimental evaluations. JAMA. 1994; 272: 1043-1048.
86.Valdes JJ, McGuire PS. and Annau Z. Xanthines alter behavior maintained by intracranial electrical stimulation and an operant schedule. Psychopharmacology. 1982; 76: 325-328.
87.Walker RB, Fitz LD & Williams LM. The effect of ephedrine isomers and their oxazolidines on locomotor activity in rats. Gen Pharmac.1993; 24: 669-673.
88.Wise RA. Addictive drugs and brain stimulation reward. Ann Rev Neurosci. 1996; 19: 319-340.
89.Wise RA & Bozarth MA. Brain reward circuitry: Four elements “wired” in apparent series. Br Res Bull. 1984; 12: 203-208.
90.Wise RA, Newton P, Leeb K, Burnette B, Pocock D, et al. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology. 1995; 120: 10-20.
91.Yeomans JS, Mathur A & Tampakeras M. Rewarding brain stimulation: Role of tegmental cholinergic neurons that activate dopamine neurons. Behav Neurosci. 1993; 107: 1077-1087.
92.Zarevics P & Setler PE. Simultaneous rate-independent and ratedependent assessment of intracranial self-stimulation: Evidence for the direct involvement of dopamine in brain reinforcement mechanisms. Brain Res. 1979; 169: 499-512.

Bozarth MA, Pudiak CM (2021) Predicting Addiction Liability from Brain Stimulation Reward Data: A Comparison of the Acute Effects of Cocaine, Pseudoephedrine, Nicotine, and Caffeine. J Subst Abuse Alcohol 8(2): 1092

Received : 26 Jun 2021
Accepted : 28 Jul 2021
Published : 30 Jul 2021
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X