Comparative behavioral profile of cocaine and norcocaine in rats and monkeys

The effects of cocaine and norcocaine were compared using locomotor activity, fixed-ratio 100 (FR 100) and fixed-interval 4 min (FI 4 min) food reinforcement and free feeding paradigms in rat and intravenous self-administration tests in rhesus monkeys. Cocaine was shown to significantly increase locomotor activity at doses of 20 and 40 mg/kg, while norcocaine had no effect at these doses and produced convulsions and death at 60 and 80 mg/kg. Both compounds significantly reduced food consumption at one or more of the doses tested. Cocaine and norcocaine at doses of 20 and 40 mg/kg, produced decreases in FR responding. Cocaine at doses of 10, 20, and 40 mg/kg, produced increases in FI responding; norcocaine had no effect following 10 mg/kg and decreased responding at 20 and 40 mg/kg. Cocaine (0.2 mg/kg/inj) and norcocaine (0.5, 0.2, 0.8 mg/kg/inj) maintained intravenous self-administration in all three monkeys tested. The data indicate that norcocaine is a pharmacologically active metabolite of cocaine which could account for some of the activity heretofore attributed to cocaine. However, the lack of any stimulatory effect of norcocaine or locomotor activity and the lack of increased responding produced by norcocaine on fixed-interval behavior suggest that norcocaine differs qualitatively from cocaine.     

Food deprivation and stimulant self-administration in rats: differences between cocaine and d-amphetamine

The effects of food deprivation (24 h) on response rates of rats self-administering d-amphetamine and cocaine were compared. Food deprivation clearly increased rates of responding for both drugs but did so to a significantly greater extent for cocaine than for d-amphetamine. Consistent with other findings, the results suggest that the neural substrates underlying cocaine and d-amphetamine reinforcement are not identical.     

Characteristics of beta-phenethylamine self-administration by dog.

Phenethylamine (PEA), a biologically active amine found in the brain, maintained intravenous self-administration behavior by dogs previously trained to respond for amphetamine. Systematic changes in the unit dose of PEA (1.5 to 6.0 mg/kg/infusion) were negatively related to the number of infusions (91.3 to 29.5, respectively) per 4hr session. The mean intake of PEA was 165 mg/kg/session. Pretreatment with chlorpromazine (0.5 to 2.0 mg/kg, IV, 30 min prior to the session) produced a dose-dependent increase in the number of self-administered PEA infusions. However, there were no changes in responding for PEA following pretreatment with either the dopaminergic antagonist pimozide (5 to 40 micrograms/kg, IV, 30 min prior to the session) or the adrenergic antagonist phenoxybenzamine (1 to 8 mg/kg, IV, 30 min prior to the session). These data suggest that the reinforcing properties of PEA are not dependent on either a dopaminergic or adrenergic system.     

Generalization of norcocaine to the discriminative stimulus properties of cocaine.

In rats trained to discriminate 10 mg/kg cocaine from 1 mg/kg saline, norcocaine, the N-demethylated metabolite, at doses of 2.5 mg/kg, 5 mg/kg and 10 mg/kg, produced a dose response curve similar to that of cocaine and generalized to cocaine at the two higher doses. As with cocaine, the discriminative stimulus produced by the norcocaine was partially attenuated by the dopaminergic antagonist pimozide and the amine depletor reserpine. Benzoylecgonine, benzoylnorecgonine and ecgonine methyl ester in doses of 10 mg/kg and 20 mg/kg did not generalize to cocaine.     

Cocaine,d-amphetamine,and pentobarbital effects on responding maintained by food or cocaine in rhesus monkeys

The effects of IM injections of cocaine, d-amphetamine, and pentobarbital were studied in rhesus monkeys whose lever-press responding was maintained under a second-order fixed-interval, fixed ratio schedule of reinforcement. Within each session, fixed-interval components, ending with the IV injection of 30 g/kg cocaine (one group of monkeys) or the delivery of a 300 mg food pellet (second group of monkeys), alternated with fixed-interval components ending without an injection of cocaine or the delivery of food (extinction). Drug pretreatments generally caused comparable dose-related decreases in the overall rates of responding reinforced either by cocaine or by food. Response rates during extinction usually increased and then decreased as the dose of each drug increased. An analysis of the drug effects on response rates in different temporal segments of the fixed intervals showed that in both the reinforcement and extinction components, the normally low control rates of responding which occurred earlier in the intervals were usually increased, while higher control rates which occurred later in the intervals were increased less or decreased. Thus, the effects of these drugs were relatively independent of the reinforcing event (food or cocaine) and tended to depend more on the ongoing rate of responding under these conditions.     

Antagonism of the behavioral effects of cocaine and d-amphetamine by prazosin

Key pecking by pigeons was maintained under a 30-response fixed-ratio schedule of food delivery; lever pressing by squirrel monkeys was maintained under a 3-min fixed-interval schedule of food delivery. Administered alone, d-amphetamine (0.1–3.0 mg/kg), cocaine (1.0–3.0 mg/kg) and bupropion (1.0–30 mg/kg) either did not affect or decreased fixed-ratio responding of pigeons, whereas d-amphetamine (0.056–0.3 mg/kg) either increased or decreased (0.56 mg/kg) responding of monkeys maintained under the fixed-interval schedule. Prazosin, a selective centrally-active alpha₁ antagonist, produced a dose-dependent reversal of the rate-decreasing effects of d-amphetamine and cocaine but not of bupropion on fixed-ratio responding in pigeons. Prazosin also reversed both the rate-increasing and rate-decreasing effects of d-amphetamine on fixed-interval responding of squirrel monkeys. In contrast, the non-selective alpha-antagonist phentolamine enhanced d-amphetamine-induced decreases in fixed-ratio responding. These findings suggest that the behavioral effects of d-amphetamine and cocaine are produced at least in part by activation of central alpha₁ receptors. Prazosin may be a useful tool for better understanding the mechanisms through which cocaine, amphetamine, and other abused stimulant drugs exert their potent behavioral effects.     

Intravenous cocaine self-administration in rats is reduced by dietaryl-tryptophan

Rats were trained to self-administer intravenously-delivered cocaine. Four lever-press responses resulted in a cocaine infusion (0.2 mg/kg) during daily 24-h sessions. The rats were also trained to obtain water from tongue-operated solenoid-driven drinking spouts. Ground food and water from a standard drinking bottle were also available. When cocaine injections reached stable levels,l-tryptophan was mixed with the rats' food for 5 days. Three concentrations ofl-tryptophan (2, 4, and 8%) were tested in different groups of five rats each. Three other groups of five rats each received the samel-tryptophan treatments; however, in these rats saline was substituted for cocaine and a sweet drinking solution consisting of glucose and saccharin (G + S) replaced water in the automatic drinking device. Two other groups consisting of five rats each self-administered a higher (0.4 mg/kg) or lower (0.1 mg/kg) unit dose of cocaine and food adulterated with 4% tryptophan. At the two higher concentrationsl-tryptophan reduced cocaine infusions by at least 50% during the 5 days of treatment, and cocaine infusions returned to baseline levels within 48 h after the regular diet was restored. Responding reinforced by the G + S solution was not altered by any of thel-tryptophan concentrations. Food intake was substantially lowered by the 8%l-tryptophan concentration; however, water intake, responding on an inactive lever, and the number of saline infusions were not affected by addition ofl-tryptophan to the food.l-Tryptophan had the same magnitude of effect on self-administration of the 0.1 and 0.2 mg/kg unit doses of cocaine, but behavior maintained by the highest cocaine dose (0.4 mg/kg) was resistant to the effect ofl-tryptophan. The results of this experiment indicate thatl-tryptophan reduces behavior reinforced by IV cocaine infusions.     

Discriminative stimulus properties of cocaine,norcocaine, and N-allylnorcocaine

A discriminative stimulus paradigm was employed to train eight male and female Wistar rats to discriminate 5.0 mg/kg cocaine HCl from 2.0 ml/kg saline. Subjects responded in a two bar operant chamber on an FR 30 schedule for food reinforcement. All sessions followed a 10 minute pretreatment with either saline, the training dose of cocaine, four probe doses of cocaine HCl (1.0, 2.5, 7.5, 10 mg/kg), four probe doses of norcocaine (1.0, 2.5, 5.0, 7.5 mg/kg) or four probe doses of N-allylnorcocaine (5.0, 7.5, 10, 20 mg/kg). All probe doses were tested using an extinction procedure. The three highest doses of cocaine generalized to cocaine while the 1.0 mg/kg dose of cocaine generalized to saline. The two highest doses of norcocaine generalized to cocaine while the 2.5 mg/kg dose of norcocaine resulted in 57% responding on the cocaine lever with the 1.0 mg/kg dose generalizing to saline. Only the highest dose of N-allylnorcocaine was found to generalize to cocaine with the intermediate doses resulting in an intermediate level of responding occurring on the cocaine lever. The 5.0 mg/kg dose of N-allylnorcocaine generalized to saline.     

Intravenous self-administration of cocaine under concurrent VI schedules of reinforcement

Under concurrent VI (conc VI) schedules of reinforcement, organisms match the proportion of responses to the proportion of reinforcers obtained from the available options. This result is the basis of the matching law, a major theoretical view of the control of choice between and among available reinforcers. The present experiment examined the extent to which IV cocaine self-administration by monkeys under conc VI schedules of reinforcement was predicted by the matching law. One group of rhesus monkeys (n=4) was prepared with chronic indwelling IV catheters and allowed to respond in a two-lever situation under conc VI schedules of reinforcement for cocaine injections. Three doses of cocaine (0.025, 0.05 and 0.1 mg/kg per injection) were made available under various conc VI schedules with an average inter-injection interval of 3 min. The same injection was available for each response, the difference between the options being the schedule of reinforcement. Each dose and schedule condition was in effect for at least ten consecutive sessions and until responding was stable. In a second group of monkeys (n=3), a comparable experiment was conducted with responding maintained by the delivery of 1-g food pellets. Overall response rate maintained by cocaine was inversely related to dose. In addition, response rate decreased over the course of a session, apparently due to accumulation of cocaine. With regard to choice, more responding was maintained by the schedule that arranged more frequent injections. Choice was well predicted by the matching law, with a consistent tendency toward undermatching but no consistent bias toward one or the other option. Results were similar for behavior maintained by food, though two of three monkeys showed an unexplained bias toward the left lever. With regard to drug self-administration, these results demonstrate that in a choice situation, with all other variables being equal, injections that are available more frequently in time maintain behavior more strongly than less frequently available injections. Undermatching implies that the relative proportion of behavior maintained by the two options is somewhat less than the relative proportion two injections obtained. The finding that choice maintained by cocaine under conc VI schedules was comparable to choice maintained by food extends the generality of the conclusion that drugs and non-drug reinforcers control behavior by similar mechanisms.     

Intravenous self-administration of cocaine under concurrent VI schedules of reinforcement

Under concurrent VI (conc VI) schedules of reinforcement, organisms match the proportion of responses to the proportion of reinforcers obtained from the available options. This result is the basis of the matching law, a major theoretical view of the control of choice between and among available reinforcers. The present experiment examined the extent to which IV cocaine self-administration by monkeys under conc VI schedules of reinforcement was predicted by the matching law. One group of rhesus monkeys (n=4) was prepared with chronic indwelling IV catheters and allowed to respond in a two-lever situation under conc VI schedules of reinforcement for cocaine injections. Three doses of cocaine (0.025, 0.05 and 0.1 mg/kg per injection) were made available under various conc VI schedules with an average inter-injection interval of 3 min. The same injection was available for each response, the difference between the options being the schedule of reinforcement. Each dose and schedule condition was in effect for at least ten consecutive sessions and until responding was stable. In a second group of monkeys (n=3), a comparable experiment was conducted with responding maintained by the delivery of 1-g food pellets. Overall response rate maintained by cocaine was inversely related to dose. In addition, response rate decreased over the course of a session, apparently due to accumulation of cocaine. With regard to choice, more responding was maintained by the schedule that arranged more frequent injections. Choice was well predicted by the matching law, with a consistent tendency toward undermatching but no consistent bias toward one or the other option. Results were similar for behavior maintained by food, though two of three monkeys showed an unexplained bias toward the left lever. With regard to drug self-administration, these results demonstrate that in a choice situation, with all other variables being equal, injections that are available more frequently in time maintain behavior more strongly than less frequently available injections. Undermatching implies that the relative proportion of behavior maintained by the two options is somewhat less than the relative proportion of injections obtained. The finding that choice maintained by cocaine under conc VI schedules was comparable to choice maintained by food extends the generality of the conclusion that drugs and non-drug reinforcers control behavior by similar mechanisms.     

Dopamine D1 and D2 mediation of the discriminative stimulus properties ofd-amphetamine and cocaine

Evidence suggests that stimulants such asd-amphetamine and cocaine act presynaptically by increasing the amount of dopamine (DA) available to stimulate postsynaptic DA receptors. Since two subpopulations of DA receptors (D₁ and D₂) exist, we investigated the role of both of these receptor subtypes in mediating the internal state produced by these stimulants. Two groups of rats (N=8/group) were trained to discriminate intraperitoneal (IP) injections of eitherd-amphetamine (1 mg/kg) or cocaine (10 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination task. After stable performance was established (i.e., more than 85% correct under each training condition), substitution and combination tests were conducted with selective D₁ and D₂ agonists and antagonists. The D₂ agonist quinpirole (0.0313–0.125 mg/kg) mimicked both stimulant cues while the D₁ agoinst SKF 38393 (5–20 mg/kg) substituted partially for cocaine but notd-amphetamine. Combination tests with DA antagonists indicated that both the D₁ antagonist SCH 23390 (0.0063–0.25 mg/kg) and the D₂ antagonist haloperidol (0.125–0.5 mg/kg) attenuated the effects of both stimulants; in addition, the substitution of cocaine (20 mg/kg) ford-amphetamine was blocked by both DA antagonists. The ability of both D₁ and D₂ antagonists to attenuate the stimulus effects ofd-amphetamine and cocaine raises the possibility that a synergistic (enabling) interaction between D₁ and D₂ receptors may modulate stimulant cues.     

Interaction of expectancy and the pharmacological effects ofd-amphetamine: subjective effects and self-administration

The study examined the effects of expectation on the subjective effects and oral self-administration of 15 mgd-amphetamine (AMP) and placebo in 40 volunteers who reported no prior use of stimulants other than caffeine. A balanced placebo design was used to create four groups: told Placebo/got Placebo (P/P), told Placebo/got Stimulant (P/S), told Stimulant/got Placebo (S/P), told Stimulant/got Stimulant (S/S). There were three sessions. On one session (INFO), participants received a capsule containing AMP or placebo and were given information about the contents of the capsule according to the balanced placebo design. On another session (NO INFO), participants received no information about the capsule's contents and were given placebo. On the final session, participants were allowed to choose either the INFO or NO INFO capsule. Participants came to the laboratory to ingest their capsules, and then returned to their normal environments where they completed subjective effects questionnaires every 2 h for 8 h. Expectancies influenced the subjective effects reported during the INFO session, regardless of whether subjects actually received AMP or placebo: subjects who expected a stimulant had higher ratings of feel drug and like drug. The pharmacological effects of AMP were also evident on the INFO sessions: AMP produced its prototypic subjective effects regardless of subjects' expectancies. Significant interactions between drug and expectancy were obtained on self-report measures of anxiety and arousal: anxiety was higher for groups who received substances that did not match their expectations (P/S and S/P) and arousal increased most in volunteers who expected placebo but received stimulant. Choice of drug was determined primarily by pharmacology: participants who received AMP on the INFO session usually chose that capsule, regardless of information about its identity (P/S: 8/10; S/S: 9/10). In contrast, participants who received placebo on the INFO session chose this capsule at chance levels, regardless of information about its identity (S/P: 3/10; P/P: 6/10). Thus, expectancy influenced some of the subjective effects of AMP and placebo, but the pharmacological effects of the AMP were instrumental in determining whether volunteers would self-administer the drug.     

Amphetamine self-administration by humans: modulation by contingencies associated with task performance

The effect of task performance feedback and associated monetary earnings on drug self-administration were evaluated using eight subjects in a residential laboratory setting. The hypothesis was that if subjects believed thatd-amphetamine impaired performance and reduced monetary earnings,d-amphetamine self-administration would decrease. Subjects performed computer tasks every day: on certain days that they received capsules, subjects were given bogus feedback regarding their performance (“better” or “worse” than average). On sample days, subjects were required to taked-amphetamine (10 mg BID) or placebo (0 mg BID) capsules. On choice days, subjects could choose between eitherd-amphetamine or placebo. Subjects received feedback on their task performance on 2 sample days and 2 of 4 choice days. Subjects received no feedback on the remaining two choice days. When subjects received no feedback, they chosed-amphetamine over placebo 78% of the time, and when they were given better feedback messages, they chosed-amphetamine 87.5% of the time. In contrast,d-amphetamine self-administration decreased significantly to 25% when subjects were told that it impaired their performance on work tasks and resulted in reduced earnings. In reality,d-amphetamine had little effect on work task performance. However, compared to placebo,d-amphetamine significantly increased subjective ratings of “Stimulated” and “Good Drug Effect” and significantly decreased ratings of “Tired” and “Sleepy”. These results demonstrate thatd-amphetamine served as a reinforcer under conditions in which drug self-administration did not influence monetary earnings, but thatd-amphetamine self-administration could be modified by feedback/monetary earnings. Thus, contingencies associated with performance have important implications for drug use in the workplace.     

Drug level of d- and l-amphetamine during intravenous self-administration

Rats were allowed to self-administer dextro and levo isomers of amphetamine in doses of 0.25, 0.50, 0.75 and 1.0 mg/kg/injection for 6 h/day. Total body level of drug was calculated at the time of responding for each drug injection. Body level of amphetamine initially increased and then decreased (0–2 h), and thereafter remained relatively constant for the remainder of the experimental session (2–6 h). During 2–6 h of self-administration, calculated whole body levels of both d- and l-amphetamine remained relatively constant across injection doses. In another study, blood was removed several times during 2–6 h at the time of responding for drug injection. Again, no difference in blood level of ¹⁴C-amphetamine was found across a range of injection doses. Mean blood levels were 0.48 g/ml for l-amphetamine and 0.18 g/ml for d-amphetamine. Drug intake averaged 2.0 mg/kg/h for l-amphetamine and 0.79 mg/kg/h for d-amphetamine.     

The effects of pimozide and phenoxybenzamine pretreatments on amphetamine and apomorphine potentiation of the acoustic startle response in rats

A series of three experiments investigated the individual roles of neurons containing dopamine (DA) and norepinephrine (NE) in modulating the amplitude of the acoustic startle response (ASR) in rats. Experiment I investigated the effects of 0.1, 0.5, and 2.5 mg/kg pimozide or 5, 10, and 20 mg/kg phenoxybenzamine alone on startle amplitude. Experiments II–III investigated the effects of pretreatment with either 2.5 mg/kg pimozide or 10 mg/kg phenoxybenzamine on the potentiation of startleamplitude by either d-amphetamine (8 mg/kg), l-amphetamine (32 mg/kg), or apomorphine (3 mg/kg). Treatment with pimozide (2.5 mg/kg given 85 min before testing) and phenoxybenzamine (10 mg/kg, given 25 min before testing) resulted in a significant reduction in startle amplitude, supporting the conclusion that neurons containing NE and DA both tonically facilitate the ASR. The startlepotentiating effect of d- and l-amphetamine and apomorphine were totally blocked by pretreatment with pimozide (2.5 mg/kg, injected 2 h before these drugs), which supports the hypothesis that these agents potentiate startle at least in part by acting through dopaminergic neural systems. Phenoxybenzamine pretreatment (10 mg/kg, given 0.5 h before) also blocked the startle-potentiating effects of l-amphetamine and apomorphine, which suggests that noradrenergic neural systems are also involved in the potentiation of ASR by these agents, possibly through the interaction of dopaminergic and noradrenergic neural systems. The potentiating effect of d-amphetamine on ASR magnitude was not attenuated by phenoxybenzamine.     

Smoked cocaine self-administration in females

Although approximately 32% of all smoked cocaine (crack) users are women, most studies investigating cocaine use have recruited only male subjects. Therefore, this study examined the smoked cocaine self-administration patterns of female crack abusers. A work requirement, where up to five tokens were earned by subjects, was followed by the administration of a sample delivery of one of three dose sizes [5.0 mg (placebo), 0.2 mg/kg, 0.4 mg/kg] of cocaine. The three dose sizes of cocaine were administered in counterbalanced order across subjects, with each subject receiving one dose size within a session and all dose sizes across the three experimental sessions. A self-administration phase followed the sample delivery, during which a token could be exchanged every 30 min for monetary reimbursement or a delivery of cocaine in the same dose size as the sample delivery. The results show that females' patterns of behavioral and subjective responding to smoked cocaine exhibit clear dose-related effects, thus affirming this self-administration model as safe and appropriate for use with women.     

Behavioral and neurochemical sensitization following cocaine self-administration

To determine if behavioral and neurochemical sensitization results from cocaine self-administration, rats were trained to self-administer cocaine for 20 consecutive days (26.5 ± 2.6 mg/kg, IV/day). At 24 h or 21 days after discontinuing cocaine self-administration or yoked saline control, rats were administered an acute injection of saline IP, followed 60 min later by cocaine (15 mg/kg, IP). Cocaine-induced changes in motor activity were monitored with a photocell apparatus and alterations in extracellular dopamine in the ventral striatum were measured with microdialysis. There was no difference between treatment groups in the basal level of extracellular dopamine as determined by in vitro calibration. Neither the motor stimulant response nor the increase in extracellular dopamine following an acute cocaine challenge given after 24 h of withdrawal was different between rats which self-administered cocaine and yoked saline controls. However, when the cocaine challenge was given 21 days after discontinuing cocaine self-administration both the motor response and extracellular dopamine content in the ventral striatum were significantly augmented in rats that self-administered cocaine. While no correlation was observed between the average amount of cocaine self-administered each day and the cocaine-induced alterations in extracellular dopamaine at either 24 h or 21 days of withdrawal, a significant positive correlation was measured between the increase in photocell counts and the average daily cocaine administration at 21 days of withdrawal. These data show that cocaine self-administration produces an augmentation in the acute behavioral and neurochemical response to a cocaine challenge that resembles the sensitization previously demonstrated with repeated noncontingent administration.     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

Nicotine reinforcement in rats with histories of cocaine self-administration

Few reports have described conditions under which nicotine self-administration occurs in rats. In this study, rats which initially lever pressed for cocaine infusion (0.05 mg/kg) during 1 h experimental sessions continued to obtain similar infusion numbers when nicotine (0.03 mg/kg) was available. When saline was substituted for nicotine, infusions decreased from 11.8±4.5/h to 5.4±1.1/h but returned to pre-saline levels when it was reintroduced (12.0±5.5/h). These results indicate that nicotine can serve as a positive reinforcer for rats under the historical and schedule conditions described.     

Time course of changes in cocaine self-administration behavior in rats during immunization with the cocaine vaccine IPC-1010

RATIONALE: Following a 6-week immunization period consisting of three biweekly injections of the cocaine vaccine IPC-1010, the reacquisition of cocaine self-administration behavior in rats was previously shown to be reduced in a manner that was dependant on serum antibody level. The present studies were conducted to examine additional issues relevant to the clinical use of the vaccine. OBJECTIVES: One experiment was conducted to address the issue of whether exposure to cocaine during the immunization period would influence the ability of the vaccine to block cocaine self-administration. A second experiment was conducted to determine if the reductions in drug-seeking behavior and drug intake by the vaccine were behaviorally specific, or if behavior maintained by a non-drug reinforcer would be similarly affected. METHODS: Identical second-order schedules of cocaine (1 mg/kg) or food pellet (45 mg) delivery were used in rats. In both studies, the time course of changes in behavior during the 6-week immunization period was examined in vaccine and alum-treated control rats following baseline and extinction conditions. RESULTS: The cocaine vaccine IPC-1010 induced average serum antibody levels of 0.07 mg/ml and significantly reduced self-administration behavior during the 2-week period following the third vaccine boost in a subgroup of rats with serum antibody levels greater than the average value. Cocaine self-administration behavior at this time point significantly correlated with serum antibody level. IPC-1010 did not alter responding maintained by food throughout the immunization period although serum antibody levels reached a similar average of 0.06 mg/ml in this group of rats. CONCLUSIONS: These findings suggest that the reductions in drug-seeking behavior and drug intake after immunization with IPC-1010 did not result from a reduced ability of the rats to respond on the lever. Furthermore, daily exposure to cocaine during the immunization period did not influence the ability of the vaccine to reduce cocaine self-administration behavior that emerged gradually over time. These findings also confirm the need for a sufficiently high antibody level to blunt the reinforcing effects of cocaine.