Cocaine Choice Research Articles

Amphetamine-Induced Dopamine Release: Markedly Blunted in Cocaine Dependence and Predictive of the Choice to Self-Administer Cocaine

Objective: Dopamine is an important mediator of the reinforcing effects of cocaine, and alterations in dopamine function might be involved in cocaine dependence. The goals of the present study were to characterize pre- and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Specifically, dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). Furthermore, the relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated. Method: Twenty-four cocaine-dependent participants and 24 matched healthy subjects underwent [ 11 C]raclopride scans under a baseline condition and following intravenous amphetamine administration (0.3 mg/kg). Cocaine-dependent participants also completed cocaine self-administration sessions in which a priming dose of cocaine was followed by the choice to either self-administer subsequent cocaine doses or receive a monetary reward. Results: Cocaine dependence was associated with a marked reduction in amphetamine-induced dopamine release in each of the functional subregions of the striatum (limbic striatum: –1.2% in cocaine-dependent participants versus –12.4% in healthy subjects; associative striatum: –2.6% versus –6.7%, respectively; sensorimotor striatum: –4.3% versus –14.1%). Blunted dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for cocaine over money. Conclusions: Cocaine dependence is associated with impairment of dopamine function, and this impairment appears to play a critical role in relapse.

Lasting influence of social hierarchy on impulsivity and cocaine choice in cynomolgus monkeys

Position in the social dominance hierarchy influences brain function and sensitivity to cocaine. This study examined the effects of social reorganization and assessed whether impulsivity predicted new social rank and cocaine choice. Twenty-four male cynomolgus monkeys were used, 12 of which had previously been group-housed for more than 3 years. Monkeys were reorganized into 6 groups consisting of 4 previously dominant, 4 previously subordinate or 4 previously intermediate-ranked monkeys, plus 3 groups of previously singly housed monkeys. Monkeys were individually housed for several months before reorganization, during which time impulsivity was assessed by placing an opaque box into each monkey’s home cage. Latency to touch the box was recorded: the shorter the latency, the more “impulsive” the monkey. Latencies did not predict new social rank, but were influenced by previous social rank, such that the 5 least impulsive monkeys were previously dominant. Once hierarchies stabilized, monkeys self-administered cocaine under a concurrent schedule of food and cocaine (0.003–0.56 mg/kg/injection) availability. Like impulsivity, cocaine choice was influenced by previous rather than current social rank. These results indicate that exposure to social variables has long-lasting effects on behavior and sensitivity to cocaine in monkeys. Support: DA 10584.

Effects of delay to reinforcement on the choice between cocaine and food in rhesus monkeys

Although a delay between behavior and reinforcer has been shown to weaken behavior, little is known about the effects of delay on drug choice. The present study examined effects of delay between lever press and reinforcer presentation on the choice between a drug and non-drug reinforcer and between different drug doses. Monkeys (n=4) were allowed to choose 32 times/day between cocaine and four food pellets. The delay between lever press and a preferred dose of cocaine (0.05 mg/kg/injection) was increased systematically from 0 to 240 s, while the delay to food remained at 0 s. A second group of monkeys (n=4) was allowed to choose between 0.05 mg/kg/injection and a lower dose of cocaine (0.025 mg/kg/injection). Next, a delay that resulted in less than 20% choice of 0.05 mg/kg/injection cocaine was selected and delay to the alternative was varied. Results were similar across groups. The choice of 0.05 mg/kg/injection approximated 100% at 0 delay and decreased to near 0 as delay increased. As the delay to alternative was subsequently increased from 0 to 240 s, choice of 0.05 mg/kg/injection increased, though full cocaine choice was not generally restored. The delay estimated to maintain 50% choice (indifference point) was lower for the cocaine-food choice (mean=64 s) than for the cocaine-cocaine choice (mean=207 s). This experiment demonstrates that the choice between cocaine and a non-drug or drug alternative can be modified by increasing the interval between behavior and drug injection. Overall, the results are consistent with a temporal discounting model of drug choice.

Response to cocaine, alone and in combination with methylphenidate, in cocaine abusers with ADHD

Attention deficit hyperactivity disorder (ADHD) is prevalent in adult cocaine abusers. Yet, it remains to be determined how the response to cocaine differs in cocaine abusers with ADHD compared to cocaine abusers without ADHD. Further, since ADHD is commonly treated with stimulants, such as methylphenidate (MPH), it is important to examine whether MPH maintenance alters the response to cocaine in cocaine abusers with ADHD. Thus, the first phase of this study compared the response to cocaine in adult cocaine abusers with ADHD to those without ADHD. The second phase assessed the effects of oral sustained-release methylphenidate (MPH-SR) maintenance (40 and 60 mg) on the response to cocaine only in those with ADHD. Cocaine abusers with ADHD ( N = 7) and without ADHD ( N = 7) who were not seeking treatment remained inpatient initially for 1 week, when the effects of cocaine alone were tested (Phase 1). Cocaine abusers with ADHD remained inpatient for an additional 3 weeks, during which the effects of cocaine during oral MPH-SR maintenance were tested (Phase 2). During cocaine fixed dosing sessions, participants received four injections of i.v. cocaine (0, 16 or 48 mg/70 kg), spaced 14 min apart. During cocaine choice sessions, participants had a choice between receiving i.v. cocaine (16 or 48 mg/70 kg) or two tokens, each exchangeable for US$ 2. Subjective effects related to ADHD symptoms (e.g. ratings of “Able to Concentrate”) were significantly lower in cocaine abusers with ADHD compared to those without ADHD when placebo cocaine was administered. Active cocaine produced similar increases in cardiovascular and positive subjective effects in both groups and there was no difference in cocaine choice between the two groups. These data suggest that the response to cocaine is not different between cocaine abusers with ADHD compared to those without ADHD. When the cocaine abusers with ADHD were maintained on MPH-SR, cardiovascular effects were increased, however, this did not warrant termination of any test session. Maintenance on MPH-SR decreased some of the positive subjective effects of cocaine. Further, maintenance on a high dose of MPH-SR decreased cocaine choice. Thus, oral MPH-SR is safe in combination with repeated cocaine doses and decreases some of the positive and reinforcing effects of cocaine in cocaine abusers with ADHD.

Effects of the 5-HT1A agonist (??)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on cocaine choice in cynomolgus monkeys

Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, but the underlying receptor mechanisms are poorly understood. The present study examined the effects of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01-0.1 mg/kg, i.v.) on cocaine self-administration in the context of a choice procedure. Five adult male cynomolgus monkeys self-administered cocaine (saline, 0.003-0.03 mg/kg per injection) under a concurrent fixed-ratio 50 schedule of food (1-g banana-flavored pellets) and cocaine presentation. Allocation of responses to the cocaine-associated lever (cocaine choice) increased in a dose-related manner from < or =20% of total responses when saline or 0.003 mg/kg per injection cocaine was the alternative to food to > or =75% when 0.03 mg/kg per injection cocaine was available. In four of five monkeys, when choice was between a low cocaine dose and food, 0.01 mg/kg 8-OH-DPAT increased injection-lever responding. At cocaine doses which occasioned > or =75% cocaine choice, 8-OH-DPAT did not alter response allocation. In the fifth monkey, 8-OH-DPAT only decreased injection-lever responding. When choice was between saline and food, 8-OH-DPAT did not reliably shift responding to the injection lever, except at doses that disrupted operant performance. These results suggest that a 5-HT1A receptor agonist can increase the reinforcing strength of a low cocaine dose relative to a concurrently available non-drug reinforcer.

Effects of punishment on choice between cocaine and food in rhesus monkeys

Punishment is widely used in an effort to control drug-taking behavior; however, only a few preclinical studies have investigated the effects of punishment on drug self-administration. Such studies may contribute to more rational use of punishment to control drug use. To evaluate the effects of punishment on choice between cocaine and food in rhesus monkeys. Rhesus monkeys were trained under a concurrent-choice schedule of food delivery (1 g pellets, fixed-ratio 100 schedule) or cocaine injections (0-0.1 mg/kg per injection, fixed-ratio 10 schedule). Full cocaine choice dose-effect curves were determined under baseline conditions and under test conditions in which a putative punisher (intravenous histamine injection; 0.0032-0.032 mg/kg per injection) was paired with either food or cocaine delivery. Under baseline conditions, cocaine produced a dose-dependent increase in cocaine choice. Histamine functioned as a punisher of both food- and cocaine-maintained responding. Pairing histamine with food delivery reduced food choice, increased cocaine choice, and produced left shifts in the cocaine choice dose-effect curve. Conversely, pairing histamine with cocaine decreased cocaine choice, increased food choice, and produced right shifts in the cocaine choice dose-effect curve. The magnitude of histamine's punishing effects was directly related to histamine dose and probability of histamine delivery, and inversely related to the magnitude of the reinforcer. These results demonstrate that a primary effect of punishment in the context of food vs cocaine choice is not only a decrease in the behavior being punished, but also an increase in the unpunished alternative behavior.

Influence of handling or aversive stimulation during rats' neonatal or adolescence periods on oral cocaine self-administration and cocaine withdrawal.

Adverse early life events may influence vulnerability for drug intake. The influence of handling or aversive stimulation during neonatal or adolescent periods on adult cocaine oral self-administration and withdrawal were investigated. Neonatal or adolescent rats were exposed to a modified unpredictable stress paradigm or handling for 10 days. When adults, oral cocaine was offered through the two-bottle choice paradigm for 30 days. Rats were submitted to the forced swimming test after cocaine withdrawal. Overall, there was a significant increase of cocaine choice throughout the days of cocaine consumption and an interaction between interventions and cocaine daily choice. Control rats started cocaine intake at a lower level and increased cocaine choice over time, while animals submitted to neonatal interventions started cocaine intake at higher levels of choice, with less increase in cocaine intake during the period of cocaine exposure. Rats receiving aversive stimulation during adolescence also started taking cocaine solution at higher levels. Significantly higher immobility duration and shorter latency to immobility during the forced swimming were detected in these same adolescents that received unpredictable stress, when compared to the control or handled rats, while there was no difference for rats stimulated neonatally. Therefore, early life events increase initial preference for cocaine and promote changes in its abuse pattern, according to the intensity of the event and the age of the individual at the time of the event. Moreover, adverse experiences during adolescence, but not in neonatal phases, increase the vulnerability to depressive-like behaviors during cocaine withdrawal of adult rats.

Assessment of the relative reinforcing strength of cocaine in socially housed monkeys using a choice procedure.

Position in the social hierarchy can influence brain dopamine function and cocaine reinforcement in nonhuman primates during early cocaine exposure. With prolonged exposure, however, initial differences in rates of cocaine self-administration between dominant and subordinate monkeys dissipate. The present studies used a choice procedure to assess the relative reinforcing strength of cocaine in group-housed male cynomolgus monkeys with extensive cocaine self-administration histories. Responding was maintained under a concurrent fixed-ratio 50 schedule of food and cocaine (0.003-0.1 mg/kg per injection) presentation. Responding on the cocaine-associated lever increased as a function of cocaine dose in all monkeys. Although response distribution was similar across social rank when saline or relatively low or high cocaine doses were the alternative to food, planned t tests indicated that cocaine choice was significantly greater in subordinate monkeys when choice was between an intermediate dose (0.01 mg/kg) and food. When a between-session progressive-ratio procedure was used to increase response requirements for the preferred reinforcer (either cocaine or food), choice of that reinforcer decreased in all monkeys. The average response requirement that produced a shift in response allocation from the cocaine-associated lever to the food-associated lever was higher in subordinates across cocaine doses, an effect that trended toward significance (p = 0.053). These data indicate that despite an extensive history of cocaine self-administration, most subordinate monkeys were more sensitive to the relative reinforcing strength of cocaine than dominant monkeys.

Dose and schedule determinants of cocaine choice under concurrent variable-interval schedules in rhesus monkeys.

Drug abuse can be characterized as a condition in which the choice to self-administer a drug is excessive, even exclusive of the choice of other reinforcers. Under concurrent interval schedules of reinforcement, subjects typically distribute behavior to match reinforcement allocation. However, research has shown that when behavior is maintained by different doses of cocaine under concurrent variable-interval (conc VI) schedules, exclusive choice of the higher dose is the rule. The present study was designed to examine the generality of this finding to other behavioral conditions. Rhesus monkeys ( n=5) lever pressed under a conc VI 60-s VI 60-s or a conc VI 600-s VI 600-s schedule of cocaine (i.v.) presentation. Doses differing by 4-fold (0.025 versus 0.1, 0.05 versus 0.2 mg/kg per injection) were available for lever pressing. Monkeys responded more on the lever associated with the higher dose when saline or a lower dose was the alternative. The distribution of responses was well predicted by relative drug intake, but with consistent undermatching. Exclusive high-dose responding was seen in about half of the individual session intervals under the shorter schedule, rarely under the longer schedule, and was not seen over the session. Under conc VI schedules, behavior was apportioned between two different doses in a manner that favored the higher dose but undermatched relative intake. Exclusive high-dose choice may occur when cocaine is frequently available but is not an invariable outcome of the choice between a low and a high dose of cocaine.

Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys

Selective kappa opioid receptor agonists usually decrease cocaine self-administration in procedures that use rate-based measures of reinforcement; however, the rate-altering effects of kappa agonists complicate interpretation of these findings. To evaluate the effects of the selective kappa agonist U50,488 and the selective kappa antagonist nor-binaltorphimine (nor-BNI) on concurrent choice between cocaine and food in rhesus monkeys. The concurrent-choice procedure provides a rate-independent measure of the relative reinforcing effects of cocaine in comparison with food. Four rhesus monkeys were trained to respond under a concurrent-choice schedule for food (1-g pellets) or cocaine (0-0.1 mg/kg per injection). Saline and increasing doses of U50,488 (0.0032-0.1 mg/kg per h) were administered by pseudo-continuous i.v. infusion (one infusion every 20 min) during sequential 3-day blocks. In a separate experiment, monkeys were treated with nor-BNI (3.2 mg/kg, i.v.), and cocaine choice was re-determined during pseudo-continuous infusion with saline or U50,488 (0.1 mg/kg per h). During saline treatment, cocaine maintained a dose-dependent and monotonic increase in cocaine choice. Monkeys responded primarily for food when low cocaine doses were available (0-0.01 mg/kg per injection) and primarily for cocaine when higher cocaine doses were available (0.032-0.1 mg/kg per injection). U50,488 produced a dose-dependent increase in cocaine choice, manifested as leftward shifts in the cocaine-choice, dose-effect curve. U50,488 also dose-dependently decreased overall response rates. Nor-BNI did not alter cocaine choice, but it attenuated the effects of U50,488. These results suggest that continuous treatment with U50,488 produces a kappa receptor-mediated increase in the relative reinforcing effects of cocaine in comparison with food.

Conversation with Charles R. Schuster.

Conversation with Charles R. Schuster.

Effects of chronic methadone treatment on cocaine- and food-maintained responding under second-order, progressive-ratio and concurrent-choice schedules in rhesus monkeys

The effects of chronic infusion with saline or methadone (0.032–1.0 mg/kg/h) were examined on cocaine- and food-maintained responding in rhesus monkeys using three procedures. In one procedure, cocaine injections (0.0032–0.032 mg/kg per injection) and food pellets were available under a second-order schedule during alternating daily sessions. During saline treatment, cocaine maintained a dose-dependent increase in the number of cocaine injections per day, and monkeys usually responded for the maximum number of pellets. Methadone dose-dependently decreased cocaine self-administration, and methadone doses that decreased cocaine self-administration had variable effects on food-maintained responding. In the second procedure, 0.032 mg/kg per injection cocaine or food pellets were available under a progressive-ratio schedule. During saline treatment, cocaine and food maintained similar break points. Methadone produced a dose-dependent and non-selective decrease in break points maintained by both cocaine and food. In the third procedure, cocaine injections (0–0.1 mg/kg per injection) and food pellets were available under a concurrent-choice schedule. During saline treatment, increasing unit doses of cocaine produced a dose-dependent increase in cocaine choice. Methadone had little effect on the cocaine choice dose-effect curve up to doses that eliminated responding. These results provide little evidence to suggest that chronic methadone altered the reinforcing effects of cocaine; rather methadone appeared to non-selectively decrease rates of operant responding.

Gabapentin maintenance decreases smoked cocaine-related subjective effects, but not self-administration by humans

Data from research with laboratory animals indicate that cocaine self-administration can be reduced by λ-aminobutyric acid (GABA) agonists. Yet, the effectiveness of GABA agonists to decrease human cocaine self-administration has not been investigated under controlled laboratory conditions. The purpose of this study was to assess the effects of gabapentin, a GABA agonist, on cocaine-related behaviors, including self-administration, in human research participants under controlled laboratory conditions. During this 48-day double-blind, crossover design study, the effects of gabapentin (0, 600, and 1200 mg/d) maintenance on response to cocaine (0, 12, 25, and 50 mg) were investigated in seven cocaine abusers. Active cocaine significantly increased choice to self-administer cocaine, subjective-effect ratings (e.g., “Good Drug Effect”), blood pressure and heart rate (HR). Gabapentin did not reduce cocaine choice or cardiovascular measures, but it did decrease some subjective effects of cocaine (e.g., “Good Drug Effect” and “Anxious”). These data suggest that the cocaine–gabapentin combination was well-tolerated, and because some cocaine-related subjective effects were reduced by maintenance on relatively low gabapentin doses, future studies should test higher gabapentin doses.

Choosing to take cocaine in the human laboratory: effects of cocaine dose, inter-choice interval, and magnitude of alternative reinforcement

Cocaine abuse involves a variety of behaviors including the initiation of cocaine-seeking, the self-selected patterning of cocaine administrations, and the cessation of cocaine-taking. To date, most human laboratory models of cocaine self-administration have only assessed the amount of cocaine consumed under a fixed set of conditions. This double-blind, randomized, within-subject, inpatient study evaluated a novel model of human cocaine self-administration that aimed to quantify the reinforcing value of cocaine after cocaine-taking was initiated. Cocaine-dependent volunteers ( n=8) sampled cocaine (12.5, 25 or 50 mg per 70 kg i.v.) or placebo and were subsequently allowed to choose between another injection of the same dose or money over six trials during 12 experimental sessions. The value of the monetary alternative increased with each trial from $1 to 16. Each cocaine dose was assessed under three inter-choice intervals: 15 min, 30 min, and an interval selected by the volunteer. Injection choices increased dose dependently; however, there was little relationship between the value of the alternative reinforcer and the choice to take cocaine. Most volunteers exclusively chose injections when active cocaine was available and money when placebo was available. Inter-choice interval did not affect cocaine choices. These results illustrate the persistence of cocaine self-administration once cocaine-taking has been initiated.

Voluntary Self-Administration of Both Morphine and Cocaine by Rats

Voluntary self-administration of cocaine and/or morphine was studied in rats. Male rats were offered water bottles or bottles containing either cocaine or morphine, both cocaine and morphine (combination) or cocaine and morphine as a mixture. Alternating the three drug-containing bottles had no effect on drug choice. When offered alone, rats consumed about 12 ± 8 mg/kg/day of cocaine or 0.3 ± 0.3 mg/kg/day of morphine. When both drugs were offered in combination, they consumed a higher amount of cocaine (22 ± 7), but the same amount of morphine (0.4 ± 0.3). Availability of cocaine/morphine mixture kept morphine consumption constant (0.3 ± 0.1), but markedly decreased cocaine intake (0.3 ± 0.2). Addition of saccharin to the drug solutions only slightly increased consumption of both drugs, whereas saccharin added as a competitor or distracter to the drug solution reduced cocaine but not morphine self-administration. Animals showed wide interindividual variations but surprisingly small intraindividual variations in self-administration of cocaine or morphine under all conditions. No correlation between cocaine and morphine intake was apparent in the combination situation. Forcing animals first with cocaine had no effect on subsequent intake of cocaine or morphine presented in combination. However, forcing animals first with morphine subsequently increased morphine and reduced cocaine intake. In conclusion, morphine intake was the same if offered alone, in combination or as a mixture, whereas cocaine intake increased during a combination but decreased in the mixture situation. Cocaine pre-exposure had no effect on subsequent voluntary morphine or cocaine choice, whereas morphine pre-exposure increased subsequent voluntary morphine but decreased cocaine intake. These results suggest the possibility of two reward centers, one for each drug, the morphine center exerting a dominant influence over the cocaine center.

On hyperbolic discounting and uncertain hazard rates

The value of a future reward should be discounted where there is a risk that the reward will not be realized. If the risk manifests itself at a known, constant hazard rate, a riskneutral recipient ...

Relationship between drug preference and indicators of psychiatric impairment.

This study was conducted to investigate the relationship between the indicators of psychiatric disorders of individuals and their choice of either cocaine or heroin, drugs that differ markedly in their pharmacological effects. Cocaine acts as an intense stimulant, and heroin has profound sedative effects. This investigation examined the relationship between preference for heroin or cocaine and indicators of psychiatric impairment. Data from 282 subjects were grouped according to drug of choice and analyzed. Ninety-three percent of these subjects were African-American, 32% were female, and the average age was 34. Univariate and multivariate statistical analyses, such as discriminant analyses, were used to determine group differences. The results are evaluated and interpreted in relation to both the current empirical findings and to the hypotheses and theories postulated as a result of earlier clinical observations on drug of choice and psychopathology. Discriminant analysis yielded an overall correct classification rate of 75%. The discriminant function suggests that members in the cocaine drug of choice group as contrasted with members in the heroin preference group can be characterized as more socially inhibited and more self-defeating after adjusting for differences in age, duration of use of illicit substances, and marital status. Those who favored cocaine as contrasted with those who favored heroin were more likely to have never married, be younger, and have used illicit substances for a shorter period of time.

Effects of buprenorphine on the self-administration of cocaine by humans.

Seven male research volunteers reporting intravenous cocaine and morphine use participated in 12 cocaine self-administration sessions. A session consisted of sublingual buprenorphine pretreatment (0, 2, 4mg) 50min before seven self-administration trials. The first three trials were sampling trials, in which subjects were given each of the three reinforcers available for that session; the remaining four trials were choice trials in which subjects could choose between two doses of cocaine and tokens exchangeable for special privileges. Each buprenorphine dose was tested for four consecutive days under different cocaine dose/token combinations (e.g. 8mg vs 16mg vs two tokens). Following placebo, under all choice conditions, subjects reliably chose higher doses of cocaine over lower doses, and tokens about as often as high cocaine doses. Buprenorphine (4mg) significantly decreased high-dose cocaine choice and increased token choice, when the available cocaine doses were 16 and 32mg/70kg. Both buprenorphine doses significantly increased ratings of "sedated" and opiate symptoms and decreased ratings of "bad drug effect" following all cocaine doses. Both buprenorphine doses, in combination with cocaine doses greater than 8mg, significantly increased self-reported "high" and occasionally increased "stimulated" scores above values seen following cocaine alone. The results demonstrate that in the presence of non-drug alternative to cocaine (tokens), buprenorphine decreased high-dose cocaine choice. Despite the decrease, subjects were clearly intoxicated from a drug combination that mimicked a cocaine-heroin ("speedball") effect. Although buprenorphine may be useful in reducing cocaine use, the complex relationship between this reduction in use, behavioral alternatives, and the subjective effects of the drug combination remains unclear.

Influence of an alternative reinforcer on human cocaine self-administration

Identifying factors that modulate cocaine self-administration is fundamental to the development of effective strategies to treat and prevent cocaine abuse. In the presert study, the influence of an alternative reinforcer on the probability of cocaine use was examined in four adult humans under controlled laboratory conditions. During eleven test sessions, subjects chose between cocaine hydrochloride vs. placebo or between cocaine vs. varying amounts of money (0-$2.00/choice). Subjects made a maximum of 10 exclusive choices per session. Cocaine and placebo were administered intranasally in 10 mg unit doses under double-blind conditions. Subjects exclusively chose cocaine over placebo demonstrating that the drug functioned as a reinforcer. During sessions comparing cocaine vs. money, choice of cocaine decreased as the amount of money available in the monetary option increased, with all subjects exclusively choosing the monetary option in the $2.00 per choice condition. These results systematically replicate and extend to humans prior findings in laboratory animals demonstrating that the availability of alternative, nondrug reinforcers can significantly decrease cocaine use.

Discriminative effects of cocaethylene in rats trained to discriminate cocaine or ethanol

Two groups of rats were trained to discriminate between the stimulus properties of either intraperitoneally administered 10.0 mg/kg cocaine or 600 mg/kg ethanol and its vehicle in a two-lever operant chamber. Once trained, both groups exhibited a dose-related decrease in discriminative performance when tested with lower doses. A dose of 10 mg/kg cocaine, as well as doses of 10–30 mg/kg cocaethylene, in the ethanol-trained animals produced no greater than 38.9% responding on the ethanol-appropriate lever. Combinations of the approximate ethanol ED 50 dose with either 10 mg/kg cocaine or 20 mg/kg cocaethylene did not increase ethanol lever responding. In contrast, in the cocaine-trained animals, administration of cocaethylene produced dose-responsive cocaine-like discrimination with 30 mg/kg producing 88.9% responding on the cocaine-appropriate lever. In addition, 600 mg/kg ethanol co-administered with a (2.5 mg/kg) dose of cocaine that was poorly discriminated produced 85% of responses on the cocaine-appropriate lever. The peak effect of cocaine and cocaethylene were observed to occur in 15–30 min post-administration with cocaine choice behavior decreasing at a faster rate than seen for cocaethylene discrimination. Results are discussed in light of ethanol and cocaine producing a heightened, as well as prolonged, euphoria in humans.