Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans

Rationale: Data in laboratory animals suggest that D₁ receptor agonists may have potential utility for the treatment of cocaine abuse. Objective: The effects of ABT-431, a selective agonist at the dopamine D₁ receptor, on the reinforcing, cardiovascular and subjective effects of cocaine were investigated in humans. Method: Nine experienced cocaine smokers (8M, 1F), participated in nine self-administration sessions while residing on an inpatient research unit: three doses of ABT-431 (0, 2, 4 mg IV) were each given in combination with three doses of smoked cocaine (0, 12, 50 mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus $5 merchandise vouchers) was utilized, with sessions consisting of: (a) one sample trial, where participants received the cocaine dose available that day, and (b) five choice trials, where participants chose between the available cocaine dose and one merchandise voucher. Results: ABT-431 did not affect the number of times participants chose to smoke each dose of cocaine, but produced significant dose-dependent decreases in the subjective effects of cocaine, including ratings of “High,”“Stimulated,” dose liking, estimates of dose value, “Quality,” and “Potency.” Furthermore, there was a trend for ABT-431 (4 mg) to decrease cocaine craving. ABT-431 also increased heart rate, while decreasing systolic and diastolic pressure at each dose of cocaine. Conclusions: These data suggest that D₁ agonists may have potential utility for the treatment of cocaine abuse. Received: 18 August 1998/Final version: 16 October 1998     

Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine

RATIONALE: Dopaminergic compounds have been targeted as potential treatments for cocaine abuse because of the known role of dopamine systems in drug reinforcement. Recent preclinical and human data have focused on the D1/5 antagonist, SCH 39166 (ecopipam), as a potential therapeutic agent. OBJECTIVES: The objective of the present study was to determine whether treatment with chronic ecopipam can blunt or block the subjective effects of cocaine in the absence of significant behavioral impairment or toxic physiological effects. METHODS: Four doses of ecopipam (0, 10, 25, and 100 mg p.o.) were administered daily for 1 week each in double-blind, random order to inpatient cocaine-dependent volunteers (n = 10). Cocaine challenge doses (0, 25, and 50 mg/70 kg i.v.) were administered on the 7th day in ascending order, 1 h apart. RESULTS: Ecopipam alone produced reliable dose-dependent deficits in performance on the digit symbol substitution task (DSST) and the circular lights task, but not a balance task. Impairment on the DSST waned with repeated dosing suggesting the development of tolerance. Ecopipam resulted in few direct subjective effects. Cocaine alone produced dose-dependent changes in prototypic subjective and physiological measures, however, ecopipam largely failed to alter either cocaine's direct effects or the desire for cocaine. CONCLUSIONS: Although the performance effects verify that these doses of ecopipam were behaviorally active, the absence of an attenuation of cocaine's effects of craving for cocaine in this chronic dosing paradigm suggests this compound is unlikely to be an effective pharmacotherapy for cocaine abuse.     

Cocaine-like subjective effects of nicotine are not blocked by the D1 selective antagonist ecopipam (SCH 39166)

The effects of ecopipam (a D(1) selective antagonist) or triazolam pretreatment on the subjective and physiological effects of intravenously administered nicotine were examined in 10 cigarette-smoking cocaine abusers. Under double-blind, randomized conditions, subjects received oral capsule pretreatment (0, 30 or 100 mg ecopipam, or 0.25 mg/70 kg triazolam), followed 120 min later by an intravenous injection of 2 mg/70 kg nicotine or saline. Subjective ratings, heart rate and blood pressure were assessed before and repeatedly after each intravenous injection. Compared to oral placebo pretreatment, both ecopipam and triazolam pretreatment produced significant elevations in subject-reported capsule effect and observer ratings of sleepiness/sedation. Nicotine increased ratings of 'drug effect', 'rush', 'high', 'stimulated', 'liking', 'good effects' and 'bad effects', and produced modest increases in heart rate and blood pressure. Following both intra-venous saline and nicotine injection, ecopipam tended to reduce heart rate and blood pressure. Although both ecopipam and triazolam lowered several subjective ratings following intravenous saline injection, neither ecopipam nor triazolam affected nicotine subjective effects. In contrast to Romach et al. (Arch Gen Psychiatry 56: 1101-1106, 1999), who showed that pretreatment with ecopipam blocked cocaine subjective effects, the current study found no attenuation of the subjective effects of nicotine, and thus, provides no support for the hypothesis that D(1) receptors mediate the cocaine-like subjective effects of nicotine.     

Nicotine alters some of cocaine's subjective effects in the absence of physiological or pharmacokinetic changes.

Tobacco smoking and cocaine use often co-occurs and the frequency of smoking has been positively correlated with the likelihood of cocaine use. In addition, nicotine pretreatment has been shown to increase the rate of cocaine self-administration in rats and to enhance cue-induced cocaine craving in humans. The present study was conducted to investigate whether nicotine pretreatment via a transdermal patch alters the behavioral, physiological, and pharmacokinetic effects of an acute dose of cocaine in nondependent human volunteers. Seven male tobacco smokers who used cocaine occasionally provided informed consent and participated in this placebo-controlled, four-visit study. Following pretreatment with a transdermal nicotine patch (placebo, 14 mg), subjects were challenged with an acute dose of intranasal cocaine (placebo, 0.9 mg/kg). Nicotine pretreatment attenuated cocaine-induced increases in reports of "high" and "stimulated" and increased the latency to detect cocaine effects and cocaine-induced euphoria. Nicotine did not alter cocaine's effects on heart rate, skin temperature, and blood pressure or plasma cocaine, benzoylecgonine (BE), or ecgonine methylester (EME) concentrations. Our findings indicate that nicotine pretreatment alters some of the positive subjective effects of cocaine in humans without affecting cocaine's effects on physiologic responses or pharmacokinetic profiles.     

Smoked cocaine discrimination in humans: effects of gabapentin

Gamma-aminobutyric acid (GABA) agonists, such as the GABA analogue, gabapentin, may provide new avenues for pharmacological treatment of cocaine dependence. The purpose of this study was to develop a smoked cocaine drug discrimination procedure in humans to test the effects of gabapentin maintenance on the discriminative stimulus, subjective, cognitive and cardiovascular effects of smoked cocaine. Eight male, nontreatment-seeking, cocaine-dependent volunteers, residing on an inpatient research unit for 47 days completed a within-subjects, counter-balanced design. Participants learned to discriminate between cocaine (25 mg) and placebo, and once the criterion for discrimination was met, smoked cocaine dose-effect functions (0, 6, 12, 25 and 50 mg) were determined under three gabapentin maintenance conditions (0, 600 and 1200 mg/day po). The highest dose of gabapentin tested (1200 mg/day) decreased the discriminative stimulus effects of cocaine (6 mg), decreased cocaine craving by 41-53% following cocaine administration (6 and 12 mg), and increased heart rate following either placebo or cocaine (12 mg) administration. Gabapentin did not significantly affect psychomotor task performance or the subjective effects of cocaine. Although the direction of gabapentin's effects was appropriate for a potential treatment medication, i.e., a decrease in cocaine-elicited craving and a decrease in cocaine's discriminative stimulus effects, these effects were limited to low doses of cocaine. The results suggest gabapentin may not produce effects sufficiently robust to be clinically useful, at least at this dose regimen.     

Dopamine D3 as well as D2 receptor ligands attenuate the cue-induced cocaine-seeking in a relapse model in rats

Environmental cues associated with the previously abused drug elicit craving and relapse to drug use in humans. Several reinstatement paradigms are used in animals to examine the relapse-preventing efficacy of possible medical treatments. The purpose of the present study was to investigate the effect of D3 dopamine receptor ligands in a relapse model where animals with stable cocaine self-administration behavior were exposed to all the environmental and reinforcement-contingent discrete cues associated for the previous cocaine-intake in a single extinction session after 3-week long abstinence period. The following compounds were studied: SB-277011-A as a selective D3 antagonist, BP-897 as a D3 partial agonist/D2 antagonist and haloperidol as a preferential D2 receptor antagonist. In addition, in the same paradigm we investigated the effect of the above ligands on relapse to natural reward-seeking behavior using sucrose as natural reward. SB-277011-A (5 and 20 mg/kg), BP-897 (1 mg/kg) and haloperidol (0.2 mg/kg) significantly inhibited the secondary cues-induced cocaine-seeking behavior. None of the above drugs significantly influenced the cue-controlled sucrose-seeking behavior. These results confirm the importance of the D3 as well as the D2 dopamine receptor in modulating the cue-induced cocaine relapse and the possible usefulness of the D3 dopamine receptor ligands as potential medication in cocaine addicts.     

Animal models of drug dependence using the drug self-administration method

This paper will review 1) experimental models of drug-seeking behavior and 2) mechanisms underlying the behavior, focusing on cocaine self-administration. After the acquisition of self-administration, vigorous lever-pressing is generally observable after the drug was replaced by saline. This lever-pressing behavior under saline infusion can be considered "drug-seeking behavior". Drug-seeking behavior is reinstated by non-contingent injection of the drug, stress exposure and presentation of drug-associated stimuli even after extinction. This is called a relapse/reinstatement model. Electrophysiological studies showed that the majority of accumbal neurons is tonically inhibited during cocaine self-administration and exhibited phasic increases in firing time-locked to cocaine self-infusion, which might represent the craving state or drive animals to drug-seeking behavior. Voltammetry and microdialysis studies indicated that the timing of drug-seeking responses can be predicted from fluctuations in accumbal extracellular dopamine concentration. Whereas dopamine D2-like agonists reinstated extinguished cocaine-seeking behavior, D1-like agonists prevented the relapse in cocaine-seeking behavior induced by cocaine itself. Given that an AMPA receptor antagonist, but not dopamine antagonist, prevented cocaine-seeking behavior induced by cocaine, glutamate transmission in the nucleus accumbens is thought to be important for expression of craving or drug-seeking behavior.     

Physiological, subjective and reinforcing effects of oral and intravenous cocaine in humans

RATIONALE: There is little comparative information on the qualitative similarity, relative potency and reinforcing effects of oral cocaine versus cocaine administered via other routes. METHODS: The present study used a within-subject, double-blind, double-dummy design to compare the physiological, subjective and reinforcing effects of placebo and oral (62.5, 125, 250 mg/70 kg) and intravenous (IV) (12.5, 25, 50 mg/70 kg) cocaine in volunteers with histories of cocaine abuse. RESULTS: Cocaine produced dose-dependent increases on heart rate and blood pressure, with effects lasting longer after oral than IV cocaine. Subjective ratings (e.g., "rush," "drug effect," "liking") were qualitatively similar and dose-dependently increased after oral and IV administration, and the duration of effects was similar under both routes. On a money versus drug choice measure of reinforcement, the monetary amounts at which participants chose drug over money increased as a function of cocaine dose under both routes of administration. At doses that produced comparable subjective, physiological, and reinforcing effects, oral cocaine was not identified as cocaine as frequently as IV cocaine. Across measures, the data suggested that IV cocaine was approximately 10 times more potent than oral cocaine. CONCLUSIONS: Overall, the results of this study support qualitatively similar effects of oral and IV cocaine and suggest that oral cocaine may be an effective tool for studying cocaine's effects in human laboratory studies.     

Controversies in translational research: drug self-administration

RATIONALE: Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable. OBJECTIVE: The objective of this study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans and to compare these results to clinical outcomes. RESULTS: Across species, heroin self-administration was decreased by all three medication approaches, paralleling their demonstrated clinical utility. The heroin data emphasize the importance of assessing a medication's abuse liability preclinically to predict medication abuse and compliance and of considering subject characteristics (e.g., opioid dependence) when interpreting medication effects. For cocaine, the effects of ecopipam, modafinil, and aripiprazole were consistent in the laboratory and clinic, provided that the medications were administered repeatedly before self-administration sessions. Modafinil attenuated cocaine's reinforcing effects in the human laboratory and improved treatment outcome, while ecopipam and aripiprazole increased the reinforcing effects of cocaine and do not appear promising in the clinic. CONCLUSIONS: The self-administration model has reliably identified medications to treat opioid dependence, and the recent data with modafinil suggest that the human laboratory model also identifies medications to treat cocaine dependence. There have been numerous false positives when subjective effects are the primary outcome measure, but not when self-administration is the outcome. Factors relevant to the predictive validity of self-administration procedures include medication maintenance and the concurrent assessment of a range of behaviors to determine abuse liability and the specificity of effect.     

Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys.

The simultaneous i.v. administration of heroin and cocaine, called "speedball," is often reported clinically, and identification of effective pharmacotherapies for polydrug abuse is a continuing challenge. This study compared the effects of treatment using combinations of dopamine and opioid antagonists with each antagonist alone on speedball self-administration by rhesus monkeys. Speedballs (0.01 mg/kg/inj cocaine and 0.0032 mg/kg/inj heroin) and food (1 g banana pellets) were available in four daily sessions on a second-order schedule of reinforcement [FR4 (VR16:S)]. Monkeys were treated for 10 days with saline or ascending 1:10 dose combinations of the dopamine antagonist flupenthixol and the opioid antagonist quadazocine. The combination of flupenthixol (0.018 mg/kg/day) + quadazocine (0.18 mg/kg/day) significantly reduced speedball self-administration in comparison to the saline treatment baseline (p < .05), whereas, the same doses of each antagonist alone had no significant effect on speedball-maintained responding. Treatment with 0.018 mg/kg/day flupenthixol + 0.18 mg/kg/day quadazocine produced a 3-fold rightward shift in the speedball (3:1 cocaine-heroin combination) dose-effect curve. Food-maintained responding was similar during treatment with saline and with flupenthixol + quadazocine combinations. These findings suggest that medication mixtures designed to target both the stimulant and opioid component of the speedball combination, may be an effective approach to polydrug abuse treatment.     

Antagonism of cocaine self-administration by selective dopamine D(1) and D(2) antagonists

Effects of the dopamine D(1) antagonist SCH 39166 were compared with those of the D(2) antagonist eticlopride in squirrel monkeys responding under a second-order fixed-interval schedule of i.v. self-administration of cocaine. Dose-response curves were determined for a range of doses of self-administered cocaine (0.01-1.7 mg/kg/injection) alone and after pretreatment with SCH 39166 (0.01-0.1 mg/kg) or eticlopride (0.001-0.006 mg/kg). Cocaine maintained self-administration behavior in a dose-related manner; as the dose of cocaine was increased, rates of responding first increased and then either decreased or leveled off. Optimum doses (0.03-0.3 mg/kg) maintained high rates of responding (0.7-1.7 responses per second) among the different monkeys, and patterns of responding that were characteristic for second-order schedules. Pretreatment with either SCH 39166 or eticlopride altered self-administration behavior in all monkeys. In most cases, dose-response curves for cocaine were shifted to the right, indicative of surmountable antagonism, and a 3 to 6-fold increase in dose of cocaine was necessary to restore optimal performances. In some instances, dose-response curves were shifted either downward or downward and to the right, indicating that the antagonistic effects of SCH 39166 and eticlopride were not always fully surmountable. These results show that self-administration of cocaine can be comparably modified by drugs that selectively block dopamine D(1) or D(2) receptors.     

Memantine increases cardiovascular but not behavioral effects of cocaine in methadone-maintained humans

Previous work has suggested that maintenance on the noncompetitive N-methyl-d-aspartate (NMDA) antagonist, memantine, increased the subjective effects of smoked cocaine in experienced cocaine users. To determine whether this phenomenon occurs in opioid-dependent individuals, eight (seven male, one female) methadone-maintained cocaine smokers participated in a 47-day inpatient and outpatient study to assess the effects of memantine on smoked cocaine self-administration, subjective effects, and cardiovascular responses. The participants were maintained on memantine (0 mg and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition during inpatient phases, participants smoked a sample dose of cocaine base (0, 12, 25, and 50 mg) once, and were subsequently given five choice opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher (US 5.00 dollars). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose were varied systematically. Memantine maintenance did not alter the subjective or reinforcing effects of cocaine. Several cardiovascular responses, however, including peak and initial diastolic pressures following cocaine, were significantly greater during memantine maintenance, although these elevations were not clinically significant. Taken together, these findings corroborate earlier data suggesting that this dose of memantine will not be helpful in the pharmacotherapy of cocaine abuse.     

Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice

RATIONALE: The novel antipsychotic aripiprazole in use for treatment of schizophrenia is a partial agonist at dopamine D2 receptors with actions at a variety of other receptors as well. Cocaine is believed to exert an important part of its rewarding effect by increasing extracellular levels of dopamine that subsequently act at dopamine D2 receptors. OBJECTIVES: As a partial agonist, aripiprazole may antagonize effects at D2 receptors and we accordingly tested whether aripiprazole could antagonize self-administration of cocaine. Because D2-like receptor agonists are self-administered, a D2 receptor partial agonist like aripiprazole might itself be reinforcing. Thus, we also assessed whether mice would acquire self-administration of aripiprazole. MATERIALS AND METHODS: A single session, mouse self-administration procedure was used. RESULTS: Oral pretreatment with aripiprazole dose-dependently decreased cocaine self-administration under a fixed ratio 1 schedule at the peak cocaine dose (0.03 mg/kg/infusion), reaching significance at 0.2 and 0.4 mg/kg of aripiprazole. Using 0.4 mg/kg, aripiprazole decreased rates of cocaine self-administration without shifting the peak of the dose-response function. There was no effect of aripiprazole per se, suggesting that its inhibitory action was due to effects on cocaine self-administration rather than non-specific motor effects. Aripiprazole was not found to be self-administered in the tested dose range (0.0003-0.3 mg/kg/infusion). The three highest doses (0.03, 0.1, and 0.3 mg/kg/infusion) even caused significant decreases in nose-poking activity, possibly due to extrapyramidal side effects. CONCLUSIONS: These data are consistent with a potential role for aripiprazole in treatment of cocaine addiction without abuse potential per se.     

Effects of pergolide on intravenous cocaine self-administration in men and women

Clinical evidence suggests that pergolide, a D₁/D₂ dopamine receptor agonist, may be useful in maintaining cocaine abstinence. We investigated pergolide’s effects in a laboratory model of IV cocaine self-administration by humans. Twelve inpatient volunteers (7M, 5F), who reported spending an average of $170/ week on cocaine, received pergolide (0.05 mg BID) for 8 days and placebo for 8 days, with drug order balanced across subjects. Self-administration sessions occurred on the last 4 days of maintenance on each medication. A modified seven-trial progressive ratio choice procedure (0, 8, 16, 32 mg/70 kg cocaine versus $5) was utilized, with sessions consisting of: (a) two sample trials, where participants responded to receive the dose and tokens available that day, and (b) five choice trials, where participants chose between the available dose and tokens. Following each trial, the response requirement for the chosen option increased by 400. Maintenance on pergolide 1) decreased cocaine-induced increases in ratings of “High,”“Stimulated,” cocaine “Potency,” estimates of street value, and heart rate, 2) increased ratings of “I want cocaine,” and 3) had no effect on cocaine self-administration. The increased desire to use cocaine during pergolide maintenance suggests that it has limited treatment utility at this dose, but given the attenuation of cocaine’s subjective and cardiovascular effects, an investigation of a wider range of pergolide doses on cocaine self-administration and subjective effects is warranted. Received: 29 April 1997/Final version: 14 October 1997     

SDZ 208-911, an amino-ergoline with partial dopamine agonist properties,dose dependently increases cocaine self-administration in the rat

Brain dopamine neurotransmission appears to be an important component of the neural pathways involved in the maintenance of intravenous (IV) cocaine self-administration in rats. The effects of a novel partial dopamine agonist, SDZ 208–911, on intravenous cocaine self-administration in rats was studied. SDZ 208–911 at a dose range of 0.025–1.6 mg/kg SC dose-dependently increased the number of lever presses and drug intake in rats exposed to limited (3-h) daily access to cocaine on a continuous reinforcement schedule (0.75 mg/kg per injection). This behavioral profile is similar to that observed following administration of dopamine antagonist drugs and has been hypothesized to reflect a compensatory increase in drug intake due to a reduction of the reinforcing efficacy of the drug, probably because of functional antagonism at the receptor site. These results suggest that dopamine partial agonists may act as functional dopamine antagonists in the face of pharmacologically induced activation of brain dopamine function.     

Failure of ondansetron to block the discriminative or reinforcing stimulus effects of cocaine in the rat.

Ondansetron (GR38032F), a serotonin 5HT3 antagonist, is active in numerous behavioral paradigms and neurochemical systems. Since 5HT3 antagonists have been suggested as therapeutic agents for the treatment of drug abuse, the action of ondansetron on cocaine drug discrimination and self-administration paradigms in rats was investigated. Doses of ondansetron (0.001 - 1.0 mg/kg) had no effect on the discriminative stimulus properties of 10 mg/kg cocaine. In contrast SCH23390, a dopamine D1 antagonist known to block cocaine discrimination, acted as previously reported. Ondansetron did not augment the effects of SCH23390, but at higher doses, combinations of ondansetron and SCH23390 produced disruption of lever pressing in the presence of cocaine. Ondansetron (0.001-1.0 mg/kg) had no effect on the self-administration of various doses of cocaine, nor did it have any effect on reacquisition of cocaine self-administration in animals with a history of active administration followed by a period of abstinence. As before, SCH23390, known to block cocaine self-administration, acted as previously reported. Although other 5HT antagonists may prove to be efficacious in cocaine abuse, ondansetron appears unlikely to alter the subjective or rewarding stimulus properties of cocaine.     

A preliminary,controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients

Based on pre-clinical studies suggesting that magnesium (Mg) reduces cocaine self-administration and potentiates the antinociceptive effects of morphine, we conducted a preliminary randomized clinical trial investigating Mg for the treatment of illicit cocaine and opiate use. Eighteen methadone-maintained patients who used illicit opiates and cocaine received either Mg (732 mg/day) or placebo for 12 weeks. Overall, findings showed that the percentage of urine screens testing positive for opiates in the Mg group (22.6%) was half that of the placebo group (46.4%), p = .04; the difference was even greater in the "medication compliant" sample (Mg: 16.3%, placebo: 47.9%), p = .02. Cocaine craving was lower in the Mg compared to the placebo group, but there was no difference between groups in cocaine use. These preliminary findings suggest that Mg may have a beneficial effect for reducing illicit opiate use. It is possible that a higher dose of Mg than was used in this study may be needed to decrease cocaine use.     

Neuronal nitric oxide synthase inhibition decreases cocaine self-administration behavior in rats

RATIONALE: Inhibitors of nitric oxide synthase (NOS) have been shown to alter behaviors related to cocaine addiction, including its self-administration. However, previous studies have largely used mixed-action NOS inhibitors and have not examined the effects of a neuronal NOS inhibitor on cocaine self-administration. OBJECTIVES: Pretreatment with the neuronal NOS inhibitor 7-nitroindazole (7-NI) was used and its effects on cocaine self-administration were compared with those produced by pretreatment with an indirect dopamine receptor agonist (cocaine) and a D(1)-like dopamine receptor antagonist (SCH 23390). METHODS: Rats were trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery, which measures drug-seeking behavior independently from drug intake. Pretreatment with various doses of 7-NI, cocaine, and SCH 23390 were tested in combination with the training dose of cocaine followed by studies examining the effects of a selected dose of each pretreatment drug in combination with a range of cocaine doses. Other rats were trained under a second-order schedule of food pellet delivery and pretreated with 7-NI, cocaine, or SCH 23390 to determine the behavioral specificity of the effects of these drugs for cocaine-maintained responding. RESULTS: The results demonstrated that 7-NI reduced responses maintained by the cocaine training dose and produced a downward shift in the cocaine dose-response curve. Changes in drug intake were minor by comparison. Cocaine pretreatment produced effects similar to 7-NI, while the changes observed after SCH 23390 pretreatment were different from 7-NI and cocaine. The reductions in cocaine-maintained responding after 7-NI pretreatment were behaviorally specific because there was no effect of 7-NI on food-maintained responding within the dose range examined. CONCLUSIONS: By selectively reducing drug-seeking behavior, these data suggest that 7-NI may enhance the reinforcing effects of cocaine.     

GR38032F, a serotonin 5-HT3 antagonist, fails to alter cocaine self-administration in rats.

Recent data have supported a role for serotonin (5-HT) in the self-administration of cocaine by laboratory rats. More specifically, it has been suggested that 5-HT3 receptor antagonists may be useful in the treatment of drug abuse. To assess this possibility, we compared the effects of the 5-HT3 antagonist, GR38032F, with the dopamine D2 receptor blocker, haloperidol, on the intravenous self-administration of cocaine (0.5 mg/kg/infusion) in rats. The serotonin antagonist (0.01, 0.1 or 1.0 mg/kg, IP) failed to alter self-administration (0.5 mg/kg/infusion). In contrast, haloperidol (0.125 mg/kg, IP) increased responding for cocaine (0.5 mg/kg/infusion), and shifted the dose-response curve for cocaine self-administration to the right. These data fail to support a role for the serotonin 5-HT3 receptor system in the reinforcing properties of this psychostimulant. Rather, the 5-HT1 or 5-HT2 receptors may be the critical subtype.     

Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats

It was recently reported that levo-tetrahydropalmatine (l-THP), a dopamine (DA) D1 and D2 receptor antagonist purified from the Chinese herb Stephanie, appears to be effective in attenuating cocaine self-administration, cocaine-triggered reinstatement and cocaine-induced conditioned place preference in preclinical animal models. The present study was designed to contrast l-THP's effects on cocaine self-administration under fixed-ratio (FR) and progressive-ratio (PR) reinforcement, and to study l-THP's effects on cocaine-enhanced brain stimulation reward (BSR). Systemic administration of l-THP produced dose-dependent, biphasic effects, i.e., low-to-moderate doses (1, 3, 10 mg/kg) increased, while a high dose (20 mg/kg) inhibited cocaine self-administration behavior under FR2 reinforcement. The increased cocaine self-administration is likely a compensatory response to a reduction in cocaine's rewarding effects, because the same low doses of l-THP dose-dependently attenuated cocaine self-administration under PR reinforcement and also attenuated cocaine-enhanced BSR. These attenuations of PR cocaine self-administration and cocaine-enhanced BSR are unlikely due to l-THP-induced sedation or locomotor inhibition, because only 10 mg/kg, but not 1-3 mg/kg, of l-THP inhibited locomotion, sucrose self-administration and asymptotic operant performance in the BSR paradigm. In vivo microdialysis demonstrated that l-THP slightly elevates extracellular nucleus accumbens DA by itself, but dose-dependently potentiates cocaine-augmented DA, suggesting that a postsynaptic, rather than presynaptic, DA receptor antagonism underlies l-THP's actions on cocaine reward. Together, the present data, combined with previous findings, support the potential use of l-THP for treatment of cocaine addiction.