Biomedical subjects

Joshua A Lile

Publications and source records attributed to Joshua A Lile.

17 recordsLinked to original sources

PubMed2006

The reinforcing, subject-rated, performance, and cardiovascular effects of d-amphetamine: influence of sensation-seeking status.

Individual differences that may contribute to vulnerability to abuse drugs have been identified. Sensation-seeking status has been shown to influence both vulnerability to drug use and response to acute drug administration. The purpose of the present experiment was to examine the reinforcing effects of d-amphetamine in high and low sensation-seeking subjects using a modified progressive-ratio procedure. A battery of subject-rated, performance, and cardiovascular measures was also included to better characterize the effects of d-amphetamine in these groups. Ten high sensation seekers and ten low sensation seekers that were matched for education, age, drug use, height, and weight, first sampled doses of d-amphetamine (0, 8, and 16 mg). In subsequent sessions, subjects were offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. d-Amphetamine functioned as a reinforcer and produced prototypical stimulant-like effects (e.g., increased subject-ratings of Like Drug, enhanced performance, and increased heart rate). High sensation seekers were more sensitive than low sensation seekers to the reinforcing and some of the subject-rated effects of d-amphetamine. The results of the present experiment extend those of previous findings by demonstrating that the reinforcing effects of d-amphetamine vary as a function of the biologically based sensation-seeking personality trait. These results suggest that increased stimulant drug use and abuse among high sensation seekers may be related, in part, to increased sensitivity to the reinforcing effects of stimulants among these individuals.

Adult↗

PubMed2006

The effects of eticlopride and the selective D3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys.

The dopamine D3 receptor is mainly expressed in regions of the brain associated with the limbic system. D3 receptor blockade may antagonize cocaine reinforcement while producing less severe extrapyramidal side effects than blockade of D2 receptors. The purpose of the present studies was to evaluate the effects of a selective D3 receptor antagonist and a non-selective D2/D3 receptor antagonist on food- and cocaine-maintained responding under two schedules of cocaine self-administration. Adult male rhesus monkeys were trained to respond under multiple schedules of food (1.0 g pellets) and cocaine (0.01-0.3 mg/kg/injection) presentation. In one experiment (n=4), the schedule was a fixed-interval (FI) 3-min and a second study (n=6) was conducted using a second-order fixed-ratio 5 (FI 6-min:S) schedule. The D3 antagonist PNU 99194-A (0.3-3.0 mg/kg), which is 14-fold selective for D3 relative to D2 receptors, or the D2/D3 antagonist eticlopride (0.001-0.03 mg/kg) was administered immediately prior to the experimental session for at least 5 consecutive sessions. Under the multiple FI 3-min schedule of food and cocaine presentation, PNU 99194-A and eticlopride decreased food- and cocaine-maintained responding in a dose-dependent manner and irrespective of cocaine dose. Under the multiple second-order schedule of food and cocaine presentation, at least one dose of PNU 99194-A and eticlopride decreased cocaine- and food-maintained responding. These findings indicate that PNU 99194-A can decrease operant responding in monkeys, but not in a manner that would suggest selectivity of cocaine- over food-maintained responding. Future studies with more selective D3 antagonists are needed to better address the role of this receptor subtype in cocaine addiction.

Animals↗

PubMed2006

A low dose of aripiprazole attenuates the subject-rated effects of d-amphetamine.

Despite increased reports of amphetamine abuse and dependence, a putative pharmacotherapy has yet to be identified. In a previous study from our laboratory, 20 mg aripiprazole, an atypical antipsychotic that has partial agonist activity at D(2) receptors, attenuated many of the behavioral effects of d-amphetamine. Aripiprazole (20 mg) also impaired performance on a computerized version of the DSST when administered alone, indicating that the attenuation observed may have been functional as opposed to receptor mediated. The present experiment was conducted to determine whether a lower dose of aripiprazole (10 mg) could acutely attenuate the discriminative-stimulus, subject-rated, and physiological effects of d-amphetamine (2.5-15 mg) without impairing performance as measured with a computerized version of the DSST. The results of the present experiment indicate that 10 mg aripiprazole attenuated some abuse-related behavioral effects of d-amphetamine and was generally devoid of effects, including significant performance impairment, when administered alone. These findings suggest that 10 mg aripiprazole would be a reasonable starting dose for the treatment of stimulant abuse and dependence. Future research should examine the effects of chronic aripiprazole administration in combination with methamphetamine or cocaine.

Adult↗

PubMed2006

Pharmacological determinants of the reinforcing effects of psychostimulants: relation to agonist substitution treatment.

Illicit use of psychostimulants, such as cocaine and methamphetamine, continues to pose a significant public health concern. On the basis of the relative success at treating opiate and tobacco users with agonist substitution treatments, this strategy has been pursued in the search for a pharmacotherapy for psychostimulant addiction. The reinforcing effects of drugs are central to their abuse liability; therefore, gaining a better understanding of the factors that determine the reinforcing effects of psychostimulants should inform the development of an effective treatment. Although the reinforcing effects of drugs are known to be multiply determined, the author's dissertation research focused on pharmacological factors. This review presents results from that research as well as findings reported in the extant literature, suggesting that the reinforcing effects of psychostimulant drugs are determined both by their pharmacodynamic and pharmacokinetic profiles. There is evidence to support the conclusion that affinity for dopamine transporters appears to be of critical importance, whereas serotonin transporters seem to serve a modulatory function. A more rapid rate of onset may enhance a drug's reinforcing effects, but a drug with a slow onset can still maintain self-administration. A drug's duration of action may only influence the rate but not the strength of responding that is maintained. Slow-onset, long-acting monoamine transporter ligands can be expected to have reinforcing effects and therefore abuse liability, which has implications for the use of these drugs as pharmacotherapies. Nonetheless, on the basis of promising preclinical and clinical findings, this appears to represent a viable treatment strategy.

Central Nervous System Stimulants↗

PubMed2006

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans.

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential.

Adolescent↗

PubMed2005

Methylphenidate increases cigarette smoking.

RATIONALE: Methylphenidate (Ritalin) and d-amphetamine (Dexedrine), stimulants commonly prescribed for behavioral problems associated with attention deficit hyperactivity disorder (ADHD), produce a similar constellation of behavioral effects. The results of previous studies suggest that d-amphetamine increases rates of smoking and the reinforcing effects of smoking. The effects of methylphenidate on smoking have not been assessed although it is the most commonly prescribed pharmacotherapy for ADHD and individuals with ADHD are at increased risk for smoking. OBJECTIVE: In this experiment the acute effects of a range of doses of methylphenidate (5, 10, 20, and 40 mg) and placebo were assessed in ten cigarette smokers who were not attempting to quit and were without ADHD or other Axis I psychiatric disorders. METHODS: Each dose of methylphenidate was tested once, whereas placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, latency to the first cigarette, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum, and caloric intake during the 4-h smoking session was calculated. RESULTS: Methylphenidate dose dependently increased the total number of cigarettes smoked, number of puffs, and carbon monoxide levels. As expected, methylphenidate dose dependently decreased the number of food items consumed and caloric intake. CONCLUSIONS: The results of this experiment suggest that methylphenidate, like d-amphetamine, increases rates of cigarette smoking.

Adolescent↗

PubMed2005

Reinforcing effects of modafinil: influence of dose and behavioral demands following drug administration.

RATIONALE: The reinforcing effects of stimulant drugs are modulated by behavioral demands following drug administration. OBJECTIVE: The objective of this study was to assess the reinforcing effects of modafinil, a drug with purportedly low abuse potential, under different behavioral demands using a modified progressive-ratio procedure. METHODS: The reinforcing effects of oral modafinil (0, 100, 200, and 400 mg) were assessed in six healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems for three 50-min blocks. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room for three 50-min blocks. Two sampling sessions (one performance and one relaxation session) always preceded two self-administration sessions (one performance and one relaxation session), and the order of performance and relaxation sessions was constant within a dose condition. RESULTS: Modafinil significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Modafinil produced comparable stimulant-like subjective ratings under both the performance and relaxation conditions. CONCLUSION: The findings of the present experiment demonstrate that modafinil can function as a reinforcer and that the reinforcing effects of modafinil are influenced by behavioral demands following drug administration, similar to those of other stimulant drugs.

Adult↗

PubMed2005

Oxazepam does not modulate the behavioral effects of d-amphetamine in humans.

Benzodiazepines, which are gamma-aminobutyric acid-A (GABA(A)) receptor positive modulators, can block the behavioral effects of psychomotor stimulants. In the present study, the ability of oxazepam, which may have less abuse potential compared to some other benzodiazepines, to attenuate the discriminative-stimulus, subject-rated and psychomotor performance effects of d-amphetamine in humans was determined. Six healthy participants (2 female, 4 male) learned to discriminate 15 mg oral d-amphetamine. After acquiring the discrimination (i.e., > or = 80% correct responding on 4 consecutive days), the effects of d-amphetamine (0, 2.5, 5, 10 and 15 mg), alone and in combination with acutely administered oxazepam (0 and 20 mg) were assessed. d-Amphetamine alone functioned as a discriminative stimulus, produced stimulant-like subject-rated effects (e.g., increased ratings of Stimulated on a Drug-Effect Questionnaire) and enhanced psychomotor performance. Oxazepam alone increased subject ratings of sedation (e.g., increased ratings of Sluggish, Fatigued and Lazy on a Drug-Effect Questionnaire) and impaired psychomotor performance. Oxazepam alone did not occasion d-amphetamine-like discriminative-stimulus effects, and had no effect on the discriminative-stimulus or subject-rated effects of d-amphetamine when given in combination. The results of this experiment are discordant with previous research and suggest that benzodiazepines differ in their ability to modulate the behavioral effects of d-amphetamine.

Adult↗

PubMed2005

Discriminative stimulus and self-reported effects of methylphenidate, d-amphetamine, and triazolam in methylphenidate-trained humans.

Asymmetrical generalization between drugs on drug-discrimination procedures has been demonstrated for sedative and stimulant drugs in animals and to some extent with sedative drugs in humans. The aim of this experiment was to examine the discriminative-stimulus effects of d-amphetamine in methylphenidate-trained humans. A previous study demonstrated that methylphenidate substitutes for d-amphetamine in d-amphetamine-trained humans. Six healthy human participants first learned to discriminate 30 mg oral methylphenidate. Doses of oral methylphenidate, d-amphetamine, triazolam, and placebo were then tested to determine whether they share discriminative-stimulus and self-reported effects with 30 mg methylphenidate. Methylphenidate and d-amphetamine dose-dependently increased methylphenidate-appropriate responding and produced prototypical stimulant-like effects. Triazolam produced low levels of methylphenidate-appropriate responding and prototypical sedative-like effects. The results of this experiment are concordant with previous studies and suggest that the behavioral effects of oral methylphenidate and d-amphetamine overlap extensively and that the discriminative-stimulus effects of methylphenidate and d-amphetamine are symmetrical.

Adult↗

PubMed2005

Aripiprazole attenuates the discriminative-stimulus and subject-rated effects of D-amphetamine in humans.

The results of animal research suggest that the use of partial agonists at dopamine (DA) D2 receptors may be an effective strategy for the treatment of stimulant dependence. Aripiprazole is an atypical antipsychotic that has partial agonist activity at D2 receptors. In this experiment, seven human participants with a history of nontherapeutic stimulant use learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (ie > or =80% correct responding on four consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with aripiprazole (0 and 20 mg), were assessed. D-Amphetamine alone functioned as a discriminative stimulus, produced prototypical subject-rated drug effects (eg increased ratings of Active, Alert, Energetic) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion D-amphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of D-amphetamine, as well as some of the subject-rated drug effects. These data are consistent with previous preclinical findings and suggest that DA partial agonists deserve further evaluation as potential pharmacotherapies in the management of stimulant dependence. Future studies should investigate the ability of aripiprazole or related compounds to attenuate the behavioral effects of stimulants associated with a greater degree of dependence, such as methamphetamine or cocaine, in dependent individuals.

Adult↗

PubMed2004

A comparison of the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") with cocaine in rhesus monkeys.

The purpose of the present study was to compare the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to cocaine. Rhesus monkeys (n=4) responded under a within-session, exponentially increasing, progressive-ratio (PR) schedule of cocaine reinforcement. Breaking point (BP) for the PR schedule was defined as the final response requirement completed before 2 h had elapsed without an injection delivered. Saline and doses of cocaine (0.003-0.3 mg/kg/injection) and MDMA (0.01-0.56 mg/kg/injection) were substituted for the training dose of cocaine for at least five consecutive sessions. Both cocaine and MDMA functioned as reinforcers, but self-administration of MDMA occurred at fewer doses and a significantly lower peak BP was obtained for MDMA. These data demonstrate that MDMA functions as a reinforcer, although its reinforcing efficacy appears to be less than that of cocaine.

Amphetamines↗

PubMed2004

Acute administration of the GABA reuptake inhibitor tiagabine does not alter the effects of oral cocaine in humans.

Drugs affecting central gamma-aminobutyric acid (GABA) systems may have promise as treatments for cocaine addiction. In the present study, tiagabine (Gabatril), a GABA reuptake inhibitor, was investigated for its ability to modify the discriminative-stimulus, reinforcing, subject-rated, performance and cardiovascular effects of oral cocaine in non-treatment seeking cocaine users. Initially, acute doses of 4 mg tiagabine were tested alone and in combination with oral cocaine in four participants to establish the safety of cocaine-tiagabine combinations. A higher dose of tiagabine (8 mg) was then tested in a larger group (n = 6). Participants learned to discriminate 150 mg of oral cocaine. The effects of cocaine (0-150 mg, p.o.) administered alone and in combination with tiagabine were then determined. Subject-rated, performance and cardiovascular measures were obtained at regular intervals. The reinforcing effects of cocaine, tiagabine and cocaine-tiagabine combinations were assessed using the Multiple-Choice Procedure. Cocaine alone produced prototypical behavioral and physiological effects (i.e., functioned as a discriminative and reinforcing stimulus, produced stimulant-like subject-rated effects, improved performance and increased heart rate). In general, acute administration of tiagabine did not alter the effects of oral cocaine. These findings suggest that tiagabine would not be effective at preventing continued cocaine use by blocking its acute, abuse-related effects.

Administration, Oral↗

PubMed2004

Reinforcing effects of methylphenidate: influence of dose and behavioral demands following drug administration.

RATIONALE: The reinforcing effects of stimulant drugs such as D-amphetamine, caffeine, and cocaine are modulated by behavioral demands following drug administration. OBJECTIVE: The objective of this study was to assess the reinforcing effects of methylphenidate under different behavioral demands using a modified progressive-ratio procedure. METHODS: The reinforcing effects of oral methylphenidate (0, 10, 20, and 40 mg) were assessed in seven healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems for three 50-min blocks. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room for three 50-min blocks. Two sampling sessions (one performance and one relaxation session) always preceded two self-administration sessions (one performance and one relaxation session) and the order of relaxation and performance sessions was constant within a dose condition. RESULTS: Methylphenidate significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Methylphenidate produced comparable stimulant-like subject ratings under both the performance and relaxation conditions. CONCLUSION: The findings of the present experiment suggest that the reinforcing effects of methylphenidate, like D-amphetamine and cocaine, are influenced by behavioral demands following drug administration.

Administration, Oral↗

PubMed2004

Effects of the dopamine reuptake inhibitor PTT on reinstatement and on food- and cocaine-maintained responding in rhesus monkeys.

RATIONALE: High-affinity, slow-onset, long-acting dopamine transporter (DAT) inhibitors are being considered as potential agonist replacement therapies for cocaine addiction, and therefore the ability of these drugs to reinstate cocaine seeking and to selectively decrease cocaine-maintained responding should be assessed. OBJECTIVES: The purpose of these experiments was to evaluate the effects of the active enantiomer of a high-affinity, slow-onset, long-acting DAT inhibitor, (-)2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT), and cocaine on food- and cocaine-maintained responding and on extinguished responding previously maintained by cocaine in non-human primates using a within-subjects design. METHODS: Rhesus monkeys (n=3) responded under a multiple fixed-ratio schedule of food (1 g) and drug reinforcement, and cocaine dose-response curves (saline, 0.003-0.3 mg/kg per injection) were determined. The effects of pretreatment with (-)PTT (0.001-0.056 mg/kg, i.v.) and cocaine (0.03-0.3 mg/kg, i.v.) were determined when the dose of cocaine that maintained peak response rates (0.03 mg/kg per injection) or saline was available. RESULTS: (-)PTT and cocaine reduced cocaine intake; (-)PTT affected cocaine self-administration only at doses that also decreased food-maintained responding. (-)PTT and cocaine reinstated responding that was previously reinforced by cocaine at lower doses than were necessary to decrease cocaine-maintained responding. For all studies, PTT was at least 1.0 log-unit more potent than cocaine. Compared to cocaine, PTT had a longer duration of action in all behavioral measures. CONCLUSIONS: These results suggest that PTT would decrease cocaine use, but only at doses that disrupted other behaviors. It appears that the potency of this class of drugs to reinstate cocaine-seeking is substantially greater than their potency at decreasing cocaine self-administration.

Animals↗

PubMed2003

Baclofen does not alter the reinforcing, subject-rated or cardiovascular effects of intranasal cocaine in humans.

RATIONALE: There is evidence from research in animals and humans that the gamma-aminobutyric acid B receptor subtype (GABA(B)) agonist baclofen may have promise as a pharmacotherapy for cocaine addiction. OBJECTIVES: In the present study, the ability of baclofen to modify the reinforcing, subject-rated and cardiovascular effects of intranasal cocaine in humans was determined. METHODS: Non-treatment-seeking volunteers ( n=7) with recent histories of cocaine use were recruited to participate in this placebo-controlled, double-blind study. Baclofen (0, 10, 20 and 30 mg) was administered orally, followed approximately 1.5 h later by intranasal cocaine (4 mg [placebo] and 45 mg). Subject-rated and cardiovascular measures were taken prior to baclofen administration and then at regular intervals after cocaine was administered. The reinforcing effects of cocaine and cocaine-baclofen combinations were assessed using the Multiple-Choice Procedure. RESULTS: Intranasal cocaine significantly increased the crossover point on the Multiple-Choice Procedure relative to placebo, suggesting that this cocaine dose functioned as a reinforcer. This dose of intranasal cocaine also produced increases in subject-rated effects typical of psychostimulants and elevated cardiovascular measures. The time course for the effects of cocaine was consistent with its pharmacokinetic profile following intranasal administration; increases in subject-rated and cardiovascular effects were observed almost immediately following administration and peaked at approximately 30 min. Pretreatment with baclofen had no significant effect alone, nor in combination with cocaine, on any outcome. CONCLUSIONS: These data demonstrated that acute administration of three clinically relevant baclofen doses did not influence the acute behavioral effects of intranasal cocaine in humans.

Administration, Intranasal↗

PubMed2003

The reinforcing efficacy of psychostimulants in rhesus monkeys: the role of pharmacokinetics and pharmacodynamics.

This study was undertaken to investigate pharmacological variables that influence the reinforcing efficacy of psychostimulants. Rhesus monkeys (n = 9) responded under a within-session, exponentially increasing, progressive ratio schedule of cocaine reinforcement. Doses of cocaine, methylphenidate (MP), cocaine analogs [(+/-)-2beta-propanoyl-3beta-(2-naphthyl)-tropane (WF-23), HD-23; (+/-)-2beta-propanoyl-3beta-(2-isopropenyl)tropane (WF-60), HD-60; and 2beta-propanoyl-3beta-(4-tolyl)-tropane (HD-11, WF-11), and 2beta-propanoyl-3beta-(4-tolyl)-tropane (HD-11, WF-11), PTT], and MP analogs [(alphaR,2R)-alpha-(2-naphthalenyl)-2-piperidineacetic acid methyl ester, HDMP-28; and (alphaR,2S)-alpha-(2-naphthalenyl)-2-pyrrolideneacetic acid methyl ester, HDMP-29] that varied in their pharmacokinetic and pharmacodynamic properties were substituted for cocaine. These drugs were chosen according to their selectivity for dopamine transporters (DAT) and 5-hydroxytryptamine (serotonin) transporters (5-HTT) as assessed in rodents and their duration of action. In addition, data pertaining to the rate of onset at DAT were collected for the cocaine analogs using an ex vivo binding assay in rodent tissue. Finally, the pharmacodynamic profile of select drugs was confirmed in primate brain tissue. All drugs had reinforcing effects except HDMP-29. The rank ordering of the peak breaking points (BPs) was cocaine = MP = HDMP-28 >or= HD-60 >or= PTT >or= HD-23 > HDMP-29. The time to peak DAT occupancy for the cocaine analogs was greater than 30 min. The potency to maintain peak BP was significantly correlated with DAT affinity. There was not a linear relationship between monoamine transporter affinity and reinforcing efficacy, but it appeared that in nonhuman primates there is a range of DAT affinity under which maximal responding is maintained. Interestingly, the 5-HTT-selective cocaine analog HD-60 functioned robustly as a reinforcer at several doses in all monkeys tested. These data question the dogma regarding the role of pharmacokinetic factors and the relative influence of DAT and 5-HTT in stimulant reinforcement.

Animals↗

PubMed2002

The reinforcing efficacy of the dopamine reuptake inhibitor 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) as measured by a progressive-ratio schedule and a choice procedure in rhesus monkeys.

The present series of experiments was undertaken to investigate the variables that influence the reinforcing efficacy of psychostimulants. The time of onset for dopamine transporter (DAT) occupancy of the long-acting, high-affinity DAT blocker 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) was measured using an ex vivo binding assay in rodents and was determined to be significantly longer than for cocaine (30 min versus 2 min). To assess the reinforcing efficacy of PTT relative to cocaine, a discrete-trials drug-drug choice procedure (n = 3) and a progressive-ratio (PR) schedule (n = 4) were used in rhesus monkeys. Cocaine (0.003-0.56 mg/kg/injection) and PTT (0.003-0.03 mg/kg/injection) maintained responding greater than saline under the PR schedule. Maximal breaking points were significantly higher for cocaine compared with PTT. A separate group of monkeys prepared with double-lumen catheters was allowed to choose between cocaine (saline and 0.03-0.3 mg/kg/injection) and PTT (saline, and 0.01 and 0.03 mg/kg/injection). Under these conditions, PTT was not preferred over saline. When saline or 0.01 mg/kg/injection PTT was available as alternatives to cocaine, the highest dose of cocaine maintained greater than 80% choice. When 0.03 mg/kg/injection PTT was the alternative to cocaine, cocaine choice declined to approximately 50%, and total cocaine intake was decreased by ~70% at the highest cocaine dose. These results suggest that the reinforcing efficacy of PTT is less than cocaine in nonhuman primates. Data from studies with PTT indicate that slow-onset, long-acting DAT inhibitors can decrease cocaine self-administration while not functioning robustly as reinforcers, and support the further investigation of these drugs as treatment for cocaine addiction.

Animals↗