Cocaine-like Stimulus Effects Research Articles

Dopamine β-Hydroxylase Inhibitors Enhance the Discriminative Stimulus Effects of Cocaine in Rats

Inhibitors of dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic cells, have shown promise for the treatment of cocaine abuse disorders. However, the mechanisms underlying the beneficial effects of these compounds have not been fully elucidated. We used the drug discrimination paradigm to determine the impact of DBH inhibitors on the interoceptive stimulus properties of cocaine. Sprague-Dawley rats were trained to discriminate cocaine (5.6 mg/kg) from saline using a multicomponent, food-reinforced discrimination procedure. On test days, subjects were pretreated with the nonselective DBH inhibitor disulfiram (0-100.0 mg/kg i.p.) or the selective DBH inhibitor nepicastat (0-56.0 mg/kg i.p.) 2 hours prior to a test session either alone or in combination with cumulatively administered cocaine (0-5.6 mg/kg i.p.). Neither disulfiram nor nepicastat substituted for the cocaine stimulus when tested up to doses that nonspecifically reduced responding. However, in combination studies, pretreatment with either disulfiram or nepicastat produced leftward shifts in the cocaine dose-response function and also conferred cocaine-like stimulus effects to the selective NE transporter inhibitor, reboxetine (0.3-5.6 mg/kg i.p.). These results indicate that pharmacological inhibition of DBH does not produce cocaine-like interoceptive stimulus effects alone, but functionally enhances the interoceptive stimulus effects of cocaine, possibly due to facilitated increases in DA released from noradrenergic terminals. These findings suggest that DBH inhibitors have low abuse liability and provide support to clinical reports that some subjective effects produced by cocaine, particularly aversive effects, are enhanced after DBH inhibition.

The dopamine D3 receptor partial agonist CJB 090 inhibits the discriminative stimulus but not the reinforcing or priming effects of cocaine in squirrel monkeys

Dopamine D3 receptor mechanisms have been implicated in the abuse-related behavioral effects of cocaine. The purpose of this study was to investigate the effects of the D3 receptor partial agonist CJB 090 on the discriminative stimulus, reinforcing and priming effects of cocaine in squirrel monkeys. Complementary studies were conducted to compare CJB 090's effects on food-maintained behavior and species-typical unconditioned behaviors. Monkeys were trained to: (1) discriminate cocaine from saline using a two-lever choice procedure, (2) self-administer cocaine on a second-order fixed-interval, fixed-ratio schedule of i.v. drug injection, or (3) self-administer food on a comparable second-order schedule of food delivery. A final group of monkeys served in quantitative observational studies of unconditioned behaviors. In cocaine discrimination studies, pretreatment with CJB 090 significantly attenuated cocaine's discriminative stimulus effects. CJB 090 also significantly attenuated the partial cocaine-like stimulus effects of the preferential D3 receptor agonist PD 128907 but not the preferential D2 receptor agonist sumanirole. CJB 090 did not attenuate either self-administration of cocaine or cocaine-induced reinstatement of extinguished drug-seeking at a dose that reduced responding maintained by food. CJB 090 did not induce scratching or biting (species-typical effects of D2/3 receptor agonists) or catalepsy (typical effect of D2/3 receptor antagonists). The results provide no evidence that CJB 090 reduced either the reinforcing or priming effects of cocaine but do suggest that CJB 090, acting via a D3 receptor mechanism, antagonized the discriminative stimulus effects of cocaine at a dose that did not induce adverse side effects.

Modulation of the Reinforcing and Discriminative Stimulus Effects of Cocaine by the Dopamine D3 Receptor Partial Agonist CJB 090 [N‐(4‐(4‐(2,3‐Dichlorophenyl)piperazin‐4‐(pyridine‐2‐yl)benzamide] in Squirrel Monkeys

Dopamine D3 receptor mechanisms have been implicated repeatedly in the behavioral effects of cocaine. This study evaluated the effects of the D3 receptor partial agonist CJB 090 in monkeys trained to: 1) discriminate cocaine from vehicle, 2) self‐administer cocaine on a second order fixed‐interval, fixed‐ratio schedule of i.v. drug injection or 3) self‐administer food on a comparable second order schedule of food delivery. In cocaine discrimination studies, CJB 090 did not substitute for cocaine, but significantly attenuated cocaine's discriminative stimulus effects when administered as a pretreatment. CJB 090 also significantly attenuated the partial cocaine‐like stimulus effects of the D3 receptor agonist PD128907, but enhanced the partial cocaine‐like stimulus effects of the D2 receptor agonist sumanirole. In self‐administration studies, CJB 090 did not attenuate responding maintained by i.v. injections of cocaine at a dose that reduced responding maintained by food. In a separate group of monkeys, observational tests revealed that CJB 090 did not induce scratching or biting (species‐typical effects of D2/3 receptor agonists) or catalepsy (typical effect of D2/3 receptor antagonists). The results provide little evidence that CJB 090 reduced cocaine's reinforcing effects. However they do suggest that CJB 090, acting primarily via a D3 receptor mechanism, antagonized the discriminative stimulus effects of cocaine at a dose that did not induce adverse observable effects.Supported by DA011054, NIDA‐IRP, RR00168. We thank J. Cao for CJB 090 synthesis.

Separation of the locomotor stimulant and discriminative stimulus effects of cocaine by its C-2 phenyl ester analog, RTI-15

During a routine evaluation of several analogs of cocaine, we observed that the C-2 phenyl ester, RTI-15, appeared to suppress motor activity in rats. We subsequently examined RTI-15 for its cocaine-like stimulus effects as well as for its locomotor activity effects. RTI-15 dose-dependently generalized from the cocaine stimulus in rats trained to discriminate 10 mg/kg cocaine from saline with complete substitution (⩾80% cocaine-lever responding) occurring at 24 mg/kg. During automated locomotor activity tests in mice, cocaine (3–60 mg/kg) dose-dependently increased activity counts and movement time across the entire 1 h test session. RTI-15, however, had little affect on activity counts and movement time from 10–30 mg/kg, and decreased these measures at 60 mg/kg, the highest dose tested. These results indicate that while changing the C-2 methyl ester of cocaine to a C-2 phenyl ester increases dopamine-transporter selectivity, it dissociates its locomotor activity effects from its discriminative stimulus effects suggesting that the underlying mechanisms mediating these effects are not identical.

Effects of the putative dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 on the discriminative stimulus properties of cocaine.

Recent evidence suggests that the putative dopamine (DA) autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232, share some neurochemical and behavioral effects with both psychostimulants and neuroleptics. The ability of (+)-AJ 76 and (+)-UH 232 to mimic or antagonize the stimulus effects of cocaine was investigated in rats trained to discriminate 5 mg/kg (N = 8) or 10 mg/kg (N = 8) of cocaine from saline in a two-lever, water-reinforced, drug discrimination task. In the cocaine (10 mg/kg) group, administration of (+)-AJ 76 (2.5-20 mg/kg) engendered only a partial substitution for cocaine (maximum 60% cocaine-lever responses). Given in combination with cocaine (10 mg/kg), (+)-AJ 76 (2.5-40 mg/kg) did not significantly attenuate the cocaine cue. A fixed dose of (+)-AJ 76 (2.5 or 10 mg/kg) plus various doses of cocaine (1.25-5 mg/kg) did not alter the cocaine dose-response curve. (+)-UH 232 (2-16 mg/kg) produced primarily saline-appropriate responding in rats trained to discriminate 5 mg/kg of cocaine and was unable to block the interoceptive cocaine state when given in combination with cocaine (5 mg/kg). (+)-UH 232 (2 or 8 mg/kg) also did not alter the cocaine dose-response curve. These results suggest that (+)-AJ 76 and (+)-UH 232 elicit only weak or no cocaine-like stimulus effects and, unlike neuroleptics, do not attenuate the cocaine cue.

Cocaine cue in pigeons: time course studies and generalization to structurally related compounds (norcocaine, WIN 35,428 and 35,065-2) and (+)-amphetamine.

1 Pigeons trained to discriminate between the presence or absence of effects induced by cocaine hydrochloride (5.6 mg/kg) were tested for generalization with norcocaine and two phenyltropane analogues (WIN 35,428 and WIN 35,065-2). Separate dose-effect curves were obtained at different intervals after the injections so that possible changes both in potency and duration of action could be evaluated.2 Results showed that all of these drugs fully generalized to cocaine. The order of potency was WIN 35,428 > norcocaine > WIN 35,065-2 > cocaine when tested either at 15 or 60 min after injection. The cocaine-like effects were strongest for all drugs when tested 15 min after injection as compared to the tests at the 60 min interval. The decay of the cocaine-like stimulus effects occurred at about the same rate.3 Apomorphine (0.3, 0.56 and 1 mg/kg), morphine (3 and 5.6 mg/kg), Delta(9)-tetrahydrocannabinôl (0.3 and 0.56 mg/kg), and lysergic acid diethylamide (LSD-25, 0.056 and 0.1 mg/kg) did not induce more than 30% cocaine appropriate responses. (+)-Amphetamine produced 73% and 85% cocaine appropriate responses depending on the injection-test interval used, 15 and 30 min respectively.4 The amphetamine homologue, para-hydroxyamphetamine (3.8 mg/kg) did not generalize to cocaine. Tests with 30 mg/kg of procaine produced 40% cocaine appropriate responses. Cocaine is effective also when administered by gavage into the opening of the proventriculus.5 The use of the drug discrimination technique for studying structure activity relationships of drugs is discussed.