Robert S. Mansbach

Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine

Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens, olfactory tubercles and anterior striatum reversed the disruption of PPI caused by amphetamine (AMPH), but did not disrupt AMPH potentiation of ASR baseline. These findings strongly suggest that increased mesolimbic DA activity is one substrate of the AMPH-induced disruption of PPI; in contrast, AMPH potentiation of baseline startle amplitude may be independent of mesolimbic DA activation.

Parametric determinants in pre-stimulus modification of acoustic startle: interaction with ketamine

Prepulse inhibition of the acoustic startle response is a form of reflex modification known to be sensitive to drugs and to subtle procedural manipulations. The present study examined the importance of prepulse length and prepulse-pulse interval in the expression of prepulse inhibition and its modification by the noncompetitive N-methyl-d-aspartate antagonist, ketamine. In contrast to a previous report, ketamine disrupted prepulse inhibition at doses of 5.6 and 10 mg/kg when its short time course was taken into consideration. In a second experiment, the amount of prepulse inhibition was found to be directly related to prepulse length, with prepulse inhibition produced by shorter prepulse durations slightly more sensitive to disruption by ketamine. A third experiment examined prepulse-pulse time intervals (30–2000 ms). While prepulse inhibition produced by prepulses occurring 60–500 ms before the startle stimulus was disrupted by 10 mg/kg of ketamine, prepulses preceding the startle stimulus by only 30 ms produced either no effect or slight prepulse facilitation under control conditions, and significant prepulse facilitation when ketamine was administered. A fourth experiment examined the time course of prestimulus modification by continuous lead stimuli, ranging in onset from 15 to 75 ms before the startle stimulus. Prepulse facilitation, when observed, tended to occur in earlier portions of the session and was enhanced by ketamine. These results suggest that prestimulus modification of the startle reflex has important parametric and experiential determinants that may influence the effects of drugs. Some of these temporal determinants may have relevance to sensorimotor function in schizophrenia.

Failure of Delta(9)-tetrahydrocannabinol and CP 55,940 to maintain intravenous self-administration under a fixed-interval schedule in rhesus monkeys.

The lack of procedures which can unequivocally demonstrate cannabinoid self-administration in animals has been an obstacle to the study of the neural basis for the reinforcing effects of this drug class. Because Δ9-tetrahydroeannabinol (Δ9-THC) produces a relatively slow-onset, long-lasting behavioral effect, a self-administration procedure with widely spaced drug deliveries was evaluated as an alternative to fixed-ratio schedules which typically require frequent, closely spaced injections to demonstrate reinforcing effects. Three adult male rhesus monkeys were surgically implanted with intravenous catheters and trained to self-administer phencyclidine (PCF) under a 10 min fixed-interval schedule of reinforcement. Three injections were available each day, separated by 2 h periods during which responding had no programmed consequences. In an attempt to link the effect of the drug with the response which produced it, each 20 s injection was paired with a red light which remained illuminated for 10 min. PCP (100 μg/kg/injection) maintained steady rates of responding during each availability period, ranging from approximately 0.2 to 0.7 responses/s. During 7 day substitution periods, Δ9-THC (17–100 μg/kg/injection) maintained low rates of responding which occasionally surpassed those during vehicle substitutions, but fell far below rates maintained by PCP. Substitution tests with the potent Δ9-THC analog CP 55,940 also resulted in low rates of responding. These results demonstrate that Δ9-THC is a poor reinforcer in animals, even under conditions where some of its unfavourable biodispositional properties are taken into consideration.

Cocaethylene inhibits dopamine uptake and produces cocaine-like actions in drug discrimination studies

Recent studies have demonstrated the presence of a novel cocaine metabolite, cocaethylene, present in post-mortem tissue and blood samples from accident victims who tested positive for both cocaine and ethanol (Hearn et al., 1991). We report in this study that cocaethylene potently inhibits presynaptic dopamine uptake in vitro and effectively substitutes for cocaine in a drug discrimination protocol in rats

Effects of NMDA receptor ligands on sensorimotor gating in the rat.

Pre-pulse inhibition of the acoustic startle response is a model of reflex modification which is thought to reflect sensorimotor gating mechanisms and is sensitive to disruption by non-competitive N-methyl-D-aspartate (NMDA) antagonists such as phencyclidine. The effects of two competitive antagonists, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) (3-30 mg/kg) and cis-4-phosphonomethyl-2-piperidine-carboxylate (CGS 19755) (1-10 mg/kg), the non-competitive NMDA antagonist dizocilpine (0.5 mg/kg), and NMDA itself (1-30 mg/kg) were studied in the pre-pulse inhibition model. Rats were exposed to sessions in which 122 dB[A] startle-eliciting stimuli were presented either alone or preceded by weak 80 dB[A] prepulses with durations of 3, 10 and 30 ms, which under control conditions reduced the magnitude of the startle response. Neither NPC 12626 nor CGS 19755 produced disruption of pre-pulse inhibition as normally observed with phencyclidine-like drugs. NMDA also did not affect pre-pulse inhibition. As in previous experiments, dizocilpine produced a significant disruption of pre-pulse inhibition at all pre-pulse durations. These data suggest that actions at the phencyclidine binding site, and not the NMDA site, are responsible for the disruption of pre-pulse inhibition by phencyclidine-like drugs, and support reports of differences in the behavioral effects of competitive and noncompetitive NMDA antagonists. The effects of phencyclidine-like drugs on pre-pulse inhibition may represent a useful pharmacological model of schizophrenia-like cognitive deficits.

Effects of mazindol on behavior maintained or occasioned by cocaine

The effects of mazindol, cocaine and D-amphetamine were studied in rhesus monkeys trained to self-administer cocaine, and in rats and squirrel monkeys trained to discriminate cocaine from saline. Non-contingent intravenous drug injections were administered to monkeys responding under a session consisting of a 5-min period during which lever-pressing produced food reinforcement and a 60-min session in which responding produced i.v. cocaine infusions (10 or 33 micrograms/kg per infusion). Acute i.v. injections of cocaine (0.1-1.7 mg/kg), D-amphetamine (0.1-1 mg/kg) and the dopamine re-uptake inhibitor mazindol (0.03-0.56 mg/kg) given 5 min before the session decreased self-administration of cocaine, but also decreased rates of behavior maintained by the presentation of food. In both rats and squirrel monkeys trained to discriminate cocaine from saline in a two-lever, food-maintained procedure, mazindol, cocaine and D-amphetamine substituted for cocaine in a dose-related manner. Despite a lack of selectivity to decrease cocaine self-administration as compared to behavior maintained by food, the present data provide some rationale for further consideration of mazindol as a potential pharmacotherapy for stimulant abuse, due to its relatively low abuse liability and cocaine-like discriminative stimulus effects.

Pharmacological specificity of the phencyclidine discriminative stimulus in rats

The discriminative stimulus effects of phencyclidine (PCP), pentobarbital and the competitive N-methyl-D-aspartate antagonist 3-([+/-]-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) were examined in rats trained to discriminate PCP from saline under a 2-lever, food-maintained operant schedule. Dose-response curves were obtained for all three drugs at a PCP training dose of 1.25 mg/kg; subsequently, rats were retrained to discriminate either 0.56 or 3.0 mg/kg PCP. The dose-response to PCP was not substantially changed by raising or lowering the training dose. However, doses of pentobarbital and CPP produced augmented levels of substitution when the training dose was lowered and decreased substitution when it was raised. The changes in PCP training dose were, therefore, effective in either diminishing or amplifying the pharmacological specificity of the PCP stimulus. Under conditions where specificity was high (high training dose), neither pentobarbital (0.1-17 mg/kg) nor CPP (1-17 mg/kg) produced appreciable PCP-like stimulus effects, supporting evidence that competitive NMDA antagonists may be no more PCP-like than are barbiturates. These data provide additional evidence for differences in the behavioral effects of noncompetitive and competitive NMDA antagonists.

The acoustic startle response as a measure of behavioral dependence in rats

A series of experiments was conducted to assess the sensitivity of the acoustic startle response to chronic morphine administration and naloxone-precipitated withdrawal. Rats were implanted with two subcutaneous pellets containing either 75 mg each of morphine or containing only placebo. In experiment 1, withdrawal induced by 0.05–0.2 mg/kg naloxone dose-dependently decreased the magnitude of the startle response. Physical dependence was confirmed by a naloxone-induced acute weight loss seen in morphine-implanted rats, but naloxone had no effect on startle or body weight in nondependent animals. In experiment 2, a modified procedure with fewer trials per session and fewer test days was employed. Naloxone (0.2 mg/kg) given 4–5 days after implantation induced large startle-response decreases in morphine-dependent rats while having no effect in placebo-implanted rats. Post-naloxone saline tests revealed no significant differences in startle between morphine and placebo groups. Startle scores were significantly higher in morphine-implanted rats than in placebo rats during a saline test given 3 days following pellet implantation. In a separate group of animals, however, acute IP injections of morphine from 0.3–10 mg/kg had no significant effect on startle amplitude. The effect of repeated pairings of withdrawal with the startle environment was assessed in experiment 3. Morphine-dependent rats startled significantly less if naloxone injections were given before the startle session than if they were administered 4 h later. Conditioned withdrawal effects, expressed during a final test session when all rats received saline, were observed for the body-weight measure but not for the startle response. These results suggest that the acoustic startle response may be a useful objective measure in evaluating physical dependence produced by substances of abuse.

The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys.

Development of N-methyl-D-aspartate (NMDA) antagonists for a variety of disorders has been hindered by their production of phencyclidine (PCP)-like psychological effects and abuse potential. There is, however, evidence to suggest that this problem might be mitigated by targeting NMDA receptors subtypes, in particular, those containing the NR2B subunit. To further test this hypothesis, the NR2B selective antagonist CP-101 606 (traxoprodil) was evaluated in two animal models: drug discrimination, a model of the subjective effects of drugs in humans, and self-administration, which evaluates the reinforcing properties of the drug. In the first study, CP-101 606(3–300 μg/kg/infusion) was tested for intravenous self-administration in rhesus monkeys experienced in PCP (5.6 μg/kg/infusion, intravenously) self-administration. In the second study, CP-101 606 was tested for production of PCP-like discriminative stimulus effects in rats (3–56 mg/kg, intraperitoneally) and rhesus monkeys (0.3–5.6 mg/kg intravenously). Evidence was obtained for reinforcing effects of at least one dose of CP-101 606 in all four monkeys. In rats, CP-101 606 produced more than 80% mean PCP-lever selection (2.0 mg/kg, intraperitoneally) but, unlike PCP itself, the dose producing the highest level of substitution was accompanied by more than 50% suppression of response rates. In monkeys, CP-101 606 produced more than 90% PCP-lever selection (0.1 mg/kg intramuscularly) in three of four animals at doses that did not significantly decrease rates of responding. The data show that CP-101 606 has some PCP-like discriminative stimulus effects in rats and monkeys and functions as a positive reinforcer in monkeys. These results suggest that inhibition of NR2B subunit containing NMDA receptors plays a role in the production of the subjective effects and abuse potential associated with many subtype-nonselective NMDA receptor antagonists such as PCP.

Potent substituted-3β-phenyltropane analogs of cocaine have cocaine-like discriminative stimulus effects

Two novel phenyltropane analogs of cocaine, 3 beta-(4-chlorophenyl) tropane-2 beta-carboxylic acid methyl ester (RTI-COC-31) and 3 beta-(4-methylphenyl) tropane-2 beta-carboxylic acid methyl ester (RTI-COC-32), were evaluated for cocaine-like discriminative stimulus effects in rats. Two groups of rats were trained to discriminate 10 mg/kg cocaine from saline using a standard 2-lever discrimination procedure with correct-lever responding reinforced under a fixed-ratio 20 schedule of food reinforcement. One group of rats was used to evaluate RTI-COC-31 and the unsubstituted-3 beta-phenyltropane reference compound WIN 35,065-2 in substitution tests. Another group of rats was used to evaluate RTI-COC-32. For purposes of comparison, a cocaine dose-effect curve was also determined in each group. Both RTI-COC-31 and RTI-COC-32, as well as WIN 35,065-2, substituted completely for cocaine. RTI-COC-31 was 26.8-fold and RTI-COC-32 was 6-fold more potent than cocaine for producing cocaine-lever responding. The potent cocaine-like effects of the RTI analogs in vivo correspond with their high affinities for a cocaine recognition site on the dopamine transporter, providing further evidence that this site may mediate behavioral effects of cocaine relevant to its abuse.