Steven R. Goldberg

Discriminative stimulus effects of intravenous l-nicotine and nicotine analogs or metabolites in squirrel monkeys

Squirrel monkeys were trained to emit one response after IV administration of l-nicotine (0.4 or 0.2 μmol/kg) and a different response after IV administration of saline. After stable discriminative performances were established, subjects were tested with cumulative doses of l-nicotine (0.02–2.2 μmol/kg), d-nicotine (0.02–19.7 μmol/kg), l-nornicotine (0.2–12.0 μmol/kg), l-cotinine (56.8–567.5 μmol/kg), and dl-anabasine (0.6–19.7 μmol/kg). All of the drugs produced dose-related increases in the percentage of drug-appropriate responses emitted, from predominately saline-appropriate responses after low doses, to predominately drug-appropriate responses at the highest doses studied. Relative potency comparisons indicated that l-nicotine was 28 times more potent than d-nicotine, 29 times more potent than l-nornicotine, and approximately 2000 times more potent than l-cotinine. Each of the drugs also produced decreases in rates of responding, with potency order similar to that obtained for the discriminative effects. The effects of l-cotinine may be attributed to trace amounts of l-nicotine, which existed within the l-cotinine. The effects of dl-anabasine were lethal in one subject and were consequently not studied in the other subjects.

Methohexital and cocaine self-administration under fixed-ratio and second-order schedules

Behavior maintained by either cocaine or methohexital was compared under two different schedules of drug delivery. Under a fixed-ratio 10 schedule, each tenth response produced an injection and responding was characterized by pauses alternating with high rates that were sustained until the drug injection. Under a second-order schedule, each tenth response produced a brief visual stimulus, and the first sequence of ten responses emitted after the lapse of a ten-minute interval produced the stimulus and the drug injection. Responding under the second-order schedule was characterized by an overall positive acceleration in responding that consisted of fixed-ratio response patterns terminating in the presentation of a brief stimulus. Under either schedule, each drug maintained maximal rates of responding at intermediate doses. In most respects, rates and patterns of responding depended more on the schedule of drug delivery than on the particular drug maintaining responding.

Interaction of haloperidol and SCH 23390 with cocaine and dopamine receptor subtype-selective agonists on schedule-controlled behavior of squirrel monkeys

Involvement of D1 and D2 dopamine receptors in the effects of cocaine on schedule-controlled behavior was evaluated in squirrel monkeys responding under a multiple fixed-interval 5-min, fixed-ratio 10 schedule (mult FI FR) of food delivery. Cocaine and the D2 agonist quinpirole increased responding under the FI at certain doses and disrupted the temporal patterning of behavior. Higher doses of these drugs decreased responding. In contrast, the D1 agonist SKF 38393 was devoid of behavioral activity up to 10 mg/kg where response suppression was obtained without significant modification of the temporal distribution of responding. The D2 antagonist haloperidol (0.001–0.03 mg/kg) did not alter the behavioral effects of cocaine up to doses that had pronounced behavioral effects on their own. However, haloperidol attenuated the behavioral effects of quinpirole. In contrast, the D1 antagonist SCH 23390 partially attenuated the response rate-suppressant effects of cocaine without blocking cocaine-induced disruptions of temporal response patterning. SCH 23390 did not antagonize the behavioral effects of SKF 38393. These results suggest that independent stimulation of either D1 or D2 receptors alone does not play a major role in the effects of cocaine on schedule-controlled behavior of squirrel monkeys.

Stereoselective behavioral effects of N6-phenylisopropyl-adenosine and antagonism by caffeine

Effects of the (-)- and (+)-isomers of N6-(phenylisopropyl)-adenosine (PIA) were studied in rats trained to respond under fixed-interval and fixed-ratio schedules of food reinforcement. Both isomers of PIA decreased response rates; however, the (-)-isomer decreased response rates at doses as low as 0.1 μM/kg and was 100–300 times more potent than the (+)-isomer. The potency differences suggest that the effects observed were due to actions at A1-adenosine receptors. Caffeine, an adenosine-receptor antagonist, when administered alone in doses of 10–154 μM/kg, increased response rates under the fixed-interval schedule and did not affect rates of responding under the fixed-ratio schedule. Higher doses decreased response rates under both schedules. Caffeine shifted the (-)-PIA dose-effect curve to the right. At a low dose of caffeine (25.7 μM/kg), which alone modestly increased response rates under the 5-min fixed-interval schedule, the disruptions in rates and patterns of responding produced by (-)-PIA were restored to resemble control performances. The higher dose of caffeine (77.2 μM/kg), which alone produced larger increases in rates of responding under the fixed-interval schedule, restored overall response rates to control levels when administered in combination with (-)-PIA. However, patterns of responding after the combination of doses remained disrupted. These effects suggest that some of the behavioral effects of caffeine are a result of mechanisms other than adenosine-receptor blockade.

Discriminative stimulus effects of intravenous nicotine in squirrel monkeys

Three squirrel monkeys were trained to emit one response after IV administration of nicotine (0.1 or 0.18 mg/kg depending on the subject) and a different response after IV administration of saline. Subjects emitted nicotine-appropriate responses with substitutions of higher doses, but only emitted saline-appropriate responses after substitutions of lower doses. Discrimination performance was then maintained at 0.1 mg/kg of nicotine in all subjects. Neither morphine nor cocaine substituted for the effects of nicotine in any subjects across a range of doses up to those that suppressed responding. Ethyl-beta-carboline-3-carboxylate, an inverse agonist at the benzodiazepine receptor, substituted or partially substituted for nicotine in both subjects in which it was studied.

Evaluation of deprenyl for cocaine-like discriminative stimulus effects in rats

The antiparkinsonian agent l-deprenyl is metabolized to l-methamphetamine and l-amphetamine and, at higher doses, can facilitate the release and inhibit the reuptake of dopamine. Since l-deprenyl can affect dopamine release and reuptake it was important to evaluate it for cocaine-like discriminative stimulus effects. Male Fisher rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-lever, operant-conditioning procedure using schedules of food-delivery or stimulus-shock termination. l-Deprenyl (17 mg/kg, i.p.) produced full generalization to cocaine under the food-delivery schedule but this or higher doses produced only partial generalization to cocaine under the stimulus-shock termination schedule. d-Deprenyl produced full generalization to cocaine under both schedules at i.p. doses of 5.6 to 10 mg/kg. These cocaine-like discriminative stimulus effects occur only at doses that are well above the clinically relevant dose range for l-deprenyl.

Acquisition of a nose-poke response in rats as an operant

Acquisition of a nose-poke operant response was investigated in rats. The baseline level of this response was high and acquisition with food reinforcement occurred rapidly, particularly when compared with a leverpress operant response. A variety of control procedures clearly indicated that this response was acquired due to the contingency between nose pokes and food reinforcement.The response was also sensitive to manipulations of delay of reinforcement and food-deprivation level. Acquisition was slowed with longer delays of reinforcement and with decreases in deprivation level. Therefore, the nose-poke response appears to be particularly useful for the study of the acquisition of operant responses.

Effects of morphine, ethylketocyclazocine,N-allylnormetazocine and naloxone on locomotor activity in the rabbit

Locomotor activity was studied in the rabbit following injections of morphine, ethylketocyclazocine andN-allylnormetazocine. All three drugs produced only depression of activity. The opioid antagonist naloxone antagonized the effects of both morphine and ethylketocyclazocine. Naloxone (0.1 mg/kg) did not antagonize the effects ofN-allylnormetazocine. Naloxone alone depressed locomotor activity at doses above 0.3 mg/kg. This effect of naloxone was partially antagonized by 0.1 mg/kg ethylketocyclazocine, but not by 0.1 mg/kg morphine. The GABA agonist muscimol (0.1 and 1.0 mg/kg) also did not antagonize the effect of naloxone on locomotor activity. Finally, amphetamine did not produce a great deal of locomotor activation in the rabbit, which may indicate that increasing activity in the rabbit by drug intervention may be inherently difficult. These results indicate that the opioids have effects in the rabbit that are clearly different from those observed in rodents, where morphine andN-allylnormetazocine have been reported to produce locomotor activation, and naloxone typically has little effect. In addition, the effects of the opioids on locomotor activity were clearly distinguishable from their effects on learning in the rabbit. While morphine and ethylketocyclazocine were approximately equipotent in depressing locomotor activity, morphine is much less potent than ethylketocyclazocine in retarding acquisition of the classically conditioned nictitating membrane response in the rabbit.

Effects of adenosine analogs alone and in combination with caffeine in the squirrel monkey

Effects of the adenosine analogs R-N6-phenylisopropyl-adenosine (R-PIA) and 5-N-ethylcarboxamidoadenosine (NECA), alone and in combination with caffeine, were studied in squirrel monkeys trained to respond under multiple fixed-interval fixed-ratio schedules of reinforcement. Both drugs produced dose-related decreases in rates of responding, with little difference between effects in the two components. NECA was about ten times more potent than R-PIA in producing these effects, the order of potency suggests that these effects may be mediated by actions at A2-adenosine receptors. Effects of either drug were antagonized by caffeine. Caffeine when administered alone increased rates of responding. The increases in response rates produced by caffeine were altered by R-PIA only at doses of R-PIA that alone decreased response rates. Effects of caffeine were either enhanced or attenuated by doses of NECA that were inactive when administered alone. These results do not support the notion that increases in rates of behavior, e.g., psychomotor-stimulant effects, produced by caffeine are due to its antagonist actions at adenosine receptors.

Cardiovascular effects of cocaine: underlying mechanisms

At the 1993 annual meeting of the College on Problems of Drug Dependence in Toronto Canada, a symposium entitled ‘Cardiovascular effects of cocaine: Underlying mechanisms’ was presented. The purpose of this symposium was to present a wide range of state-ofthe-art research on the cardiovascular effects of cocaine, including both animal and human studies. The timeliness of this symposium is supported by the continued upward trends in the mentions for cocaine in the Drug Abuse Warning Network (DAWN) surveys of both emergency rooms and medical examiners. Increases in cocaine mentions have occurred in both of these surveys in each of the last two years for which data are available (1991- 1992). Undoubtedly, the cardiovascular effects of cocaine played some role in these increasing trends. The papers that follow grew out of four presentations at that symposium. The paper by Gillis et al. (1995) reviews their extensive animal research on locus of action for cocaine in producing its sympathetic nervous system mediated effects. They conclude that rather than having a central nervous system origin, the sympathetic mediated cardiovascular effects are primarily due to actions of cocaine in the periphery. While contradicted by other studies using more indirect measures of sympathetic nervous system function which have pointed to a central origin for the cardiovascular effects of cocaine (e.g., Wilkerson, 1988), the techniques used by Gillis et al. to directly measure sympathetic nerve activity presents a strong case for a peripheral site of action for cocaine. The research reviewed in the paper by Schindler et al. (1995) utilized more traditional techniques to explore the pharmacological basis for the cardiovascular effects of co