Harlan E. Shannon

Ro 15-1788 antagonizes the discriminative stimulus effects of diazepam in rats but not similar effects of pentobarbital

The benzodiazepine antagonist properties of Ro 15-1788 were evaluated in rats trained to discriminate between saline and either 1.0 mg/kg of diazepam or 10 mg/kg of pentobarbital in a two-choice discrete-trial shock avoidance procedure. When administered alone, 1.0 mg/kg of diazepam and 10 mg/kg of pentobarbital produced comparable amounts of drug-appropriate responding (less than 84%), whether rats were trained to discriminate between diazepam or pentobarbital and saline. Ro 15-1788 (3-32 mg/kg, p.o.), administered 10 min before diazepam or pentobarbital, produced a dose-related blockade of the discriminative effects of diazepam in both groups of rats, but was completely ineffective in blocking the discriminative effects of pentobarbital. The dose-effect curve for the discriminative effects of diazepam was shifted to the right in a parallel fashion 3- and 13-fold by 10 and 32 mg/kg of Ro 15-1788, respectively, indicating that Ro 15-1788 acts as a surmountable, competitive antagonist of diazepam. When administered alone, Ro 15-1788 (32-100 mg/kg, p.o.) produced primarily saline-appropriate responding, although 100 mg/kg of Ro 15-1788 produced drug-appropriate responding in one out of eight rats. When administered orally 30 min after diazepam, Ro 15-1788 (32 mg/kg) completely reversed within 10 min the discriminative effects of diazepam. The blockade of diazepams discriminative effects by 32 mg/kg of Ro 15-1788 appeared to last at least as long (approximately 2 hr) as the effects of diazepam alone.

Effects of the combination of tripelennamine and Pentazocine at the behavioral and molecular levels

The purpose of the present experiments was to determine if the antihistamine tripelennamine potentiates the morphine-like effects of the narcotic-antagonist analgesic pentazocine at the behavioral level or the molecular level or both. At the behavioral level, the effects of pentazocine were determined alone and in combination with tripelennamine in rats trained to discriminate between saline and either morphine or the psychotomimetic narcotic derivative SKF 10,047. The interaction between pentazocine and tripelennamine were also evaluated in the guinea-pig ileum preparation and in the [3H]-naloxone opiate receptor binding assay. Tripelennamine significantly enhanced the morphine-like discriminative stimulus effects of pentazocine and markedly reduced the SKF 10,047-like stimulus effects of pentazocine. Naloxone antagonized the morphine-like effects of pentazocine plus tripelennamine. Pentazocine significantly constricted pupils in the rat, an effect which was additive with the mydriatic effects of tripelennamine. Inhibition of the twitch-height of the electrically stimulated guinea-pig ileum by pentazocine was not affected by tripelennamine. Further, tripelennamine did not modify the Ke for naloxone in antagonizing pentazocine. Inhibition of specific [3H]-naloxone binding by pentazocine was also not affected by tripelennamine. These results are consistent with the hypothesis that the potentiation of the morphine-like effects of pentazocine by tripelennamine which was observed behaviorally was not due to molecular interactions at the morphine receptor. At least a part of this interaction may be attributable to tripelennamine decreasing the psychotomimetic actions of pentazocine.

Phencyclidine-like discriminative stimuli of (+)- and (-)-N-allylnormetazocine in rats.

The phencyclidine(PCP)-like discriminative stimulus properties of the (+)- and (-)-isomers of the prototypic sigma-receptor agonist N-allylnormetazocine (NANM) were evaluated in rats trained to discriminate between saline and 3.0 mg/kg of PCP. The rats were trained under a FR5 schedule of stimulus-shock termination. Both (+)- and (-)-NANM produced PCP-like stimuli and were approximately one-half and one-sixth, respectively, as potent as PCP. The two isomers were equipotent in decreasing response rates. None of the effects of either (+)- or (-)-NANM were antagonized by naloxone. These results demonstrate that the PCP-like effects of NANM exhibit stereoselectivity but not stereospecificity and are additional evidence that the common actions of PCP and NANM are mediated by sigma-receptors.

β-carboline-3-carboxylate-t-butyl ester: A selective BZ1 benzodiazepine receptor antagonist

The effectiveness of beta-carboline-3-carboxylate-t-butyl ester (beta CCtB) in antagonizing the anticonvulsant, ataxic and antipunishment effects of diazepam were evaluated. In mice, beta CCtB at doses of 3 and 10 mg/kg produced a dose-related antagonism of the anticonvulsant effects of diazepam against pentylenetetrazole (80 mg/kg). A dose of 30 mg/kg of beta CCtB did not produce a further shift in the diazepam dose-effect curve, apparently because beta CCtB failed to block the muscle-relaxant effects of diazepam. Further, beta CCtB (30 mg/kg) failed to antagonize the ataxic effects of diazepam in an inverted screen test. Rats responded under a multiple schedule where in one component every twentieth response (FR20) resulted in water presentation (unpunished component) and in another component every twentieth response (FR20) resulted in both shock and water presentation (punished component). Diazepam p.o. (0.1 to 10 mg/kg) first increased and then decreased rates in the punished component but only decreased rates in the unpunished component. beta CCtB had no effect on response rates when administered alone, but antagonized the rate-increasing effects of diazepam in the punished component. beta CCtB did not alter the rate-decreasing effects of diazepam in either component. Thus, beta CCtB selectively antagonized the effects of diazepam on punished behavior as well as the anticonvulsant effects of diazepam, but beta CCtB failed to antagonize the rate-decreasing and ataxic effects of diazepam. These results are consistent with the interpretation that beta CCtB is a selective BZ1 benzodiazepine receptor antagonist.

Discriminative effects of ethylketazocine in the rat: Stereospecificity and antagonism by naloxone

Male F344 rats were trained to discriminate between saline and d,l-ethylketazocine (EKC) in a two-choice discrete-trial avoidance task and tested with the l- and d-isomers of EKC, cyclazocine, and SKF-10,047. The effectiveness of naloxone in antagonizing the discriminative effects of d,l-EKC was also determined. Each of the l-isomers tested produced dose-related stimulus control of behavior similar to that produced by d,l-EKC. l-EKC was the most potent isomer tested, being approximately twice as potent as d,l-EKC. In contrast, d-EKC was completely devoid of activity at 300-fold higher doses. l-Cyclazocine and l-SKF-10,047 were approximately 4- and 30-fold less potent, respectively, than d,l-EKC. Although both d-cyclazocine and d-SKF-10,047 produced some drug-appropriate responding, both compounds were less potent and less efficacious than their respective l-isomers and both were significantly less efficacious than d,l-EKC. Increasing doses of naloxone (0.1 - 1.0 mg/kg) produced parallel shifts to the right in the d,l-EKC dose-effect curve. These results suggest that the discriminative effects of EKC are mediated by a stereospecific naloxone-sensitive receptor.

Lack of antiemetic effects of Δ9-tetrahydrocannabinol in apomorphine-induced emesis in the dog

Abstract Clinical studies have suggested that Δ 9 -tetrahydrocannabinol (THC) may be a clinically useful antiemetic. However, the ability of THC to decrease experimentally induced emesis in animals has not been extensively studied. The present study compares the antiemetic effects of THC with chlorpromazine on apomorphine-induced emesis in the dog. THC, chlorpromazine, THC vehicle, or saline was administered i.v. 30 min prior to an i.v. infusion of apomorphine; apomorphine was infused until emesis occurred. THC had no effect on the dose of apomorphine required to produce emesis, whereas chlorpromazine increased this dose approximately 75%. Moreover, THC nearly doubled the time from the first to the last occurrence of emesis relative to control values, while chlorpromazine greatly reduced this value. In addition, THC had no effect on the stimulation of pulse rate produced by apomorphine; chlorpromazine potentiated this effect, probably through indirect mechanisms. These findings demonstrate that THC is not an antagonist of the emetic agent apomorphine in the dog.

pharmacologic and reinforcing properties of phencyclidine and the enantiomers of N-allylnormetazocine in the dog ☆

Experiments were conducted to evaluate the degree of phencyclidine (PCP)-like activity associated with the dextro and levo enantiomers of the sigma agonist N-allylnormetazocine (NANM). In chronic spinal dogs, d- and l-NANM generally produced similar physiologic and gross animal behavior effects which included miosis, tachycardia, hyperthermia, increased secretory activity (lacrimation, rhinorrhea and salivation), nystagmus and stereotyped head movements. For these effects, d- and l-NANM were generally equal in potency and both were about 1/10th as potent as PCP. However, the NANM enantiomers could be differentiated on the basis of their effects on nociceptive reflexes. Comparisons of dose-response curves and efficacies demonstrated that d-NANM was more similar to PCP in its effectiveness in depressing the flexor and skin twitch reflexes than was l-NANM. In addition, naltrexone selectively antagonized or reduced only the effects of l-NANM on reflex activity. In intact dogs, d-NANM and PCP, but not l-NANM maintained self-administration behavior under FR15 or FI900 (FR10:S) schedules of reinforcement. This represented the most stereospecific action of the NANM enantiomers. Additionally, l-NANM failed to maintain self-administration behavior, even following pretreatment with naltrexone, thus suggesting that the opiate activity of l-NANM was not responsible for its lack of reinforcing efficacy. Taken together, the data demonstrate that both d- and l-NANM have PCP-like properties, but d-NANM is pharmacologically more equivalent than l-NANM to PCP and l-NANM has additional activity which is not PCP-like.

MDA and DOM: substituted amphetamines that do not produce amphetamine-like discriminative stimuli in the rat.

Abstract3,4-Methylenedioxyamphetamine (MDA) and 2,5-dimethoxy-4-methylamphetamine (DOM) are amphetamine congeners that produce both amphetamine-like and LSD-like effects. To evaluate whether MDA and DOM should be classed with amphetamine, their capacity to produce amphetamine-like discriminative stimuli was assessed. Rats were trained to discriminate between saline and 1.0 mg/kg d-amphetamine in a two choice, discrete trial shock avoidance paradigm. Neither MDA nor DOM produced any amphetamine-appropriate responding when tested over a 30-fold dose range. The specificity of the procedure to detect amphetamine-like effects was demonstrated by the failure of LSD to produce any amphetamine-appropriate responding. These results suggest that neither MDA nor DOM should be classed as amphetamine-like agents.

Pyrazoloquinoline benzodiazepine receptor ligands: Effects on schedule-controlled behavior in dogs

The effects of diazepam and the pyrazoloquinoline benzodiazepine receptor ligands CGS8216, CGS9896, and CGS9895 on schedule-controlled responding were studied in dogs. Responding was maintained under a multiple fixed-interval (FI) 5-min fixed-ratio (FR) 30 response schedule of food presentation. Diazepam (PO) produced dose-related decreases in response rates under FR component. Under the FI, rates first increased and then decreased with increasing doses of diazepam. Diazepam also produced a dose-related disruption of the temporal pattern of responding under the FI as measured by decreases in quarter-life values. CGS8216 IV produced dose-related decreases in response rates under both components. The highest oral dose of CGS8216 also decreased rates in both components. CGS8216 was approximately 100 times more potent by the IV route as compared to the oral route. CGS9896 IV had no significant effect on responding under either component of the multiple schedule. However, with increasing doses of CGS9896 PO, response rates under both components first decreased and then returned to control values. CGS9895 PO was without significant effect on responding. When CGS8216 was administered concomitantly with graded doses of diazepam, the former drug blocked the rate-decreasing effects of diazepam under the FR component, but not the rate-increasing effects of diazepam under the FI. The present results demonstrate that although these three pyrazoloquinolines are benzodiazepine receptor ligands, they do not exhibit diazepam-like effects on schedule-controlled behavior.

Behavioral effects of CGS 8216 alone, and in combination with diazepam and pentobarbital in dogs

Beagle dogs (N = 3) responded under a multiple fixed-interval (FI) 300 sec, fixed-ratio (FR) 30 schedule of food presentation. The pyrazoloquinoline derivative CGS 8216, given either intravenously (0.01-3.0 mg/kg) or orally (0.1-30.0 mg/kg) had little effect on either the rate or temporal pattern of responding during either component. Both diazepam (0.3 to 17.5 mg/kg, PO) and pentobarbital (0.1-17.5 mg/kg, PO) produced qualitatively similar effects on behavior. Rates of responding during the FI components first increased, then decreased with increasing doses; both drugs produced only dose-related decreases in the rate of responding during the FR components. CGS 8216 antagonized some of the behavioral effects of diazepam; FI and FR response rates returned to baseline, however the effects of diazepam on quarter-life values were not appreciably altered by CGS 8216. The effects of pentobarbital on schedule-controlled responding were not antagonized by CGS 8216. These results indicate CGS 8216 is a selective benzodiazepine antagonist that does not produce benzodiazepine-like behavioral effects.