2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and Ataxia

This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.

Topics: Animals; Ataxia; Dizocilpine Maleate; Dose-Response Relationship, Drug; Eating; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory Disorders; Nootropic Agents; Phenazocine; Piperazines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

Although behavioural studies of the effects of (+/-)-N-allylnormetazocine ((+)-SKF10047) and ketamine hydrochloride have been conducted in many species, there are no data available on their effects in guinea pig. The aim of the present study was to provide an analysis of the effects of these drugs on stereotyped behaviour, locomotor activity, ataxia and righting reflex latency in guinea pigs. (+)-SKF10047 did not produce significant stereotyped behaviour nor locomotor hyperactivity at any of the doses tested (2.5-10.0 mg/kg, i.p). While righting reflex latency was not significantly affected, significant ataxia was produced at the highest (+)-SKF10047 dose used (i.e., 10 mg/kg). The results for ketamine hydrochloride were similar. Neither significant stereotyped behaviour nor locomotor hyperactivity were produced by ketamine at either dose used (12.5 and 25.0 mg/kg, i.p). However, at the lower dose (i.e., 12.5 mg/kg), significant ataxia and a significant impairment of the righting reflex were produced.

Topics: Animals; Ataxia; Guinea Pigs; Ketamine; Motor Activity; Phenazocine; Reaction Time; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Stereotyped Behavior

We have compared the ability of phencyclidine (PCP)-like or sigma ligands to induce psychomotor effects in primates. In squirrel monkeys, administration of MK-801 (0.001-0.1 mg/kg), PCP (0.03-0.3 mg/kg), (+)-SKF10047 (0.001-3.0 mg/kg) or (-)-SKF10047 (0.1-10 mg/kg) induced ataxia, head weaving and bradykinesia. In contrast, treatment with the selective sigma ligand (+)-pentazocine using doses up to 20 mg/kg failed to induce any overt behaviours. The order of potency for induction of these behaviours was: MK-801 greater than PCP greater than (+)-SKF10047 greater than (-)-SKF10047 much greater than (+)-pentazocine. In rhesus monkeys treatment with MK-801 (0.01-0.04 mg/kg), PCP (0.05-0.2 mg/kg), (+)-SKF10047 (0.75-3.0 mg/kg) or (+)-pentazocine (1-10 mg/kg), disrupted performance of a spatial delayed response task. The potency to induce cognitive disruption was positively correlated with affinity for [3H]MK-801, but not [3H](+)-SKF10047, binding sites in vitro. These findings indicate that the psychomotor and cognitive effects of PCP-like and sigma ligands in primates are mediated through interactions at NMDA, not sigma, receptors.

Topics: Animals; Ataxia; Cognition; Dizocilpine Maleate; Macaca mulatta; Male; Pentazocine; Phenazocine; Phencyclidine; Psychomotor Performance; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, sigma; Saimiri; Space Perception

A series of 1,2,3,4-tetrahydroisoquinolines, tetrahydrothieno[2,3-c]pyridines, and related compounds were evaluated for their ability to inhibit binding of [3H]-1-[1-(2-thienyl)piperidine and [3H]-N-allylnormetazocine to phencyclidine (PCP) and sigma receptors, respectively. A representative series of compounds was evaluated in behavioral assays to determine the ability of the compounds to induce PCP-like stereotyped behavior and ataxia. All of the compounds caused stereotyped behavior and ataxia, indicating their agonist actions at the PCP site.

Topics: Animals; Ataxia; Behavior, Animal; Chemical Phenomena; Chemistry; Isoquinolines; Male; Molecular Structure; Phenazocine; Phencyclidine; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Phencyclidine; Stereotyped Behavior; Structure-Activity Relationship; Tetrahydroisoquinolines

Metaphit, a derivative of phencyclidine (PCP), binds irreversibly to PCP sites and appears to act as an antagonist of PCP under some conditions and as a PCP-like agonist under other conditions. To describe further these conditions, the authors investigated the behavioral effects of metaphit by using different routes of administration, behavioral procedures and species. In pigeons, metaphit induced PCP-like catalepsy after i.c.v. administration and, after i.m. administration, produced PCP-like discriminative stimulus effects and stereotyped operant responding. In rhesus monkeys, metaphit produced ataxia and convulsions but did not induce catalepsy, anesthesia or PCP-like discriminative stimulus effects. None of the effects of PCP-type drugs [i.e., PCP, ketamine or (+/-)-SKF 10,047] in pigeons or rhesus monkeys was antagonized by metaphit. Metaphit potentiated the discriminative stimulus effects of PCP and of SKF 10,047 in pigeons. These results suggest that metaphit acts not as an antagonist of PCP but as a PCP-like agonist under these conditions. Metaphit's potentiation of behavioral effects of PCP may be related to the presumed ability of metaphit to acylate PCP receptors. The extent to which metaphit produces PCP-like behavioral effects in part may be species dependent.

Topics: Acylation; Animals; Ataxia; Catalepsy; Columbidae; Discrimination Learning; Drug Synergism; Ketamine; Macaca mulatta; Phenazocine; Phencyclidine; Receptors, Neurotransmitter; Receptors, Phencyclidine; Species Specificity; Stereotyped Behavior