Neuropharmacological studies of phencyclidine (PCP)-induced behavioral stimulation in mice

Abstract

A variety of drugs were screened to determine which were capable of blocking the behavioral stimulation produced in mice by acute administration of phencyclidine (PCP). Chlorpromazine and clozapine blocked PCP-induced stimulation, while haloperidol, reserpine, and alpha-methyl-p-tyrosine did not. The GABA receptor agonists imidazole acetic acid and muscimol blocked PCP, but other drugs that influence GABA, such as dipropylacetic acid, baclofen, and diazepam, were ineffective. Yohimbine and methysergide also blocked PCP in high dosages, but other drugs with comparable alpha-noradrenergic and serotonergic blocking properties (phentolamine, cyproheptadine, and cinnanserin) were ineffective. Cholinergic and anticholinergic drugs, beta-noradrenergic and opiate antagonists and nonspecific sedatives and convulsants were also ineffective. These findings suggest that chlorpromazine, clozapine, yohimbine, and methysergide may share a property that is unlike their primary known modes of action on dopaminergic, alpha-noradrenergic, and serotonergic neurotransmitter systems, and that this property accounts for their ability to block PCP. However, the effectiveness of GABA agonists appears to be mediated through direct activation of GABA receptors. It is suggested that chlorpromazine and imidazole acetic acid should be considered as possible drug treatments for PCP toxicity.

Propranolol Antagonizes Phencyclidine-Induced Hyperactivity and Stereotypy in Rats

“…In another study [15], a higher dose (25 mg/kg) o f propranolol (pretreatment interval not reported) in creased the activity o f rats given PCP (5 mg/kg). In mice, 2.5-37.5 mg/kg o f pro pranolol, given 35 min prior to PCP, failed to alter PCP-induced hyperactivity; a large dose (50 mg/kg) of propranolol, however, in creased the PCP-induced hyperactivity [9], Two factors may be involved in explain ing the differences between the previous and present findings. Propranolol has a relatively short, e.g., 60 min, biological half-life in ro dents [2], Also propranolol [ 13] and PCP [ 19] are both extensively metabolized by ring hydroxylation.…”

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats

“…The primary site of pharmacological action of PCP is prefrontal cortex (Jentsch et al 1998). GABA A receptor agonists such as muscimol and imidazole acetic acid block PCP-induced hyperlocomotion (Freed et al 1980). GABA transaminase inhibitors such as vigabatrin and (s)-4-allenyl GABA, which increase brain GABA concentrations, antagonize PCP-induced hyperlocomotion (Seiler and Grauffel 1992).…”

Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine

“…In the present study, we extended our electrophysiological analysis of the striatum to phencyclidine (PCP, 1-[1-phenylcyclohexyl]piperidine), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors that elicits many of the same behavioral effects as amphetamine (Freed et al, 1980;French and Vantini, 1984;Sturgeon et al, 1979). In fact, PCP seems superior to amphetamine in reproducing the symptom profile of idiopathic schizophrenia, suggesting a role for glutamatergic mechanisms in this disease (Domino and Luby, 1981;Javit and Zukin, 1991).…”