Phencyclidine: behavioral and biochemical evidence against the anticholinergic hypothesis

Phencyclidine (PCP) is known to have anticholinergic effects in various in vitro test systems and to inhibit the binding of muscarinic antagonists to rat brain membranes. In order to verify the anticholinergic properties of PCP, its interaction with oxotremorine (OXO), a muscarinic agonist, was studied in mice. OXO (1 mg/kg) in combination with PCP (10 mg/kg) was lethal in 100% of the mice studied. The lethality of this combination was completely reversed by 3.3 mg/kg methyl atropine bromide (MA), a quarternary muscarinic antagonist. Therefore, PCP appears to act as a muscarinic agonist in some peripheral systems. The central interactions between PCP and OXO were studied in mice in which the preipheral effects of OXO were blocked by MA. In a test of motor performance, OXO potentiated the effect of PCP at one dose only. Contrary to the effects of PCP in other behavioral measures, no evidence for an anticholinergic effect of PCP was observed. The in vivo anticholinergic potential of PCP was estimated by adding a brain extract from PCP-treated mice to brain muscarinic receptors in the presence of 3H-quinuclidinyl benzilate. These data suggested that PCP, after in vivo administration, does not attain a sufficient brain concentration to directly affect central muscarinic receptors. However, a direct action of PCP on peripheral muscarinic receptors was not discounted.