α-noradrenergic receptor modulation of the phencyclidine- and Δ⁹- tetrahydrocannabinol-induced increases in dopamine utilization in rat prefrontal cortex

The noncompetitive NMDA receptor antagonist phencyclidine (PCP) and the neuronal cannabinoid receptor agonist Δ⁹-tetrahydrocannabinol (THC) are two agents shown to have psychotomimetic properties in humans. Both drugs increase dopamine release and utilization in the prefrontal cortex, a brain region thought to be dysfunctional in schizophrenia. In the present series of studies, the effects of drugs acting at α-noradrenergic receptors on PCP- and THC-induced increases in prefrontal cortical and nucleus accumbens dopamine utilization in the rat were examined. Clonidine, an α₂ noradrenergic receptor agonist, completely blocked the activation of mesoprefrontal dopamine system by THC or PCP. In addition, the α₁ noradrenergic receptor antagonist prazosin blocked the PCP-induced increase in prefrontal cortical dopamine utilization. These data may provide new insights concerning pharmacological therapies for acute drug-induced psychoses and behavioral abnormalities in human PCP and THC abusers.