PHENCYCLIDINE INDUCTION OF THE HSP70 STRESS GENE IN INJURED PYRAMIDALNEURONS IS MEDIATED VIA MULTIPLE RECEPTORS AND VOLTAGE-GATED CALCIUM CHANNELS

Non-competitive N-methyl-D-aspartate receptor antagonists, including p hencyclidine, ketamine, and MK801, produce vacuoles and induce the hsp 70 stress gene in layer III pyramidal neurons of the rat cingulate cor tex. This study shows that phencyclidine (50 mg/kg) induces hsp70 mess enger RNA and HSP70 stress protein primarily in pyramidal neurons in p osterior cingulate and retrosplenial cortex, neocortex, insular cortex , piriform cortex, hippocampus, and in the basal nuclei of the amygdal a. Several neurotransmitter receptor antagonists inhibited induction o f HSP70 produced by phencyclidine (50 mg/kg): haloperidol (ED(50) = 0. 8 mg/kg), clozapine (ED(50) = 1 mg/kg), valium (ED(50) = 1 mg/kg), SCH 23390 (ED(50) = 7 mg/kg) and muscimol (ED(50) = 3 mg/kg). Baclofen ha d no effect. Nifedipine blocked the induction of HSP70 produced by phe ncyclidine in some regions (cingulate, neocortex, insular cortex) but only partially blocked HSP70 induction in other regions (piriform cort ex, amygdala). These results suggest that phencyclidine injures pyrami dal neurons via dopamine D-1, D-2, D-4, sigma and other receptors. Sev eral factors appear to contribute to this unusual multi-receptor media ted injury. (1) Phencyclidine blocks N-methyl-D-aspartate receptors on GABAergic interneurons resulting in decreased inhibition of pyramidal neurons. This may help to explain why multiple excitatory receptors m ediate the injury and why GABA(A) agonists decrease the injury produce d by phencyclidine. (2) Phencyclidine blockade of an amine transporter helps explain why dopamine receptor antagonists ameliorate injury. (3 ) Phencyclidine depolarizes neurons and produces high, potentially dam aging intracellular calcium levels probably by blocking K+ channels th at may be linked to sigma receptors. Since nifedipine prevents injury in cingulate, insula, and neocortex, it appears that calcium entry thr ough L-type voltage gated calcium channels plays a role in the pyramid al neuronal injury produced by phencyclidine in these regions. There a re similarities between the cingulate neurons injured by phencyclidine and circuits recently hypothesized to explain receptor changes in cin gulate gyrus of schizophrenic patients. The present and previous studi es also provide approaches for decreasing the clinical side effects of N-methyl-D-aspartate receptor antagonists to facilitate their possibl e use in the treatment of ischemia and other disorders.