ADAPTIVE-CHANGES IN RAT STRIATAL PREPROENKEPHALIN EXPRESSION AND DOPAMINE-OPIOID INTERACTIONS UPON CHRONIC HALOPERIDOL TREATMENT DURING DIFFERENT DEVELOPMENTAL STAGES

This study was designed to evaluate the effects of a chronic treatment with the classical neuroleptic drug haloperidol on the preproenkephalin (ppEnk) mRNA synthesis and its consequences for opioid and dopamine (DA) receptor-regulated adenylate cyclase in the developing and adult rat striatum. Prenatal exposure to haloperidol (2 mg/kg, 14 days) caused a 40% reduction of striatal ppEnk mRNA levels, but had no consequences for DA-stimulated or Met-enkephalin-inhibited adenylate cyclase activity in striatal slices from embryonic day 21 (E21) foetal brain. Postnatal treatment of rat pups from day 10 (P10) until P23 and adult rats resulted in significant increases of mRNA levels of 8 and 41%, respectively, a clear reduction of D-1 DA receptor-stimulated cAMP production and a profound desensitization of delta-opioid receptors inhibitory coupled to adenylate cyclase. Since striatal D-2 receptor-mediated inhibition of adenylate cyclase activity, in contrast to its activation through D-1 receptors, is not present in the prenatal period, this study indicates that the tonic inhibitory effect of DA on striatal ppEnk mRNA synthesis is dependent on the presence of adenylate cyclase-coupled D-2 receptors which gradually develops postnatally and further supports the idea that striatal D-1 and D-2 DA receptors have bidirectional effects on enkephalin synthesis in this brain area. The adaptive changes in D-1 DA and delta receptor-regulated adenylate cyclase activity are discussed in relation to the well-known increase in the locomotor and reinforcing effects of mu-opioid receptor agonists upon chronic neuroleptic treatment.