NEUROLEPTICS CAUSE STIMULATION OF DOPAMINE D-1 RECEPTORS AND THEIR DESENSITIZATION AFTER CHRONIC TREATMENT

Recent evidence indicates that the neuroleptic-induced increase of in vivo acetylcholine output in the striatum does not depend on the relie f of cholinergic neurons from the inhibitory control by dopamine, but on increased dopamine output onto dopamine D-1 receptors. The present microdialysis study was aimed at finding if the neuroleptic-induced in crease in striatal acetylcholine release persists after chronic treatm ent, and how it is correlated with dopamine output. Rats were chronica lly treated with the dopamine D-2 receptor antagonists, haloperidol an d (-)-sulpiride (0.5 mg/kg and 50 mg/kg i.p., respectively, daily, for 30 days). The stimulant effect of both neuroleptics on striatal dopam ine release persisted unaltered throughout the chronic treatment (by a bout 100% over basal values). In contrast, the enhancing effects of ha loperidol and (-)-sulpiride on striatal acetylcholine release remained unchanged up to day 12 of treatment. Thereafter, tolerance developed, so that both neuroleptics became totally ineffective on day 30 of tre atment. Both on day 1 and 30, the neuroleptic-induced dopamine release was reversed by gamma-butyrolactone (gamma-hydroxybutyric acid lacton e), suggesting that this effect is mediated by enhanced neuronal activ ity. On day 1 and day 10, the neuroleptic-induced acetylcholine releas e was antagonized by the blockade of dopamine D-1 receptors with SCH 3 9166 dro-7-methyl-5H-benzo[d]napht[2,1-b]azepine-12-ol, hydrochloride) (0.5 mg/kg i.p.). SKF 38393 nyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine -7,8-diol hydrochloride) (5 mg/kg i.p.) increased acetylcholine releas e by about 50% in control rats and in rats treated with (-)-sulpiride or haloperidol for up to 7 days. Its effect was blunted at day 14 and completely suppressed at day 30, suggesting that complete desensitizat ion of dopamine D-1 receptors develops after chronic neuroleptic admin istration. The initial opposite action of neuroleptics on dopamine D-1 and D-2 receptors, and the development of desensitization of dopamine D-1 receptors, after chronic neuroleptic treatment, are discussed in terms of therapeutic and collateral effects of neuroleptics.