Effects of antipsychotic drugs on dopamine and serotonin contents and metabolites, dopamine and serotonin transporters, and serotonin(1A) receptors

The effects of neuroleptics have been attributed to dopamine (DA) receptor blockade; however, other neurotransmitters, in particular serotonin (5-HT), have also been implicated. In this study, we examined the effects of cloza pine and haloperidol on the distribution of DA and 5-HT transporters, on en dogenous DA, 5-HT and their major metabolites, and on 5-HT1A receptors. Adu lt male Sprague-Dawley rats were treated with either haloperidol (1 mg/kg/d ay, i.p.), clozapine (20 mg/kg/day, i.p.) or saline for 21 days, and follow ing 3 days of withdrawal, the brains were removed. Tissue levels of DA and 5-HT and their metabolites were measured by high-performance liquid chromat ography in 16 brain regions, while quantitative autoradiography with [I-125 ]RTI-121, [H-3]citalopram and [H-3]8-OH-DPAT was employed to label DA trans porters, 5-HT transporters and 5-HT1A receptors, respectively. After halope ridol, densities of 5-HT transporters were increased in the dorsal insular cortex and in the ventral half of caudal neostriatum, while 5-HT1A receptor s augmented in cingulate cortex but decreased in the entorhinal area. After clozapine, [H-3]citalopram labelling was increased in ventral hippocampus, ventral caudal neostriatum and nucleus raphe dorsalis, but decreased in me dio-dorsal and latero-dorsal, neostriatum as well as in substantia nigra. B inding of [H-3]8-OH-DPAT following clozapine was decreased in frontal, pari etal, temporal and entorhinal cortices but increased in the CA3 division of Ammon's horn. The changes in 5-HT transporters in nucleus raphe dorsalis a nd substantia nigra, as well as the 5-HT1A receptor down-regulations caused by clozapine but not by haloperidol, may explain effects obtained with clo zapine and other atypical neuroleptics. There were no modifications in dens ities of DA transporters, nor of tissue DA levels, after the chronic neurol eptic treatments. The results are in line with previous suggestions that a certain degree of tolerance to neuroleptics develops, in spite of profound D-1 and D-2 receptor changes that persist during the entire chronic treatme nt with these psychotropic agents.