The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra,striatum and limbic forebrain in vivo

Summary The effects of serotoninergic drugs on dopaminergic neurotransmission in the substantia nigra, the striatum and the limbic forebrain of rat have been investigated. The accumulation of 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase with pargyline was used as an indirect measure of dopamine (DA) activity in vivo. The effects of the following serotoninergic drugs were tested: the 5-HT_1A receptor agonist 8-OH-DPAT, the 5-HT_1B receptor agonist trifluoromethyl-phenylpiperazine (TFMPP), CGS 12066B and RU 24969, the 5-HT_1A/1B antagonist (±)pindolol, the 5-HT_2/1C receptor antagonist ritanserin, the 5-HT_2/1C receptor agonist DL-1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI), the 5-HT₃ receptor antagonist BRL 43 694, the unselective 5-HT₁ receptor antagonist methiothepin, and carbidopa+L-5-hydroxytryptophan (L5-HTP) to achieve a general, unselective stimulation of multiple 5-HT receptors. In the substantia nigra, carbidopa + 5-HTP treatment increased the 3-MT accumulation by 26% and decreased the DA concentration to 67% of controls, tentatively suggesting a 5-HTP-induced displacement of nigral DA. A minor, non dose-related reduction in nigral 3-MT was seen after the 5-HT_1A receptor agonist 8-OH-DPAT. None of the other serotonin receptor acting drugs induced any pronounced effect on the nigral 3-MT accumulation. Taken together, the findings provide little support for the idea that one single 5-HT₁ receptor subtype serves a modulatory function on DA activity in the substantia nigra. In the striatum and the limbic forebrain, trifluoromethylphenylpiperazine dose-dependently increased the 3-MT accumulation to maximally 200%–220% of controls. In the limbic forebrain also the highest dose of RU 24 969 (15 mg/kg) increased the 3-MT accumulation (78%), whereas in the striatum the lowest does of the drug (1.5 mg/kg) decreased it by 30%. The trifluoromethylphenylpiperazine-induced stimulation of 3-MT accumulation was not blocked by ritanserin. In the limbic forebrain, also DL-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and carbidopa+Lr5-HTP treatment increased the 3-MT concentrations to 120% and 150% of controls, respectively. Paradoxically, methiothepin also induced an increase of the 3-MT accumulation in these brain regions, probably due to its DA receptor antagonism. None of the other serotoninergic drugs induced any pronounced effects on the 3-MT accumulation in these brain parts. The results may overall support the hypothesis that 5-HT₁ does modulate the DA activity in the striatum and limbic forebrain, tentatively via 5-HT_1B receptors in the striatum and 5-HT_1B and 5-HT₂ or 5-HT_1C receptors in the limbic forebrain. It may be speculated therefore, that clinical application of 5-HT₁ receptor-modulating drugs to influence central dopaminergic activity might be of therapeutical benefit, for example, in motor disorders like Parkinson's disease.Send offprint requests to H. Nissbrandt at the above address