Actions of tetrahydronorharmane (tetrahydro-β-carboline) on 5-hydroxytryptamine and dopamine mediated mechanisms ☆

Abstract The activity of 5-hydroxytryptamine (5-HT) or dopamine (DA) containing neurones of rats was blocked either by neurotoxic agents [ p -chlorophenylalanine ( p -CPA), 6-hydroxydopamine (6-OHDA)], or thermolytic lesions (raphe nuclei, medial forebrain bundle). To assess the effect of the various pretreatments on 5-HT-dependent mechanisms, the hyperactivity-syndrome-test was used. 5-Hydroxytryptophan as well as tetrahydronorharmane (THN) evoked the syndrome in a dose-dependent manner. Combined treatment led to a potentiation of the effects of the single drugs. Lesions of the raphe nuclei reduced the THN-elicited activity syndrome. 6-OHDA had no effect under the same conditions. Injection of 300 mg/kg p -CPA caused a shift to the left of the THN-curve. Following two doses of p -CPA on consecutive days, THN induced a cataleptic syndrome. To assess DA-dependent mechanisms, apomorphine-evoked stereotyped behaviour was used. Pre-treatment with 2 × 300 mg/kg p -CPA as well as lesions of the raphe nuclei reduced the compulsive licking. Thus, the integrity of 5-HT-containing neurones is obviously required for the action of apomorphine. Licking movements were diminished by THN. Pretreatment with 6-OHDA strengthened this action of THN. The effect can be explained by an inhibition of postsynaptic dopaminergic receptors by THN which is not modulated by the stimulating action of 5-HT neurones on DA-containing cells after their destruction by 6-OHDA. The ffect of p -CPA pretreatment and raphe lesions on apomorphine-induced licking was neutralized by THN and this was interpreted as a direct postsynaptic stimulation of 5-HT-receptors.