Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area

Abstract

Electrophysiological techniques were used to study the effects of fluoxetine and citalopram on the basal activity of dopaminergic neurones in the ventral tegmental area (VTA) and substantia nigra, pars compacta (SNc) of rats Acute i.v. injection of fluoxetine (20–1280 μg kg−1) caused a dose‐dependent inhibition of the firing rate of VTA dopaminergic neurones, but did not affect the activity of dopaminergic cells in the SNc. Citalopram (20–1280 μg kg−1, i.v.) inhibited the firing rate of dopaminergic neurones in the VTA, but its effect (maximal inhibition: 14 ±7%) was less pronounced than that of fluoxetine (maximal inhibition: 34 ±7%) Pretreatment with mesulergine (80 μg kg−1, i.v.), a 5‐hydroxytryptamine2C/2B (5‐HT2C/2B) receptor antagonist, blocked the inhibitory effect of fluoxetine on VTA dopaminergic cells. Selective lesions of 5‐hydroxytryptaminergic neurones by the neurotoxin, 5,7‐dihydroxytryptamine (5,7‐DHT), abolished the fluoxetine‐induced reduction of VTA dopaminergic activity In a series of experiments, fluoxetine (10 mg kg−1, i.p.) was administered once daily for 21 consecutive days. Acute i.v. administration of fluoxetine (20–1280 μg kg−1, 72 h after the last i.p. injection) did not cause any change in the basal firing rate of VTA dopaminergic neurones in treated rats, whereas it induced the typical inhibitory effect in control animals. A group of rats chronically treated with fluoxetine, received i.v. w‐chlorophenylpiperazine (mCPP; 10–320 μg kg−1), a 5‐HT2C/2B receptor agonist. This drug significantly inhibited VTA dopaminergic function in control rats, but did not modify the basal activity of dopaminergic cells in animals given chronic fluoxetine It is concluded that fluoxetine inhibits dopaminergic function in the VTA by enhancing the synaptic levels of 5‐HT, which possibly acts through the 5‐HT2C/2B receptor subtype. Repeated treatment with fluoxetine induces tolerance to its inhibitory effect on dopaminergic activity, possibly as a consequence of down‐regulation of 5‐HT2C/2B receptors. The effects of fluoxetine on VTA dopaminergic cell activity might be relevant for its therapeutic actions and may explain the origin of the reported cases of akathisia. 1995 British Pharmacological Society