The effects of GR127935, a putative 5-HT1D receptor antagonist, on brain 5-HT metabolism, extracellular 5-HT concentration and behaviour in the guinea pig.

Studies of neurotransmitter release in guinea pig and human brain indicate that the 5-HT terminal autoreceptor is the 5-HT1D subtype and that it regulates the depolarization evoked release of 5-HT. Thus, blockade of the terminal 5-HT autoreceptor should enhance 5-HT release in vivo. In the present study, we have used the recently described, selective and potent 5-HT1D receptor antagonist, GR127935, to determine if blockade of the terminal 5-HT autoreceptor enhanced 5-HT neurotransmission in the guinea pig. Neurochemical studies showed that GR127935 (0.1, 0.3 and 1.0 mg/kg i.p.) significantly increased 5-HT metabolism in forebrain regions but not in the raphe nucleus of the guinea pig. However, using in vivo dialysis, GR127935 did not significantly increase cortical 5-HT efflux when given either systemically (1 and 5 mg/kg i.p.) or by infusion via the probe directly into the cortex (10, 33 and 100 microM). Fast cyclic voltammetry studies in the guinea pig dorsal raphe slice in vitro failed to observe any significant effects of GR127935 (0.01-1 microM) on electrically evoked 5-HT release. Behavioural studies in the guinea pig were also unable to demonstrate any effects of GR127935 (0.1-3.0 mg/kg i.p.) per se or in combination with the 5-HT precursor 5-hydroxytryptophan. Taken together, results from the present neurochemical and behavioral studies in the guinea pig provide little substantial evidence that blockade of the terminal 5-HT autoreceptor following the acute administration of GR127935 increased brain 5-HT neurotransmission in vivo.