THE EFFECTS OF GR127935, A PUTATIVE 5-HT1D RECEPTOR ANTAGONIST, ON BRAIN 5-HT METABOLISM, EXTRACELLULAR 5-HT CONCENTRATION AND BEHAVIOR IN THE GUINEA-PIG

Studies of neurotransmitter release in guinea pig and human brain indi cate that the 5-HT terminal autoreceptor is the 5-HT1D subtype and tha t it regulates the depolarization evoked release of 5-HT. Thus, blocka de of the terminal 5-HT autoreceptor should enhance 5-HT release in vi vo. In the present study, we have used the recently described, selecti ve and potent 5-HT1D receptor antagonist, GR127935, to determine if bl ockade of the terminal 5-HT autoreceptor enhanced 5-HT neurotransmissi on in the guinea pig. Neurochemical studies showed that GR127935 (0.1, 0.3 and 1.0mg/kg i.p.) significantly increased 5-HT metabolism in for ebrain regions but not in the raphe nucleus of the guinea pig. However , using in vivo dialysis, GR127935 did not significantly increase cort ical 5-HT efflux when given either systemically (1 and 5 mg/kg i.p.) o r by infusion via the probe directly into the cortex (10, 33 and 100 m u M). Fast cyclic voltammetry studies in the guinea pig dorsal raphe s lice in vitro failed to observe any significant effects of GR127935 (0 .01-1 mu M) on electrically evoked 5-HT release. Behavioural studies i n the,guinea pig were also unable to demonstrate any effects of GR1279 35 (0.1-3.0 mg/kg i.p.) per se or in combination with the 5-HT precurs or 5-hydroxytryptophan. Taken together, results from the present neuro chemical and behavioural studies in the guinea pig provide little subs tantial evidence that blockade of the terminal 5-HT autoreceptor follo wing the acute administration of GR127935 increased brain 5-HT neurotr ansmission in vivo.