Ligand-binding studies have demonstrated two types of serotonin (5-HT) receptor, 5-HT1 and 5-HT2, in the brains of rodents and there is additional evidence for the existence of 5-HT1 subtypes. Recently a new drug, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT), has been identified which shows high selectivity for binding to 5-HT1 (possibly 5-HT1A) receptors and which binds to presynaptic serotonin autoreceptors in some regions of rat brain. We have shown previously, that this compound produces a hypothermic response in mice, probably via an agonist action at serotonin presynaptic receptors. Here we show that a wide range of antidepressant treatments decrease the hypothermic response to 8-OH-DPAT over a time course comparable to the onset of therapeutic action. Interestingly, repeated electroconvulsive shock (ECS) has the same effect. We propose that this change is relevant to the mechanism of action of antidepressant drugs.

Addition of baclofen to a medium containing slices of mouse frontal cortex inhibited the potassium‐evoked release of 5‐hydroxytryptamine (5‐HT) in a concentration‐dependent manner. The degree of inhibition was increased in frontal cortex tissue taken from animals treated for 14 days with amitriptyline (10 mg kg−1, twice daily) at all concentrations of baclofen tested (10−6 m − 10−4 m). Administration of either desipramine, mianserin or zimeldine (10 mg kg−1 daily) for 14 days also approximately doubled the degree of inhibition evoked by addition of baclofen (10−5 m) to the medium. One day of treatment with the antidepressant drugs did not alter the inhibitory effect of baclofen on K+‐evoked 5‐HT release. Addition of the antidepressant drugs to the medium had no effect on the K+‐evoked release of 5‐HT. Repeated administration of electroconvulsive shock (5 seizures spread out over 10 days), like amitriptyline, produced a significant enhancement of the baclofen‐induced inhibition of 5‐HT release over the range of baclofen concentrations studied. A single electroconvulsive shock had no effect. These data suggest that repeated administration of the antidepressant drugs or electroconvulsive shock increases the function of the γ‐aminobutyric acid (GABA)B receptor in the frontal cortex modulating 5‐HT release and are consistent with the finding of increased GABAB receptor number in this region following various antidepressant treatments.