Phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex

Possible antagonist effects of phentolamine at presynaptic serotonin autoreceptors were studied in slices of the occipito-parietal cortices of the rabbit and the rat. The slices were preincubated with 3H-serotonin and then superfused and stimulated electrically with single pulses or pulse trains. Nitroquipazine 1 mumol/l, a compound that inhibits the high affinity neuronal uptake of serotonin, was present in the superfusion medium in all one pulse-experiments as well as in experiments in which the effect of unlabelled serotonin was examined. In rabbit cortical slices, unlabelled serotonin reduced the single pulse-evoked overflow of tritium. Its concentration-response curve was not changed by the selective alpha 2-adrenoceptor antagonist idazoxan 1 mumol/l but was shifted to the right by phentolamine 1 and 10 mumol/l. Phentolamine 10 mumol/l also shifted to the right the concentration-inhibition curve of the selective 5-HT1-receptor agonist 5-carboxamidotryptamine. When the slices were stimulated by trains of 30 pulses at 3 Hz, phentolamine 1 and 10 mumol/l but not 0.1 mumol/l increased the evoked overflow of tritium, the maximal increase amounting to 178%; its effect was enhanced in the presence of nitroquipazine 1 mumol/l plus idazoxan 10 mumol/l (a drug combination that, when given alone, slightly increased the evoked overflow of tritium). The serotonin receptor antagonist metitepin at concentrations of 0.01-1 mumol/l also increased the overflow of tritium elicited by 30 pulses/3 Hz, the maximal increase amounting to 280%; its effect was potentiated in the presence of nitroquipazine 1 mumol/l plus idazoxan 10 mumol/l but was abolished or almost abolished in the presence of nitroquipazine 1 mumol/l plus phentolamine 10 mumol/l (a drug combination that, given alone, greatly increased the evoked overflow of tritium). When slices were stimulated by trains of 360 pulses at 3 Hz, there was no apparent antagonism of phentolamine 10 mumol/l against the inhibitory effect of unlabelled serotonin. In rat brain cortex slices, unlabelled serotonin reduced the overflow of tritium elicited by 4 pulses delivered at 100 Hz. Again, phentolamine 10 mumol/l shifted the concentration-response curve to the right. It is concluded that phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex with pA2 values of 6.44 and 5.95, respectively. Previous failures to detect the antagonistic effect against exogenous agonists were probably due to stimulation conditions that led to marked endogenous autoinhibition of serotonin release.(ABSTRACT TRUNCATED AT 400 WORDS)