Search

Rat brain tissues preincubated with [3H]serotonin ([3H]5-HT) or [3H]norepinephrine ([3H]NE) were superfused in the presence of an inhibitor of serotonin or NE uptake, respectively. The electrically (3 Hz) evoked [3H]5-HT release from slices of the medulla oblongata [containing the nucleus tractus solitarii (NTS)] from Wistar rats was inhibited by 5-HT and NE, and these effects were counteracted by metitepine and phentolamine, respectively. The evoked [3H]5-HT release in slices from the cortex, medulla oblongata, and hypothalamus of 5-7-, 9-11-, and 19-22-week-old spontaneously hypertensive rats (SHR) did not differ from that in slices from age-matched Wistar-Kyoto rats (WKY). Nor was there any difference between strains for: the inhibitory effects of 5-HT and NE and the facilitatory effect of metitepine on the evoked [3H]5-HT release; the shift to the right of the concentration-response curves of 5-HT and NE by metitepine and phentolamine, respectively; the potassium (12 mM)-evoked [3H]5-HT release from cortex synaptosomes and its inhibition by 5-HT; the electrically evoked [3H]NE release in cortex slices, its inhibition by NE, and the shift to the right of the concentration-response curve of NE by phentolamine. The results provide evidence that 5-HT release in the rat brain NTS can be inhibited by 5-HT receptors and alpha-adrenoceptors. 5-HT release and its modulation by presynaptic 5-HT1 receptors and alpha 2-adrenoceptors as well as NE release and its modulation by presynaptic alpha 2-adrenoceptors do not differ between SHR and WKY rats. It may be of therapeutic relevance that according to these results the effects of 5-HT1 receptor agonists activating presynaptic 5-HT autoreceptors are not attenuated in this type of hypertension. It has been suggested that such agonists can be developed as a new class of antihypertensive drugs.

Rat brain frontal cortex or striatal slices preincubated with 3H-serotonin were superfused with physiological salt solution and tritium overflow was evoked by electrical field stimulation at a frequency of 3 Hz. 1. GABA 1 mmol/1 inhibited the evoked overflow from frontal cortex slices by about 30%. The inhibitory effect was abolished when the frequency of electrical stimulation was 10 instead of 3 Hz. Progabide and R(-)-baclofen were more potent, whereas muscimol was less potent than GABA itself in inhibiting the evoked overflow; the IC15 values of progabide, R(-)-baclofen, GABA and muscimol were 8.3, 15, 170 and greater than 320 mumol/1, respectively. S(+)-baclofen behaved as a partial agonist with a maximum inhibitory effect by about 15%. Nipecotic acid and aminooxyacetic acid were ineffective. The same held true for bicuculline, picrotoxin and diazepam. 2. Bicuculline, picrotoxin, diazepam, phentolamine and the serotonin receptor antagonist metitepin did not influence the inhibitory effect of GABA. By contrast, S(+)-baclofen attenuated the effects of GABA and R(-)-baclofen. 3. The evoked overflow from striatal slices was inhibited by GABA and progabide (IC15 values: 480 and 13 mumol/1, respectively). Nipecotic acid was ineffective. The results suggest that exogenous GABA inhibits serotonin release in the rat brain via GABAB receptors which may be assumed to be located presynaptically.

Human cerebral cortex slices were prepared from brain tissue which had to be removed in order to gain access to deep-seated tumours. Subsequent to incubation with [3H]serotonin, the slices were superfused with physiological salt solution containing paroxetine, and 3H overflow was evoked by electrical field stimulation. The evoked tritium overflow (86% of which was accounted for by unmetabolized [3H]serotonin) was abolished by tetrodotoxin or omission of calcium from the superfusion fluid. Unlabelled serotonin decreased, and the serotonin receptor antagonist metitepin increased, the evoked overflow. The inhibition produced by serotonin was antagonized by metitepin. It is concluded that serotonin release in human cerebral cortex is modulated by inhibitory serotonin receptors, which may be localized presynaptically on the serotoninergic nerve fibers themselves. There are marked similarities between human and rat brain cortex with respect to action potential-induced, Ca2+-dependent serotonin release and its modulation via serotonin receptors.

Stimulation-evoked tritium overflow was examined in superfused rat brain cortex slices (stimulus: electrical impulses; 3 Hz) and synaptosomes (stimulus: potassium 12 mmol/l) preincubated with 3H-5-HT. 1. In slices and synaptosomes, the evoked 3H overflow was facilitated by forskolin and 8-Br-cAMP, but was not affected by AH 21-132 (an inhibitor of cAMP phosphodiesterase; cis-6-(p-acetamidophenyl)-1, 2, 3, 4, 4 a,10b-hexahydro-8, 9-dimethoxy-2-methylbenzo [c] [1,6]-naphthyridine). In the presence of AH 21-132, the facilitatory effect of forskolin on evoked overflow was increased. 2. In slices, AH 21-132 or combined administration of forskolin plus AH 21-132 did not change the percentage of basal or evoked 3H overflow represented by unmetabolized 3H-serotonin (about 30% and 60%, respectively). 3. In slices, cocaine or 6-nitroquipazine, an inhibitor of serotonin uptake, did not influence the increase in evoked overflow produced by forskolin plus AH 21-132. Forskolin plus AH 21-132 did not alter the inhibitory effect of serotonin (examined in the presence of 6-nitroquipazine) and the facilitatory effect of metitepin (a serotonin receptor antagonist) on evoked 3H overflow, but considerably decreased the inhibitory effect of clonidine or B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[5,4-d]-azepine). The present results suggest that the serotoninergic nerve terminals in the rat brain cortex are endowed with an adenylate cyclase, which is negatively coupled to the presynaptic α2-adrenoceptors, but is not linked to the presynaptic autoreceptors.