The Pharmacology of the Neurochemical Transmission in the Midbrain Raphe Nuclei of the Rat

Abstract

3 H]5-HT taken up by raphe tissue indicated various pools where the neurotransmitter release may originate from these stores differed both in size and rate constant. 5-HT release originates not only from vesicles but also from cytoplasmic stores via a transporter-dependent exchange process establishing synaptic and non-synaptic neurochemical transmission in the serotonergic somatodendritic area. Manipulation of 5-HT transporter function modulates extracellular 5-HT concentrations in the raphe nuclei: of the SSRIs, fluoxetine was found 5-HT releaser, whereas citalopram did not exhibit this effect. Serotonergic projection neurons in the raphe nuclei possess inhibitory 5-HT 1A and 5-HT 1B/1D receptors and facilitatory 5-HT 3 receptors, which regulate 5-HT release in an opposing fashion. This observation indicates that somatodendritic 5-HT release in the raphe nuclei is under the control of several 5-HT homoreceptors. 5-HT 7 receptors located on glutamatergic axon terminals indirectly inhibit 5-HT release by reducing glutamatergic facilitation of serotonergic projection neurons. An opposite regulation of glutamatergic axon terminals was also found by involvement of the inhibitory 5-HT 7 and the stimulatory 5-HT 2 receptors as these receptors inhibit and stimulate glutamate release in raphe slice preparation, respectively, Furthermore, postsynaptic 5-HT 1B/1D heteroreceptors interact with release of GABA in inhibitory fashion in raphe GABAergic interneurons. Serotonergic projection neurons also possess glutamate and GABA heteroreceptors; NMDA and AMPA receptors release 5-HT, whereas both GABA A and GABA B receptors inhibit somatodendritic 5-HT release. Evidence was found for reciprocal interactions between serotonergic and glutamatergic as well as serotonergic and GABAergic innervations in the raphe nuclei. Serotonergic neurons in the raphe nuclei also receive noradrenergic innervation arising from the locus coeruleus and alpha-1 and alpha-2 adrenoceptors inhibited [3 H]5-HT release in our experimental conditions. The close relation between 5-HT transporter and release-mediating 5-HT autoreceptors was also shown by addition of L-deprenyl, a drug possessing inhibition of type B monoamine oxidase and 5-HT reuptake. L-Deprenyl selectively desensitizes 5-HT 1B but not 5-HT 1A receptors and these effects are not related to inhibition of 5-HT metabolism but rather to inhibition of 5-HT transporter.

Acute and repeated treatment with the 5-HT7 receptor antagonist SB 269970 induces functional desensitization of 5-HT7 receptors in rat hippocampus

“…Enhancement of 5-HT transmission in such projection areas as the dorsal hippocampus after 1 week of SB 269970 administration has also been reported by other researchers [42]. On the other hand, some authors have found that the 5-HT 7 receptor antagonist SB 269970 significantly inhibits 5-HT efflux [51]; however, other investigators have shown that inhibition of 5-HT release is likely to be mediated by 5-HT 7 receptor agonists [22]. The mechanism of control of DRN neuronal activity by 5-HT 7 receptors seems to be indirect, since the regulation of DRN activity via the 5-HT 7 receptor is tetrodotoxin-sensitive [23].…”

Presynaptic 5-HT1B receptor-mediated serotonergic inhibition of glutamate transmission in the bed nucleus of the stria terminalis

“…Previous studies had indicated that the G i -coupled 5-HT 1A,1B,1D receptors were most often associated with an inhibitory effect on glutamatergic neurotransmission (Fitzgerald and Sanes, 1999, Pickard et al, 1999), whereas the Gq-coupled 5-HT 2A receptor subtype has been reported to enhance glutamate transmission (Fitzgerald and Sanes, 1999, Smith et al, 2001, Hasuo et al, 2002, Harsing, 2006). Consequently, we next tested the ability of several 5-HT 1 receptor subtype selective agonists and antagonists to mimic and/or block the 5-HT induced attenuation of eEPSCs amplitude.…”

Chronic treatment with monoamine oxidase-B inhibitors decreases cocaine reward in mice

“…Moreover, this possibility is in agreement with our findings that dopamine and serotonin contents are not altered in deprenyl-and pargyline-treated mice. In fact, deprenyl at therapeutic doses has been known for its ability to inhibit both dopamine and serotonin uptake (Ebadi et al 2006;Harsing 2006). A previous report ever addressed that dopamine and serotonin transporters played important roles in the reinforcing effect of cocaine since cocaine-conditioned place preference was eliminated in dopamine and serotonin transporter knockout mice (Sora et al 2001).…”