The pharmacology of the neurochemical transmission in the midbrain raphe nuclei of the rat.
Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with [(3)H]serotonin ([(3)H]5-HT), superfused and the release of [(3)H]5-HT was determined at rest and in response to electrical stimulation. Compartmental analysis of [(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 GABAA and GABAB 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.
Harsing
L G
LG
Division of Preclinical REsearch, EGIS Pharmaceuticals, Plc., Bokenyfoldi ut 116, 1165 Budapest, Hungary. lharsing@axelero.hu