Galanin : A modulator of serotonin neurotransmission : relevance for depression

Sammanfattning: Abstract-Galanin is widely distributed throughout the central nervous system with multiple and diverse biological roles. In the rat, galanin-like immunoreactivity is expressed in a population of5-hydroxytryptamine (5-HT, serotonin) neurons in the dorsal raphe (DR) with extensive projections to the forebrain areas e.g., hippocampus. The major aim of the thesis was to study in vivo, whether porcine galanin can modulate 5 -HT transmission with focus on 5-HT1A receptors associated with the mechanism of action of antidepressant drugs. This analysis was performed at both the pre- and postsynaptic level of the DR projection using behavioural, neurochernical and molecular approaches. The effects of porcine galanin were examined in the adult male rat following intraventricular (i.c.v.) administration. Galanin given i.c.v. to the rat 10 min or 2 h prior to training, dose-dependently (0.3 - 3 nmol) attenuatedthe deficit in passive avoidance (PA) induced by the 5-HT1A receptor agonist 8-OH-DPAT (0.2 mg/kg)mediated via activation of postsynaptic 5-HT1A receptors in cortico-limbic brain regions. The shortterm(10 min) and prolonged (2 h) reduction in the postjunctional 5-HT1A receptor-mediated response at I ter i.c.v. galanin was not associated with changes in the mRNA levels or agonist binding properties of cortico-limbic 5-HT1A receptors. These results suggest that an acute increase of galanin transmission in vivo can counteract limbic 5-HT1A receptor-mediated responses without significantly affecting gene expression or binding properties of 5-HT1A receptors. In the DR, galanin (3 nmol/rat) increased the KD values of 5-HT1A receptors at 10 min but not 2 It and 5 h after administration while an increase in the Bmax values was seen at 2 h but not at 10 min and 5 h after administration. The mRNA levels of 5-HT1A receptors and of galanin in the DR were significantly decreased at 2 h but not 5 h after galanin. These findings provide evidence for time-dependent, modulatory actions of galanin on 5-HT1A receptors in the DR, possibly partly via galanin-5-HT1A receptor interactions (formation of galanin/5-HT1A receptor heteromeric complexes) and partly via galanin transduction mechanisms in the DR. Galanin given i.c.v. was found to produce a long-lasting (>5 h) reduction in basal 5-HT release in the ventral hippocampus. The inhibitory effect of galanin was related to a galanin receptor activation (blocked by a galanin receptor antagonist M35) at the level of DR. I.c.v. galanin 2 h after administration decreased mRNA levels of tryptophan hydroxylase (the rate limiting enzyme in synthesis) in the DR. 8-OH-DPAT (0.3 mg/kg, s.c.) caused a reversible reduction of extracellular 5-HT levels which was almost completely blocked by i.c,v. galanin (0.5 nmol and partially by 0.15 nmol). Thus, although both galanin and 8-OH-DPAT alone reduced basal hippocampal 5-HT release, their simultaneous administration did not exhibit any synergistic effects. Galanin also attenuated S-OH-DPAT induced hypothermia and locomotor activity in rats, functional effects mediated via postsynaptic 5-HT1A receptors in neuroantomical different projections. Antidepressant drug action has been related to desensitisation of somatodendritic 5-HT1A receptors. The ability of three "5-HT related drugs" to alter 5-HT1A receptors was examined after repeated treatments (14 days). Fluoxetine (a 5-HT uptake blocker) treatment significantly increased the KD values in dorsal raphe, CA1 and dentate gyrus (DG). 8-OH-DPAT, did not affect the KD values in any of the areas tested while robalzotan (a 5-HT1A receptor antagonist) increased the KD values in the DR. Both 8-OH- DPAT and robalzotan but not fluoxetine decreased the Bmax values of the postsynaptic 5-HT1A receptors in the DG and CAI areas of the dorsal hippocampal formation without affecting the Bmax values of these receptors in the DR. Furthermore, fluoxetine and robalzotan but not 8-OH-DPAT treatment also increased the mRNA levels of the 5-HT1A receptors in the CAI area without affecting the mRNA levels of the 5-HT1A receptors in DG and DR. None of the treatments changed the mRNA levels of the neuropeptide galanin, which coexists with 5-HT in the DR. The results from the forced swim test (FST) showed that all three drugs tested caused "antidepressant-like" effects. The modulatory actions on 5- HT1A receptors caused by the three "5-HT related drugs", can be interpreted as a result of enhanced 5-HT transmission. Furthermore, the anti depre ssant- like effects in the FST appear to involve multiple adaptive changes in 5-HT1A receptor mechanisms. In conclusion, the present studies have shown that galanin is a potent in vivo inhibitor of mesencephalic cortico-limbic 5-HT neurotransmission involving strong interactions between galanin and 5-HT1A receptors. In view of these findings, galanin antagonists may represent a new therapeutic principle in depression.