Galanin and NPY in the rodent brain: rapid effects of 17β-estradiol and possible roles in hippocampal plasticity

The neuropeptides galanin and neuropeptide Y (NPY) play an important role in the reproduction of rodents, e.g. by modulating the release of gonadal hormones, the nutritional status by effects on feeding behavior and also by infl uencing mating behavior. There are ageand genderdifferences in galaninand NPY like immunoreactivities (LIs) in brain areas important for higher functions, including the hippocampal formation (HiFo) and cortex, effects that are related to the concentrations of 17β-estradiol. Neuropeptides in general are currently not considered critical in normal intergrative neuronal functions but are rather thought to act as slow modulators during periods of stress or injury. In the present thesis we attempted to investigate, if the normal cyclical changes in the female sex-hormone 17β-estradiol can affect neurotransmission in brain areas important for memory, cognition and mood. We studied not only ”long term” (days and weeks) but also ”short-term” (one hour) effects on galanin and NPY concentration in 17β-estradiol-primed ovariectomized rats and mice. Radioimmunoassay (RIA) of galanin-like immunoractivity (LI) in extracts of brain tissues from ”long-term” 17β-estradiol-treated ovx rats showed that its effects on galanin is dependent on both dose and on duration. Galaninand NPY-LI in brain tissues of young ovx rats and mice increased in response to 17β-estradiol treatment in the HiFo, frontal cortex and striatum already within an hour. This effect was not blocked by Tamoxifen®. Species differences were observed with regard to galanin, possibly due to tissue and species differences in the distribution of estrogen receptors. The mechanism(s) underlying the 17β-estradiol effects on galanin levels in the HiFo may be decreased release of galanin to the extracellular fl uid since galanin-LI decreased in microdialysis samples two hours after a single injection of 17β-estradiol. In the HiFo and caudate nucleus of mice, we found an increase in NPYtranscript after two hours by means of in-situ hybridization, perhaps a compensatory up-regulation of NPY mRNA after increased 17β-estradiolinduced release in these areas. Taken together with no effects of Tamoxifen® on the levels on galanin in the HiFo of rats, the short duration, and the fact that the density of classical estrogen receptors (ERs) seems to be limited in the striatum, we suggest that these effects are mediated through a membrane-related mechanism, perhaps not involving the classical ER route. With an antiserum raised against the C-terminal end of the fi rst 16 aminoacids of galanin the sequence important for binding of galanin(1-29) to its receptor we found evidence for a novel compound which appears to be a homologue to galanin. Chromatographical analysis revealed that it was not galanin(1-29) or the galanin related peptide GALP, but was with immunohistochemistry localised in the galanin systems in the brain and was further infl uenced by 17β-estradiol in the HiFo and frontal cortex in a similar manner as galanin(1-29). Tissue concentrations of galanin, a putative galanin homologue and NPY can be altered within one hour by 17β-estradiol treatment i.a. in the HiFo. These ”short-term” effects are most likely to be due to effects on estrogen-primed peptide release which might infl uence mechanisms important for memory, cognition and mood.