Long-term effects of young-adult methamphetamine on dorsal raphe serotonin systems in mice: Role of brain-derived neurotrophic factor.

To assess the long-term effects of chronic adolescent methamphetamine (METH) treatment on the serotonin system in the brain, we used serotonin-1A receptor (5-HT) and serotonin transporter (SERT) autoradiography, and quantitative tryptophan-hydroxylase 2 (TPH2) immunohistochemistry in the raphe nuclei of mice. Because of the modulatory role of brain-derived neurotrophic factor (BDNF) on the serotonin system and the effects of METH, we included both BDNF heterozygous (HET) mice and wildtype (WT) controls. Male and female mice of both genotypes were treated with an escalating METH dose regimen from the age of 6-9 weeks. At least two weeks later, acute locomotor hyperactivity induced by a 5 mg/kg D-amphetamine challenge was significantly enhanced in METH-pretreated mice, showing long-term sensitisation. METH pretreatment caused a small, but significant decrease of 5-HT receptor binding in the dorsal raphe nucleus (DRN) of males independent of genotype, but there were no changes in the median raphe nucleus (MRN) or in SERT binding density. METH treatment reduced the number of TPH2 positive cells in ventral subregions of the rostral and medial DRN independent of genotype. METH treatment selectively reduced DRN cell counts in BDNF HET mice compared to wildtype mice in medial and caudal ventrolateral subregions previously associated with panic-like behaviour. The data increase our understanding of the long-term and selective effects of METH on brain serotonin systems. These findings could be relevant for some of the psychosis-like symptoms associated with long-term METH use.