Neurotoxic (+)-methamphetamine treatment in rats increases brain-derived neurotrophic factor and tropomyosin receptor kinase B expression in multiple brain regions.

Methamphetamine (MA) is an abused stimulant which can result in cognitive deficits and monoamine depletions. Animal models of neurotoxic MA exposure show reductions in dopamine, serotonin, and their associated transporters. MA abuse can result in long-term attention, working memory, and executive function deficits in humans and deficits in route-based egocentric learning, novel object recognition, and novel odor preference in rodents. MA has also been shown to affect brain-derived neurotrophic factor (BDNF) in humans and rodents. This experiment examined the effects of a MA binge dosing regimen (10 mg/kg x 4 at 2 h intervals, s.c.) in Sprague-Dawley rats on BDNF, tropomyosin receptor kinase B (TrkB), and tyrosine hydroxylase (TH) mRNA expression, and plasma corticosterone. Tissues were collected 1, 7, and 24 h following the last MA dose. Expression of BDNF and TrkB mRNA was analyzed using in situ hybridization with cRNA probes. Frontal, parietal, and entorhinal cortical BDNF mRNA expression were increased by MA exposure at all time-points. Increases in BDNF mRNA were also seen in the hippocampal CA1, prefrontal cortex (PFC), piriform cortex, and locus coeruleus but only at specific times. TrkB mRNA expression was modified in several subregions of the hippocampus as well as in PFC and striatum. TH mRNA was increased at the 1 h time-point in the substantia nigra pars compacta with no differences noted at the other times. Corticosterone levels were increased at all three time-points. The findings suggest that BDNF and its receptor may be upregulated as a compensatory mechanism after MA exposure.

Neurokinin 3 receptor immunoreactivity in the septal region, preoptic area and hypothalamus of the female sheep: colocalisation in neurokinin B cells of the arcuate nucleus but not in gonadotrophin-releasing hormone neurones.

Recent evidence has implicated neurokinin B (NKB) in the complex neuronal network mediating the effects of gonadal steroids on the regulation of gonadotrophin-releasing hormone (GnRH) secretion. Because the neurokinin 3 receptor (NK3R) is considered to mediate the effects of NKB at the cellular level, we determined the distribution of immunoreactive NK3R in the septal region, preoptic area (POA) and hypothalamus of the ewe. NK3R cells and/or fibres were found in areas including the bed nucleus of the stria terminalis, POA, anterior hypothalamic and perifornical areas, dopaminergic A15 region, dorsomedial and lateral hypothalamus, arcuate nucleus (ARC) and the ventral premammillary nucleus. We also used dual-label immunocytochemistry to determine whether a neuroanatomical basis for direct modulation of GnRH neurones by NKB was evident. No GnRH neurones at any rostral-caudal level were observed to contain NK3R immunoreactivity, although GnRH neurones and fibres were in proximity to NK3R-containing fibres. Because NKB fibres formed close contacts with NKB neurones in the ARC, we determined whether these NKB neurones also contained immunoreactive NK3R. In luteal-phase ewes, 64% +/- 11 of NKB neurones colocalised NK3R. In summary, NK3R is distributed in areas of the sheep POA and hypothalamus known to be involved in the control of reproductive neuroendocrine function. Colocalisation of NK3R in NKB neurones of the ARC suggests a potential mechanism for the autoregulation of this subpopulation; however, the lack of NK3R in GnRH neurones suggests that the actions of NKB on GnRH neurosecretory activity in the ewe are mediated indirectly via other neurones and/or neuropeptides.

Decreased expression of ErbB4 and tyrosine hydroxylase mRNA and protein in the ventral midbrain of aged rats.

Decreased availability or efficacy of neurotrophic factors may underlie an increased susceptibility of mesencephalic dopaminergic cells to age-related degeneration. Neuregulins (NRGs) are pleotrophic growth factors for many cell types, including mesencephalic dopamine cells in culture and in vivo. The functional NRG receptor ErbB4 is expressed by virtually all midbrain dopamine neurons. To determine if levels of the NRG receptor are maintained during aging in the dopaminergic ventral mesencephalon, expression of ErbB4 mRNA and protein was examined in young (3 months), middle-aged (18 months), and old (24-25 months) Brown Norway/Fischer 344 F1 rats. ErbB4 mRNA levels in the substantia nigra pars compacta (SNpc), but not the adjacent ventral tegmental area (VTA) or subtantia nigra pars lateralis (SNl), were significantly reduced in the middle-aged and old animals when compared to young rats. Protein expression of ErbB4 in the ventral midbrain was significantly decreased in the old rats when compared to the young rats. Expression of tyrosine hydroxylase (TH) mRNA levels was significantly reduced in the old rats when compared to young animals in the SNpc, but not in the VTA or SNI. TH protein levels in the ventral midbrain were also decreased in the old animals when compared to the young animals. These data demonstrate a progressive decline of ErbB4 expression, coinciding with a loss of the dopamine-synthesizing enzyme TH, in the ventral midbrain of aged rats, particularly in the SNpc. These findings may implicate a role for diminished NRG/ErbB4 trophic support in dopamine-related neurodegenerative disorders of aging such as Parkinson's disease.