Human immunodeficiency virus (HIV)-infected individualswho abuse opiates show faster progression to AIDS, and enhanced incidence of HIV-1 encephalitis. Most opiates with abuse liability are preferential agonists for l-opioid receptors (MORs), and MORs are expressed on both neurons and glia, including oligodendrocytes (OLs). Tat, gp120, and other viral toxins, cause neurotoxicity in vitro and/or when injected into brain, and co-exposure to opiates can augment HIV-1 protein-induced insults to both glial and neuronal populations. We examined the effects of HIV-1 Tat 1/2 opiate exposure on OL survival and differentiation. In vivo studies utilized transgenic mice expressing Tat 1-86 regulated by an inducible glial fibrillary acidic protein promoter. Although MBP levels were unchanged on immunoblots, certain structural and apoptotic indices were abnormal. After only 2 days of Tat induction, OLs showed an upregulation of active caspase-3 that was enhanced by morphine exposure. Tat also upregulated TUNEL staining, but only in the presence of morphine. Tat significantly reduced the length of processes in Golgi-Kopsch impregnated OLs. A greater proportion of cells exhibited diminished or aberrant cytoplasmic processes, especially when mice expressing Tat were co-exposed to morphine. Collectively, our data show that OLs in situ are extremely sensitive to effects of Tat 1/2 morphine, although it is not clear if immature OLs as well as differentiated OLs are targeted equally. Significant elevations in caspase-3 activity and TUNEL labeling, and evidence of increased degeneration/ regeneration of OLs exposed to Tat 1/2 morphine suggest that toxicity toward OLs may be accompanied by heightened OL turnover. V V C

In female mammals, increased ovarian estradiol (E(2)) secretion triggers GnRH release from neurons in the basal forebrain, which drives LH secretion from the pituitary and subsequently induces ovulation. However, the neural circuits that activate this preovulatory GnRH/LH surge remain unidentified. Neurotensin is expressed in neurons of the anteroventral periventricular nucleus (AVPV), a region thought to be critical for generating the preovulatory GnRH/LH surge. E(2) induces neurotensin (Nts) gene expression in this region, and blockade of neurotensin signaling reduces the LH surge in the rat. We postulated that neurotensin signaling plays a similar role in generating the E(2)-induced GnRH/LH surge in mice. We used in situ hybridization (ISH) to determine whether E(2) induces Nts expression in the mouse and found evidence to support this proposition. Next, we determined that the neurotensin receptor (Ntsr2) is present in many GnRH-expressing neurons. Since the kisspeptin gene (Kiss1) is expressed in the AVPV and is responsive to E(2), we predicted that some neurons in this region express both Kiss1 and Nts; however, by double-label ISH, we observed no coexpression of the two mRNAs. We also postulated that Nts mRNA expression would increase in parallel with the E(2)-induced LH surge and that the central (icv) administration of neurotensin would stimulate LH secretion and activation of GnRH neurons but found no evidence to support either of these hypotheses. Together, these findings suggest that, although neurotensin neurons in the AVPV are targets for regulation by E(2), neurotensin does not appear to play a direct role in generating the GnRH/LH surge in the mouse.

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Glutamate is an important excitatory neurotransmitter that stimulates the release of gonadotrophin-releasing hormone (GnRH) and participates in the generation of the luteinising hormone (LH) surge. To determine the mechanisms of action of glutamate and possible changes in the glutamatergic input to GnRH neurones during reproductive ageing, we measured the expression and activation of the mandatory N-methyl-D-aspartate receptor subunit-1 (NMDAR1) in GnRH neurones of young and middle-aged mice prior to and during a steroid-induced LH surge. The results show that, in young animals, approximately 55% of all GnRH neurones contain immunoreactive NMDAR1 protein and this percentage does not change during the day of the LH surge. In approximately 10% of the GnRH neurones, NMDA receptor protein is phosphorylated at Ser 890 prior to the surge, whereas, in approximately 55% of the GnRH neurones, NMDAR1 subunits are phosphorylated during the LH surge. Activation of NMDAR1 receptor subunits stimulates the calcium-calmodulin-kinase IV (CaMK IV). pathway, which leads to the translocation of CaMK IV into the nucleus where this enzyme can phosphorylate the cAMP response element-binding protein (CREB) and CREB-binding protein. We show that, in young animals, approximately 20% of the GnRH neurones contain CaMK IV in their nuclei 7 h prior to the LH surge; this percentage increases to 60% at the beginning of the surge and decreases to approximately 40% some 2 h into the LH surge. In middle-aged animals, approximately 25% of the GnRH neurones contain NMDAR1 protein and only 10% of the GnRH neurones contain phosphorylated NMDAR1 protein prior to and during the surge; however 2 h after the peak of the surge, 20% of the GnRH neurones contain phosphorylated NMDAR1 subunits. Similarly, 20% of GnRH neurones contain nuclear CaMK IV and this percentage does not change during the day of the LH surge. The results suggest that, in the young animal, glutamatergic innervation of GnRH neurones during the LH surge causes the activation and phosphorylation of NMDAR1 receptor subunits which results in the translocation of CaMK IV into the nucleus. However, both, the expression and activation of NMDAR1 receptor subunits are greatly reduced in the middle-aged animals, which could result in the absence of LH surges.

Jimpy is a murine mutation in myelin proteolipid protein, leading to premature death of oligodendrocytes and severe central nervous system hypomyelination. Jimpy is a bona fide model of human Pelizaeus-Merzbacher disease. This paper describes a severe reduction in expression of κ-opioid receptors (KOP) in oligodendrocytes of jimpy mice. A cell specific reduction of >90% is apparent by 5 days of age. Expression is not reduced in neurons, and μ-opioid receptor expression is normal. Mechanism(s) leading to deficient KOP expression in jimpy mice remain unclear. We speculate that loss of KOP may be related to increased [Ca2+]i and premature death of jimpy oligodendrocytes.

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