No abstract

Methamphetamine (METH) addiction is prevalent among individuals with HIV infection. We hypothesize that HIV-positive individuals are more prone to METH use and to the development of METH dependence. To test this hypothesis, we examined the effects of METH (daily intraperitoneal injection 2.5 mg/kg for 6 days) on rearing and head movement in 12-13-week-old male HIV-1 transgenic (HIV-1Tg) rats compared to F344 control rats as an indicator of behavioral sensitization, also representing neural adaptation underlying drug dependence and addiction. Body and brain weights were also recorded. The involvement of the dopaminergic system was investigated by examining dopamine receptors 1 (D1R) and 2 (D2R) and dopamine transporter (DAT) expression in the striatum and prefrontal cortex. METH increased rearing number and duration in both F344 and HIV-1Tg rats. Rearing number was attenuated over time, whereas rearing duration remained constant. METH also induced a progressive increase in stereotypical head movement in both F344 and HIV-1Tg rats, but it was greater in the HIV-1Tg rats than in the F344 animals. The brain to body weight ratio was significantly lower in METH-treated HIV-1Tg rats compared to F344 controls. There was no significant difference in striatal D1R, D2R, or DAT messenger RNA in HIV-1Tg and F344 rats. However, D1R expression was greater in the prefrontal cortex of HIV-1Tg rats than F344 rats and was attenuated by METH. Our results indicate that METH-induced behavioral sensitization is greater in the presence of HIV infection and suggest that D1R expression in the prefrontal cortex may play a role in METH addiction in HIV-positive individuals.

We recently reported that six consecutive days of treatment with a moderate dose of methamphetamine (METH) induced greater behavioral sensitization in adult HIV-1 transgenic (HIV-1 Tg) rats than in adult Fischer 344/NHsd (F344) non-transgenic, wild-type control animals. In the present study, we evaluated the effects of a moderate dose of METH on the brains of adolescent versus adult HIV-1 Tg male rats using both behavioral (METH-induced, stereotypic head movement) and physiological (rectal body temperature) parameters. We found that both the acute and behavior-sensitizing effects of METH were greater in HIV-1 Tg rats compared with controls and also in adolescent rats compared with adult animals, regardless of HIV-1 status. We determined that acute hyperthermic effects of METH as well as tolerance to METH-induced hyperthermia were greater in HIV-1 Tg rats than in controls. Taken together, these results suggest that both the neuroadaptations seen in HIV infection and the immaturity of the adolescent brain are associated with increased sensitivity to the psychoactive and behavior-sensitizing properties of METH. Thus, HIV-infected individuals and adolescents may be more vulnerable to the development of METH abuse and dependence than non-infected individuals and adults.

HIV infection and methamphetamine (Meth) abuse both may lead to oxidative stress. This study used HIV-1 transgenic (HIV-1Tg) rats to investigate the independent and combined effects of HIV viral protein expression and low dose repeated Meth exposure on the glutathione (GSH)-centered antioxidant system and oxidative stress in the brain. Total GSH content, gene expression and/or enzymatic activities of glutamylcysteine synthetase (GCS), gamma-glutamyltransferase (GGT), glutathione reductase (GR), glutathione peroxidase (GPx), glutaredoxin (Glrx), and glutathione-s-transferase (GST) were measured. The protein expression of cystine transporter (xCT) and oxidative stress marker 4-hydroxynonenal (HNE) were also analyzed. Brain regions studied include thalamus, frontal and remainder cortex, striatum, cerebellum and hippocampus. HIV-1Tg rats and Meth exposure showed highly regional specific responses. In the F344 rats, the thalamus had the highest baseline GSH concentration and potentially higher GSH recycle rate. HIV-1Tg rats showed high transcriptional responses to GSH depletion in the thalamus. Both HIV-1Tg and Meth resulted in decreased GR activity in thalamus, and decreased Glrx activity in frontal cortex. However, the increased GR and Glrx activities synergized with increased GSH concentration, which might have partially prevented Meth-induced oxidative stress in striatum. Interactive effects between Meth and HIV-1Tg were observed in thalamus on the activities of GCS and GGT, and in thalamus and frontal cortex on Glrx activity and xCT protein expression. Findings suggest that HIV viral protein and low dose repeated Meth exposure have separate and combined effects on the brain’s antioxidant capacity and the oxidative stress response that are regional specific.