Abstract
Cigarette smoking prevalence in the HIV-positive individuals is profoundly higher than that in the HIV-negative individuals. We have demonstrated that HIV-1 transgenic rats exhibit attenuated nicotine-mediated locomotor activity, altered cAMP response element binding protein (CREB) and extracellular regulated kinase (ERK1/2) signaling in the mesocorticolimbic regions. This study investigated the role of HIV-1 transactivator of transcription (Tat) protein in the alterations of nicotine-mediated behavior and the signaling pathway observed in the HIV-1 transgenic rats. Rats received bilateral microinjection of recombinant Tat1–86 (25 μg/side) or vehicle directed at ventral tegmental area (VTA) followed by locomotor testing in response to 13 daily intravenous injections of nicotine (0.05 mg/kg, freebase, once/day) or saline. Further, we examined the phosphorylated levels of CREB (pCREB) and ERK1/2 (pERK1/2) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and VTA. Tat diminished baseline activity in saline control rats, and attenuated nicotine-induced behavioral sensitization. Following repeated saline injection, the basal levels of pERK1 in the NAc and VTA and pERK2 in VTA were lower in the vehicle control group, relative to the Tat group. After repeated nicotine injection, pERK1 in NAc and VTA and pERK2 in VTA were increased in the vehicle group, but not in the Tat group. Moreover, repeated nicotine injections decreased pCREB in the PFC and VTA in the Tat group but not in the vehicle group. Thus, these findings indicate that the direct injection of Tat at the VTA may mediate CREB and ERK activity in response to nicotine-induced locomotor activity.
Highlights
The introduction of efficacious antiretroviral therapies reduces the mortality in HIV infected patients, 50% of these patients still suffer from HIV-1-associated neurocognitive disorders (HAND; Sacktor et al, 2001; Sacktor, 2002; Ellis et al, 2007; McArthur et al, 2010; Heaton et al, 2011)
The findings demonstrate that (1) Tat protein is critical for HIV-1 viral proteininduced neurochemical and behavioral changes in response to nicotine, and (2) the cAMP response element binding protein (CREB) and extracellular regulated protein kinase (ERK) signaling pathway in the mesocorticolimbic system appears to have played a role in the blunted nicotine-mediated locomotor activity by Tat protein
The current study demonstrates that rats with intra-ventral tegmental area (VTA) Tat exhibited a small decrease in body weight under saline control condition compared to the vehicle control; FIGURE 7 | Levels of ERK and CREB proteins in the VTA of intra-VTA vehicle or Tat rats. (A) Representative western blots showing the protein density of CREB, pCREB, ERK1/2, pERK1/2, and β-tubulin in the VTA of rats with intra-VTA vehicle (Veh) or Tat following repeated injections of nicotine (Veh-Nic or Tat-Nic) or saline (Veh-Sal or Tat-Sal). (B) Total and phosphorylated levels of CREB and ERK1/2
Summary
The introduction of efficacious antiretroviral therapies reduces the mortality in HIV infected patients, 50% of these patients still suffer from HIV-1-associated neurocognitive disorders (HAND; Sacktor et al, 2001; Sacktor, 2002; Ellis et al, 2007; McArthur et al, 2010; Heaton et al, 2011). Drug abuse in HIV-positive individuals results in greater neurological impairments and precipitates the development of HAND relative to those HIV-positive individuals who do not abuse. According to the Centers for Disease Control and Prevention (CDC) report about cigarette smoking among adults, the rate of cigarette smoking among HIV positive individuals is threefold greater than that in HIV negative population (CDC, 2007). HIV-positive individuals are more likely to become dependent on nicotine and less likely to quit than HIV-negative individuals (Hershberger et al, 2004; Fuster et al, 2009; Nahvi and Cooperman, 2009). Given the high risk for cigaretteassociated morbidity and mortality (Crothers et al, 2005), and the great incidence of HAND in HIV positive individuals, there is a critical need to define the molecular mechanisms underlying the enhanced susceptibility to nicotine dependence in HIV smokers
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