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, 2002; Laviolette and van der Kooy, 2004) and play a critical role in nicotine-mediated behavior (Corrigall et al., 1994; Ferrari et al., 2002). The extracellular regulated protein kinase (ERK) and its downstream transcriptional signaling protein, the cyclic AMP response element-binding protein (CREB), appear critical for long-term adaptations in individuals who exhibit drug abuse (Berhow et al., 1996; Carlezon et al., 1998; Nestler, 2001; Girault et al., 2007). Acute nicotine treatment increases CREB [http://www.selleckchem.com/products/otx015.html OTX015 order] phosphorylation in the NAc, striatum and VTA (Walters et al., 2005; Jackson et al., 2009), whereas repeated nicotine treatment in mice decreases CREB phosphorylation in the NAc, and nicotine withdrawal increases CREB phosphorylation in the VTA (Brunzell et al., 2003). Therefore, long-term nicotine  exposure leads to neural plasticity in intracellular signaling through the changes of ERK and CREB signaling (Brunzell et al., 2003, 2009; Mineur et al., 2009). Our recent study shows that HIV-1 viral proteins alter basal phosphorylation levels of CREB and ERK and their phosphorylated response to nicotine in the PFC of HIV-1 transgenic rats (Midde et al., 2011). Given the critical role of the VTA in nicotine-mediated plasticity and behavior, along with our recent report that HIV-1 viral proteins altered ERK and CREB activity in mesocorticolimbic areas, the current study examined whether the microinjection of Tat into the VTA altered nicotine-mediated behavioral sensitization and the signaling protein activity. Our  results demonstrate that Tat-induced impairment of the VTA would attenuate intravenous nicotine-induced sensitization of locomotor activity in rats. Materials and Methods Animals Male Sprague-Dawley Rats (225�C250 g) were obtained from Harlan Laboratories, Inc (Indianapolis, IN, USA). All rats were surgically preimplanted with an Intracath IV catheter (22 ga, Becton/Dickinson General Medical Corp., Grand Prairie, TX, USA), which was dorsally implanted port for chronic IV injections (Mactutus et al., 1994). Animals were pair housed in standard polyurethane cages throughout the experiment and provided normal rodent food (ProLab Rat/Mouse/Hamster Chow 3000) and water ad libitum. The catheters were flushed daily with 0.2 ml of heparinized (2.5%) saline. The colony was maintained  at 21 �� 2��C, 50 �� 10% relative humidity and a 12L:12D cycle with lights on at 0700 h (EST). The animals were maintained according to the National Institute of Health (NIH) guidelines in AAALAC accredited facilities. The experimental protocol was approved by the Institutional Animal Care and Use Committee (IACUC) at the University of South Carolina. Drugs Nicotine hydrogen tartrate salt was purchased from Sigma-Aldrich (St. Louis, MO, USA) and dissolved in sterile saline (0.9% sodium chloride). Nicotine was prepared immediately prior to injection. The nicotine solution was neutralized to pH 7.0 with NaHCO3. Nicotine (0.