Our proposed Research Program Project (PPG): The SCRIPPS Research in-MethAmphetamine-NeuroAIDS Research Program (TSRI-MANARP) seeks to determine in select animal models, the neurotoxic infection with methamphetamine (METH) neuropharmacology. Using pre-clinical models (mice, felines and macaques), we will determine the location, biological course, and functional consequence of what we hypothesize to be common pathological processes leading to a more fulminant viral injection and functional decline in treated animals. We believe that only by employing the controlled experimental settings provided in the proposed experimental plan will the precise biological interactions and risk factors for pathology be discerned. Employing three well established animal models of neuro-AIDS we propose to investigate several methamphetamine neuropharmacology and NeuroAIDS-related neurotoxicity. Each animal model brings to convergence of these toxic phenotypes. Preliminary data included with the revised application provides new evidence for synergy in METH neuropharmacology and HIV-1 pathogenesis; evidence that is bolstered by theme to investigate the role of methamphetamine on disease progression and functional pathology in our documented high risk behaviors for HIV-1 exposure associated with methamphetamine abuse; 2. The converging evidence of both sub-cortical and cortical pathologies independently associated with both agents; 3. The evidence of direct actions of amphetamines on immune status, and 4. The woeful under representation of cellular, behavioral, and pathophysiological studies in this area.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
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Special Emphasis Panel (ZDA1-RXL-E (16))
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Frankenheim, Jerry
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Scripps Research Institute
La Jolla
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Huitron-Resendiz, Salvador; Henriksen, Steven J; Barr, Margaret C et al. (2010) Methamphetamine and lentivirus interactions: reciprocal enhancement of central nervous system disease. J Neurovirol 16:268-78
Sanchez-Alavez, Manuel; Conti, Bruno; Moroncini, Gianluca et al. (2007) Contributions of neuronal prion protein on sleep recovery and stress response following sleep deprivation. Brain Res 1158:71-80
Persidsky, Yuri; Fox, Howard (2007) Battle of animal models. J Neuroimmune Pharmacol 2:171-7
Milner, Richard; Campbell, Iain L (2006) Increased expression of the beta4 and alpha5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-alpha in the central nervous system. Mol Cell Neurosci 33:429-40
Criado, Jose R; Sanchez-Alavez, Manuel; Conti, Bruno et al. (2005) Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol Dis 19:255-65
Madden, Lisa J; Flynn, Claudia T; Zandonatti, Michelle A et al. (2005) Modeling human methamphetamine exposure in nonhuman primates: chronic dosing in the rhesus macaque leads to behavioral and physiological abnormalities. Neuropsychopharmacology 30:350-9
Balosso, Silvia; Ravizza, Teresa; Perego, Carlo et al. (2005) Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors. Ann Neurol 57:804-12
Huitron-Resendiz, Salvador; Kristensen, Morten P; Sanchez-Alavez, Manuel et al. (2005) Urotensin II modulates rapid eye movement sleep through activation of brainstem cholinergic neurons. J Neurosci 25:5465-74
Sanchez-Alavez, Manuel; Gombart, Lhys M; Huitron-Resendiz, Salvador et al. (2004) Physiological and behavioral effects of methamphetamine in a mouse model of endotoxemia: a preliminary study. Pharmacol Biochem Behav 77:365-70
Huitron-Resendiz, Salvador; Sanchez-Alavez, Manuel; Wills, Derek N et al. (2004) Characterization of the sleep-wake patterns in mice lacking fatty acid amide hydrolase. Sleep 27:857-65

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