Worldwide, stimulants such as methamphetamine rank second only to cannabis in number of users, and in North America, the prevalence of amphetamine abuse is double the global rate. Methamphetamine (meth) is being found to play an increasingly important role in AIDS, as well. Evidence suggests that meth and HIV infection have additive effects on neurocognitive impairment and CNS damage. Meth is a sympathomimetic causing release of norepinephrine from peripheral nerves, and we have shown that norepinephrine promotes HIV and SIV replication. Meth's effects on the CNS, then, could be an indirect consequence of its ability to release norepinephrine from sympathetic varicosities in secondary lymphoid tissue, leading to greater viral replication and higher viral loads, and greater numbers of circulating, infected cells (primarily monocytes) that can enter the CNS. Meth's effects in the CNS could also result from effects on the blood-brain barrier (BBB). Independent lines of evidence suggest that meth, stress (a precipitating factor for much drug use, including methamphetamine), and HIV/SIV can all contribute to weakening the blood-brain barrier. We propose that these three factors could have additive effects, resulting in increased transport across the BBB of blood borne factors such as infected monocytes and inflammatory cytokines, leading to a greater likelihood of CNS infection and damage, and neuropsychological impairment. Finally, given our demonstrated effects of stress on viral replication in lymph nodes, and the additional effects we anticipate seeing due to the sympathomimetic properties of methamphetamine, we propose that beta adrenergic receptor blockade or administration of recombinant interferon-beta will abrogate the effects of methamphetamine and stress in the lymph node.
Our specific aims are 1) to examine the role played by methamphetamine and stress in alterations in innervation patterns, Type I interferon gene expression, and SIV replication in lymph nodes, and disease-related indicators in blood; 2) to examine the role played by methamphetamine and stress in altering permeability of the blood-brain barrier in SIV infected monkeys; 3) to examine whether beta adrenergic receptor blockade or administration of recombinant interferon-beta will abrogate the effects of methamphetamine in lymph nodes and at the BBB.Relevance ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA024441-02S1
Application #
7678662
Study Section
Special Emphasis Panel (ZDA1-NXR-B (20))
Program Officer
Lawrence, Diane M
Project Start
2007-09-30
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$139,527
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Other Domestic Higher Education
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Chun, K; Capitanio, J P; Lamkin, D M et al. (2017) Social regulation of the lymph node transcriptome in rhesus macaques (Macaca mulatta). Psychoneuroendocrinology 76:107-113
Capitanio, John P; Cole, Steven W (2015) Social instability and immunity in rhesus monkeys: the role of the sympathetic nervous system. Philos Trans R Soc Lond B Biol Sci 370:
Cole, Steven W; Capitanio, John P; Chun, Katie et al. (2015) Myeloid differentiation architecture of leukocyte transcriptome dynamics in perceived social isolation. Proc Natl Acad Sci U S A 112:15142-7
Capitanio, John P (2012) Social processes and disease in nonhuman primates: introduction to the special section. Am J Primatol 74:491-6
Cole, Steve W; Mendoza, Sally P; Capitanio, John P (2009) Social stress desensitizes lymphocytes to regulation by endogenous glucocorticoids: insights from in vivo cell trafficking dynamics in rhesus macaques. Psychosom Med 71:591-7
Cole, Steven W (2009) Chronic inflammation and breast cancer recurrence. J Clin Oncol 27:3418-9
Capitanio, John P (2008) Personality and disease. Brain Behav Immun 22:647-50