Increases in compulsivity, inflammation, and neural injury in HIV transgenic rats with escalated methamphetamine self-administration under extended-access conditions

Abstract

The abuse of stimulants, such as methamphetamine (METH), is associated with treatment noncompliance, a greater risk of viral transmission, and the more rapid clinical progression of immunological and central nervous system human immunodeficiency virus (HIV) disease. The behavioral effects of METH in the setting of HIV remain largely uncharacterized. We used a stateof-the-art paradigm of the escalation of voluntary intravenous drug self-administration in HIV transgenic (Tg) and wildtype rats. The rats were first allowed to self-administer METH under short-access (ShA) conditions, which is characterized by a nondependent and more "recreational" pattern of METH use, and then allowed to self-administer METH under long-access (LgA) conditions, which leads to compulsive (dependent) METH intake. HIV Tg and wildtype rats selfadministered equal amounts of METH under ShA conditions. HIV Tg rats under LgA METH selfadministration following a 4-week enforced abstinence period to model the intermittent pattern of stimulant abuse in humans, developed greater motivation to self-administer METH and selfadministered larger amounts of METH. Impairments in function of the medial prefrontal cortex (mPFC) contribute to compulsive drug and alcohol intake. Gene expression profiling of the mPFC

Central nervous system (CNS) transcriptomic correlates of human immunodeficiency virus (HIV) brain RNA load in HIV-infected individuals

“…HIV transgenic (Tg) rats on a mixed Wistar-Fischer background, which ensures variability of host genes and HIV expression levels, were used for the study 36 . Male HIV Tg rats, weighing between 350 and 400 g, were housed two per cage on a reverse 12 h/12 h light/dark cycle (lights off at 8:00 AM) in a temperature (20–22°C) and humidity (45–55%) controlled vivarium with ad libitum access to tap water and food pellets (PJ Noyes, Lancaster, NH, USA).…”

“…All of the procedures were conducted in strict adherence to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of The Scripps Research Institute and ARRIVE guidelines ( http://www.nc3rs.org.uk/page.asp?id=1357 ). A total of 18 gene expression profiles from prefrontal cortices of HIV Tg rats profiled by RNA-Seq as previously described 36 were separated into two groups based on the mean expression of brain HIV transcripts to create groups with graded levels of HIV transcription (n = 7 for high brain HIV RNA load and n = 10 for low brain HIV RNA load). Differential expression between groups was computed with DESeq2 and used as an input for the GSEA to identify pathways that were differentially regulated between samples with high and low HIV expression.…”

Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder

“…For example, METH-induced inflammation in the nucleus accumbens was shown to mediate METH reinforcing properties 11 , 78 . In the EA METH SA paradigm, large doses of METH were self-administered, likely causing oxidative stress and inflammation in multiple brain areas, including the nucleus accumbens 11 , 81 . PARKIN function has been linked to energy metabolism, and cytoskeletal arrangement as well as to protection against oxidative stress, and inflammation 25 , 26 , 29 – 31 .…”

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

“…It has been reported that cocaine self-administration in mice reduced uptake of NDEVs by the astrocytes primarily in the motor cortex, an effect that was effectively reversed by extinction training [ 205 ]. Drugs of abuse like cocaine, morphine, methamphetamine [ 206 , 207 , 208 ] can induce chronic low-level inflammation and can also potentiate inflammatory status in the context of HIV-1 [ 209 , 210 , 211 ], which together can contribute to the process of inflammaging. As discussed above presence of ApoE4 is highly prevalent in the aging HIV-1 population.…”