title: HIV-1 Transgenic Rat Prefrontal Cortex Hyper-Excitability is Enhanced by Cocaine Self-Administration.
abstract: The medial prefrontal cortex (mPFC) is dysregulated in HIV-1-infected humans and the dysregulation is enhanced by cocaine abuse. Understanding mPFC pathophysiology in this comorbid state has been hampered by the dearth of relevant animal models. To help fill this knowledge gap, electrophysiological assessments were made of mPFC pyramidal neurons (PN) from adult male HIV-1 transgenic (Tg) F344 rats (which express seven of the nine HIV-1 toxic proteins) and non-Tg F344 rats that self-administered cocaine for 14 days (COC-SA), as well as saline-yoked controls (SAL-Yoked) and experimentally naive Tg and non-Tg rats. Forebrain slices were harvested and prepared for whole-cell patch-clamp recording, and in treated rats, this occurred after 14-18 days of forced abstinence. Aged-matched rats were used for immunohistochemical detection of the L-channel protein, Cav1.2-α1c. We determined that: (i) the two genotypes acquired the operant task and maintained similar levels of COC-SA, (ii) forced abstinence from COC-SA enhanced mPFC PN excitability in both genotypes, and neurons from Tg rats exhibited the greatest pathophysiology, (iii) neurons from SAL-Yoked Tg rats were more excitable than those from SAL-Yoked non-Tg rats, and in Tg rats (iv) blockade of L-type Ca(2+) channels reduced the enhanced excitability, and (v) Cav1.2-immunoreactivity was increased. These findings provide the first assessment of the mPFC pathophysiology in a rodent model of HIV-1-mediated neuropathology with and without cocaine self-administration. Outcomes reveal an enhanced cortical excitability during chronic exposure to HIV-1 proteins that is excessively exacerbated with cocaine abuse. Such neuropathophysiology may underlie the cognitive dysregulation reported for comorbid humans.
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA.|Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Wesley N
authors.initials: WN
authors.lastname: Wayman
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA.|Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA.|Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Xiu-Ti
authors.initials: XT
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA.|Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.|Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA.
authors.forename: T Celeste
authors.initials: TC
authors.lastname: Napier
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D000071080:Cortical Excitability / Q000187:drug effects*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology / Q000821:virology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology / Q000821:virology; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D012646:Self Administration
chemical_list: D003042:Cocaine