Cocaine self‐administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus‐1 Tat

Abstract

The medial prefrontal cortex (mPFC) plays a critical role in reward-motivated behaviors. Repeated cocaine exposure dysregulates the dorsal mPFC, and this is thought to contribute to cocaine-seeking and relapse of abstinent abusers. Neuropathology of the mPFC also occurs in human immunodeficiency virus (HIV)-positive individuals, and this is exaggerated in those who also abuse cocaine. The impact of the comorbid condition on mPFC neuronal function is unknown. To fill this knowledge gap, we performed a behavioral and electrophysiological study utilising adult male rats that self-administered cocaine by pressing a lever for 14 oncedaily operant sessions. Saline-yoked (SAL-yoked) rats served as controls. Cue reactivity (CR) was used to indicate drug-seeking, assessed by re-exposing the rats to cocaine-paired cues wherein non-reinforced lever pressing was quantified 1 day (CR1) and 18–21 days (CR2) after the 14th operant session. Only cocaine self-administration (COC-SA) rats showed CR. One day after CR2, brain slices were prepared for electrophysiological assessment. Whole-cell patch-clamp recordings of dorsal (prelimbic) mPFC pyramidal neurons from COC-SA rats showed a significant increase in firing evoked by depolarizing currents as compared with those from SAL-yoked control rats. Bath application of the toxic HIV-1 protein transactivator of transcription (Tat) also depolarized neuronal membranes and increased evoked firing. The Tat-induced excitation was greater in the neurons from withdrawn COC-SA rats than in controls. Tat also reduced spike amplitude, and this co-varied with cocaine-seeking during CR2. Taken together, these novel findings provide support at the neuronal level for the concept that the increased excitability of mPFC pyramidal neurons following cocaine self-administration drives drug-seeking and augments the neuropathophysiology caused by HIV-1 Tat.

HIV-1 Transgenic Rat Prefrontal Cortex Hyper-Excitability is Enhanced by Cocaine Self-Administration

“…PN were visually identified (Olympus BX-51,Luigs and Neumann, Ratingen, Germany) within the prelimbic (PrL) mPFC subregion in layers 5/6. The PN electrophysiological profile matched that previously determined for biocytin-labeled PrL-mPFC PNs (Wayman et al, 2015a). Recorded signals were amplified and filtered (MultiClamp 700A, Molecular Devices, Union City, CA) and digitized (Digidata 1322, Axon Instruments, Molecular Devices, Union City, CA).…”

“…Fisher 344 non-Tg rats do not exhibit the robust drugtaking seen in other strains of rats, such as Lewis (Picetti et al, 2012;Meyer and Bardo, 2015) or Sprague-Dawley (Wayman et al, 2015a). Nonetheless, 0.1 mg/kg of cocaine/ infusion (ie,~33.3 μg/infusion for 300 g rats) used in the current study was sufficiently motivating for both non-Tg and Tg rats to rapidly learn the operant task and to demonstrate a clear preference for the drug-paired hole relative to the inactive hole.…”

“…Surgical instrumentation and self-administration tasks generally followed our published protocols (Wayman et al, 2015a). In brief, isoflurane-anesthetized rats were surgically fitted with an 11.5-cm jugular vein catheter connected to a port externalized on the rats' back.…”

“…Upon a nose poke, a motor-driven syringe pump (Med-Associates) delivered infusions of saline or cocaine (0.1 mg/kg/0.1 ml) via tubing connected the rat's port. The concentration was based on our pilot studies wherein we determined that performance improved with concentrations below the 1.0 mg/kg/infusion we use for Sprague-Dawley rats (Wayman et al, 2015a) and that Fischer rats readily acquired and maintained COC-SA at 0.1 mg/kg/0.1 ml of cocaine. Test sessions were 2 h per day for 14 days.…”

“…Procedures followed our published protocols (Napier et al, 2014;Wayman et al, 2015a). To overview, after forced abstinence, rats (5.5-7 months of age) were anesthetized with chloral hydrate (400 mg/kg, i.p.…”