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

Wayman, Wesley N.; Chen, Lihua; Hu, Xiu‐Ti; Napier, T. Celeste

doi:10.1038/npp.2015.366

Cited by 37 publications

(57 citation statements)

References 39 publications

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“…This was similar to that observed in our previous studies induced by bath application of HIV-1 Tat (Napier et al, 2014; Wayman et al, 2015a), and in adult HIV-1 Tg rats (Wayman et al, 2015b). The properties of such abnormal firing included (1) spontaneous firing with depolarized RMP, (2) reduced firing with deformed action potentials in response to moderate depolarizing currents (~150pA, suggesting over-activation-induced inactivation), and (3) post-hyperpolarization rebound-associated firing (suggesting a possible increase of LVA-Ca 2+ channel activity) ( Figure 1C ).…”

Section: Resultssupporting

confidence: 92%

“…Here, we determined that the HVA L-channel is the major contributor to the HIV-enhanced neuronal Ca 2+ influx, reflecting disruption of the L-channel kinetics (e.g., increased open probability and/or time) and expression. Furthermore, our previous studies also have revealed that acute Tat alters Ca 2+ homeostasis by increasing L-channel activity ex vivo and L-channel expression in vivo in mPFC pyramidal neurons (Hu, 2015; Napier et al, 2014; 2015a; Wayman et al, 2012), and that the mPFC of adult HIV-1 Tg rats (6-7 months of age) displays increased L-channel expression (Wayman et al, 2015b). Additionally, increased LVA-Ca 2+ channel activity was also implied by the occurrence of post-hyperpolarization-associated firing found in many mPFC neurons from HIV-1 Tg rats, which was rarely seen in those from non-Tg rats.…”

Section: Discussionmentioning

confidence: 94%

“…The input resistance (R in ) was calculated by fitting the V m response from the −100pA current step with the Boltzman charge-voltage equation. The inclusion criteria for data analysis were (1) a stable resting membrane potential (RMP) more hyperpolarized than −60mV for neurons from non-Tg control rats, and (2) the amplitude of initial Na + -dependent action potential (evoked by rheobase) greater than 60mV and 40mV, respectively, for neurons from non-Tg and HIV-1 Tg rats (Napier et al, 2014; Wayman et al, 2015a,b). The contribution of L-channels to action potential generation (neuronal excitability) was assessed by selectively blocking L-channel activity with acute perfusion of 5μM nifedipine (Nif) (Nasif et al, 2005a).…”

Section: Methodsmentioning

confidence: 99%

“…We have demonstrated that HIV-1 Tat abnormally increases L-channel activity and expression in the mPFC (Hu, 2015; Napier et al, 2014; 2015a; Wayman et al, 2012), and that chronic exposure to multiple HIV-1 proteins for 6 months increases L-channel expression in vivo (Wayman et al, 2015b). These findings, in combination with the established involvement of NMDAR in HIV neuropathogenesis (Haughey & Mattson, 2002; Mattson et al, 2005), led us to hypothesize that combined repetitive targeting of both over-active L-channels and NMDARs would decrease HIV-induced mPFC neuronal hyper-excitability.…”

Section: Introductionmentioning

confidence: 99%

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Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Khodr

Chen

Davé

et al. 2016

Neurobiology of Disease

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Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca2+ channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca2+ potentials (Ca2+ influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K+ influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca2+ influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca2+ potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca2+ influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca2+ dysregulation in the mPFC.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Khodr

Chen

Davé

et al. 2016

Neurobiology of Disease

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“…Substance use may increase the likelihood of engaging in behaviors that would increase HIV acquisition and transmission and drive many of the new infections, through inconsistent condom use, having multiple partners, and sharing injection needles. Both use of drug substances, such as cocaine and HIV have also been found to be directly and synergistically pathological to the prefrontal cortex and the dorsal and ventral striatum, regions involved in decision-making [6,10,11]. …”

Section: Neurocognitive Disordermentioning

confidence: 99%

Overlapping Risky Decision-Making and Olfactory Processing Ability in HIV-Infected Individuals

et al. 2017

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Objective Given neuroimaging evidences of overlap in the circuitries for decision-making and olfactory processing, we examined the hypothesis that impairment in psychophysical tasks of olfaction would independently predict poor performances on Iowa Gambling Task (IGT), a laboratory task that closely mimics real-life decision-making, in a US cohort of HIV-infected (HIV+) individuals. Method IGT and psychophysical tasks of olfaction were administered to a Washington DC-based cohort of largely African American HIV+ subjects (N=100), and to a small number of demographically-matched non-HIV healthy controls (N=43) from a different study. Constructs of olfactory ability and decision-making were examined through confirmatory factor analysis (CFA). Structural equation models (SEMs) were used to evaluate the validity of the path relationship between these two constructs Result The 100 HIV+ participants (56% female; 96% African Americans; median age = 48 years) had median CD4 count of 576 cells/μl and median HIV RNA viral load <48 copies per milliliter. Majority of HIV+ participants performed randomly throughout the course of IGT tasks, and failed to demonstrate a learning curve. Confirmatory factor analysis provided support for a unidimensional factor underlying poor performances on IGT. Nomological validity for correlations between olfactory ability and IGT performance was confirmed through SEM. Finally, factor scores of olfactory ability and IGT performance strongly predicted 6 months history of drug use, while olfaction additionally predicted hallucinogen use. Conclusion This study suggests that combination of simple, office-based tasks of olfaction and decision-making may identify those HIV+ individuals who are more prone to risky decision-making. This finding may have significant clinical, public health value if joint impairments in olfaction and IGT task correlates with more decreased activity in brain regions relevant to decision-making.

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Male HIV‐1 transgenic rats show reduced cocaine‐maintained lever‐pressing compared to F344 wildtype rats despite similar baseline locomotion

Huynh

Thompson

Larsen

et al. 2020

J Exper Analysis Behavior

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The HIV‐1 transgenic (Tg) rat model is valuable for understanding HIV‐associated neurocognitive disorders (HAND) and accompanying substance use and misuse. Tg and F344/NHsd wildtype (WT) rats were allowed to self‐administer intrajugular cocaine. For the first 7 sessions, neither genotype self‐administered cocaine (0.1 mg/kg/infusion) on a fixed ratio 1 schedule. We thus implemented a lever–cocaine “autoshaping” session followed by a series of manipulations changing dose and reinforcement schedule. Tg rats self‐administered much less cocaine than WT rats throughout the study. Of 8 Tg rats, 5 modestly increased self‐administration from sessions 36–50. Of those, only 3 showed a lever discrimination. Of 10 WT rats, 8 acquired robust self‐administration by session 19; all WT rats self‐administered cocaine by the end of the study. WT and Tg rats had similar baseline locomotor activity in the self‐administration chamber suggesting that the low levels of cocaine intake in the Tg rats did not reflect a nonspecific motor impairment in this rat strain. Concomitant measurement of activity with self‐administration revealed activity increases that followed increased cocaine intake. That relation held in Tg rats. Therefore, the present study provides evidence that HIV‐1 Tg rats are less sensitive to the reinforcing effects of cocaine than their F344 WT counterparts.

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

Cited by 37 publications

References 39 publications

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Overlapping Risky Decision-Making and Olfactory Processing Ability in HIV-Infected Individuals

Male HIV‐1 transgenic rats show reduced cocaine‐maintained lever‐pressing compared to F344 wildtype rats despite similar baseline locomotion

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