Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking

Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
Nature (Impact Factor: 41.46). 04/2013; 496(7445). DOI: 10.1038/nature12024
Source: PubMed


Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences. Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking. Here we use a rat model of compulsive drug seeking in which cocaine seeking persists in a subgroup of rats despite delivery of noxious foot shocks. We show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex, which was significantly more pronounced in compulsive drug-seeking animals. Furthermore, compensating for hypoactive prelimbic cortex neurons with in vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking. Our results show a marked reduction in prelimbic cortex excitability in compulsive cocaine-seeking rats, and that in vivo optogenetic prelimbic cortex stimulation decreased compulsive drug-seeking behaviours. Thus, targeted stimulation of the prefrontal cortex could serve as a promising therapy for treating compulsive drug use.

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Available from: Antonello Bonci, May 09, 2014
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    • "For instance, in rodents, compulsive behavior was operationalized as a resistance to the degradation of the reinforcer, that is, 15–20% of rats self-administering cocaine for several weeks kept pressing the lever despite that cocaine delivery was replaced with electric shocks (Deroche-Gamonet, Belin & Piazza, 2004). Interestingly, this behavior inflexibility has been associated with a persistent impairment in synaptic plasticity in the nucleus accumbens (Kasanetz et al., 2010) and hypoactive prelimbic cortex neurons (Chen et al., 2013). Importantly, this compulsive state is associated with both increased impulsivity and novelty seeking (Belin, Mar, Dalley, Robbins & Everitt, 2008). "
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    ABSTRACT: Background This paper is a commentary to a debate article entitled: "Are we overpathologizing everyday life? A tenable blueprint for behavioral addiction research", by Billieux et al. (2015). Methods and aim This brief response focused on the necessity to better characterize psychological and related neurocognitive determinants of persistent deleterious actions associated or not with substance utilization. Results A majority of addicted people could be driven by psychological functional reasons to keep using drugs, gambling or buying despite the growing number of related negative consequences. In addition, a non-negligible proportion of them would need assistance to restore profound disturbances in basic learning processes involved in compulsive actions. Conclusions The distinction between psychological functionality and compulsive aspects of addictive behaviors should represent a big step towards more efficient treatments.
    Journal of Behavioural Addictions 09/2015; 4(3):135-138. DOI:10.1556/2006.4.2015.017 · 1.87 Impact Factor
    • "Such studies encourage the notion that compulsivity associated with a neural circuit regulated by the OFC may be a general construct of neuropsychiatric disorders, including addiction. These cortical regions are also implicated in the production of compulsive stimulant drug seeking in rats that results in adverse consequences such as electric footshock (Chen et al. 2013; Pelloux et al. 2012, 2013). These aspects of impaired executive function are clearly relevant to addiction, but their precise causal role remains unclear. "
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    ABSTRACT: A decade ago, we hypothesized that drug addiction can be viewed as a transition from voluntary, recreational drug use to compulsive drug-seeking habits, neurally underpinned by a transition from prefrontal cortical to striatal control over drug seeking and taking as well as a progression from the ventral to the dorsal striatum. Here, in the light of burgeoning, supportive evidence, we reconsider and elaborate this hypothesis, in particular the refinements in our understanding of ventral and dorsal striatal mechanisms underlying goal-directed and habitual drug seeking, the influence of drug-associated Pavlovian-conditioned stimuli on drug seeking and relapse, and evidence for impairments in top-down prefrontal cortical inhibitory control over this behavior. We further review animal and human studies that have begun to define etiological factors and individual differences in the propensity to become addicted to drugs, leading to the description of addiction endophenotypes, especially for cocaine addiction. We consider the prospect of novel treatments for addiction that promote abstinence from and relapse to drug use. Expected final online publication date for the Annual Review of Psychology Volume 67 is January 03, 2016. Please see for revised estimates.
    Annual Review of Psychology 08/2015; 67(1). DOI:10.1146/annurev-psych-122414-033457 · 21.81 Impact Factor
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    • "Reduced activity in mPFC after PNE is correlated with poor impulse control and is likely to be directly related to elevated levels of drug seeking observed in ADHD and in rats that have chronically self-administered cocaine. Like prenatal nicotine, prolonged cocaine self-administration leads to mPFC hypoactivation and increased drug seeking, both of which are rescued through optogenetic stimulation of prelimbic prefrontal cortex (Chen et al, 2013). Together these results suggest that reduced firing in mPFC after exposure to prenatal nicotine might not only impair normal everyday executive control functions but increase one's predisposition to addiction (Dalley et al, 2011; Jentsch and Taylor, 1999). "
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    ABSTRACT: Prenatal nicotine exposure (PNE) is linked to numerous psychiatric disorders including attention deficit hyperactivity disorder (ADHD). Current literature suggests that core deficits observed in ADHD reflect abnormal inhibitory control governed by the prefrontal cortex. Yet, it is unclear how neural activity in the medial prefrontal cortex (mPFC) is modulated during tasks that assess response inhibition or if these neural correlates, along with behavior, are affected by PNE. To address this issue, we recorded from single mPFC neurons in control and PNE rats as they performed a stop-signal task. We found that PNE rats were faster for all trial-types, made more premature responses, and were less likely to inhibit behavior on 'STOP' trials during which rats had to inhibit an already initiated response. Activity in mPFC was modulated by response direction and was positively correlated with accuracy and movement time in control but not PNE rats. Although the number of single neurons correlated with response direction was significantly reduced by PNE, neural activity observed on general STOP trials was largely unaffected. However, dramatic behavioral deficits on STOP trials immediately following non-conflicting (GO) trials in the PNE group appear to be mediated by the loss of conflict monitoring signals in mPFC. We conclude that prenatal nicotine exposure makes rats impulsive and disrupts firing of mPFC neurons that carry signals related to response direction and conflict monitoring.Neuropsychopharmacology accepted article preview online, 20 July 2015. doi:10.1038/npp.2015.197.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.197 · 7.05 Impact Factor
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