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 example, prior studies have demonstrated that rats with extended (i.e., > 1 month) access to cocaine achieve higher breakpoints on a progressive ratio (PR) schedule of reinforcement, seek cocaine when it is unavailable, and continue to respond for the drug when such seeking behavior is punished by footshock (Belin et al., 2011; Deroche-Gamonet et al., 2004). A number of subsequent studies have used these and other behavioral procedures to investigate changes in neural circuits (Chen et al., 2013; Hollander et al., 2010; Jonkman et al., 2012; Xue et al., 2012) and synaptic functions (Cannella et al., 2013; Kasanetz et al., 2013) associated with compulsive cocaine-seeking. "
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    ABSTRACT: Addictions, including alcohol use disorders, are characterized by the loss of control over drug seeking and consumption, but the neural circuits and signaling mechanisms responsible for the transition from controlled use to uncontrolled abuse remain incompletely understood. Prior studies have shown that 'compulsive-like' behaviors in rodents, for example, persistent responding for ethanol (EtOH) despite punishment, are increased after chronic exposure to EtOH. The main goal of the current study was to assess the effects of chronic intermittent EtOH (CIE) exposure on multiple, putative measures of compulsive-like EtOH seeking in C57BL/6 J mice. Mice were exposed to two or four weekly cycles of CIE and then, post-withdrawal, tested for progressive ratio responding for EtOH, sustained responding during signaled EtOH unavailability and (footshock) punished suppression of responding for EtOH. Results showed that mice exposed to CIE exhibited attenuated suppression of EtOH seeking during punishment, as compared with air-exposed controls. By contrast, CIE exposure affected neither punished food reward-seeking behavior, nor other putative measures of compulsive-like EtOH seeking. Ex vivo reverse transcription polymerase chain reaction analysis of brain tissue found reduced sensitivity to punished EtOH seeking after CIE exposure was accompanied by a significant increase in gene expression of the GluN1 and GluN2A subunits of the N-methyl-d-aspartate receptor, specifically in the medial orbitofrontal cortex. Moreover, slice electrophysiological analysis revealed increased N-methyl-d-aspartate receptor-mediated currents in the orbitofrontal cortex after CIE exposure in test-naïve mice. Collectively, the current findings add to the growing body of evidence demonstrating that chronic exposure to EtOH fosters resistance to punished EtOH seeking in association with adaptations in cortical glutamatergic transmission.
    Full-text · Article · Dec 2015 · Addiction Biology
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    • "Therefore, a direct clinical translation of the previous preclinical literature (Chen et al., 2013) could be attempted by testing the hypothesis that electrical stimulation of the DLPFC significantly decreases compulsive cocaine seeking behaviors . Operationally, this hypothesis can be tested by using transcranial magnetic stimulation (TMS), a non-invasive, and safe, human brain stimulation technology based on electromagnetic induction (Lefaucheur et al., 2014; Barker et al., 1985). "
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    ABSTRACT: Recent animal studies demonstrate that compulsive cocaine seeking strongly reduces prelimbic frontal cortex activity, while optogenetic stimulation of this brain area significantly inhibits compulsive cocaine seeking, providing a strong rationale for applying brain stimulation to reduce cocaine consumption. Thus, we employed repetitive transcranial magnetic stimulation (rTMS), to test if dorsolateral prefrontal cortex (DLPFC) stimulation might prevent cocaine use in humans. Thirty-two cocaine-addicted patients were randomly assigned to either the experimental group (rTMS) on the left DLPFC, or to a control group (pharmacological agents) during a 29-day study (Stage 1). This was followed by a 63-day follow-up (Stage 2), during which all participants were offered rTMS treatment. Amongst the patients who completed Stage 1, 16 were in the rTMS group (100%) and 13 in the control group (81%). No significant adverse events were noted. During Stage 1, there were a significantly higher number of cocaine-free urine drug tests in the rTMS group compared to control (p=0.004). Craving for cocaine was also significantly lower in the rTMS group compared to the controls (p=0.038). Out of 13 patients who completed Stage 1 in the control group, 10 patients received rTMS treatment during Stage 2 and showed significant improvement with favorable outcomes becoming comparable to those of the rTMS group. The present preliminary findings support the safety of rTMS in cocaine-addicted patients, and suggest its potential therapeutic role for rTMS-driven PFC stimulation in reducing cocaine use, providing a strong rationale for developing larger placebo-controlled studies. Trial name: Repetitive transcranial magnetic stimulation (rTMS) in cocaine abusers, URL:〈〉, Registration number: ISRCTN15823943.
    Preview · Article · Dec 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
    • "Self-Stimulation despite Punishment Substance use despite negative consequences is another crucial defining feature of addiction (see DSM5 definition, American Psychiatric Association, 2013). Rat models have been established (Deroche-Gamonet et al., 2004; Pelloux et al., 2007, 2015; Chen et al., 2013) where an electric shock introduced in the cocaine self-administration schedule suppresses cocaine consumption in some animals. Following 12 days of initial exposure (acquisition), mice were allowed to have three additional sessions at FR3 but with a reduced session cut-off (60 min or 40 rewards maximum). "
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    ABSTRACT: The factors causing the transition from recreational drug consumption to addiction remain largely unknown. It has not been tested whether dopamine (DA) is sufficient to trigger this process. Here we use optogenetic self-stimulation of DA neurons of the ventral tegmental area (VTA) to selectively mimic the defining commonality of addictive drugs. All mice readily acquired self-stimulation. After weeks of abstinence, cue-induced relapse was observed in parallel with a potentiation of excitatory afferents onto D1 receptor-expressing neurons of the nucleus accumbens (NAc). When the mice had to endure a mild electric foot shock to obtain a stimulation, some stopped while others persevered. The resistance to punishment was associated with enhanced neural activity in the orbitofrontal cortex (OFC) while chemogenetic inhibition of the OFC reduced compulsivity. Together, these results show that stimulating VTA DA neurons induces behavioral and cellular hallmarks of addiction, indicating sufficiency for the induction and progression of the disease.
    No preview · Article · Nov 2015 · Neuron
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