Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking

Abstract

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.

Prenatal Nicotine Exposure Impairs Executive Control Signals in Medial Prefrontal Cortex

“…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).…”

The role of learning-related dopamine signals in addiction vulnerability

“…Interestingly, context-induced reinstatement is more prominent in goal-than in sign-trackers (Saunders and Robinson, 2013). Moreover, a context paired with ethanol injections can immediately and profoundly impair the ability to exert goal-directed control (Ostlund et al, 2010), and optogenetic suppression or activation of the prelimbic cortex, which is thought to involve goaldirected computations, can abolish or re-establish sensitivity to punishments (Chen et al, 2013). There is also preliminary evidence for this in humans (Sebold et al, subm).…”

“…Moreover, the effects of a dopamine D1 receptor antagonist on sign-tracking behaviour were less prominent following post-asymptotic training. However, the data on punishment sensitivity (Vanderschuren and Everitt, 2004;Deroche-Gamonet et al, 2004) and the importance of prefrontal mechanisms in the reassertion of control (Chen et al, 2013;Ostlund and Balleine, 2008;Sebold et al, subm) may also speak to the difference between habits and compulsions.…”

Mobilization of Medial and Lateral Frontal-Striatal Circuits in Cocaine Users and Controls: An Interleaved TMS/BOLD Functional Connectivity Study

“…Preclinical studies, eg, have demonstrated that optogenetic modulation of these mesolimbic and mesocortical circuits can modulate drug-taking behavior in a causal manner (Chen et al, 2013c;Stefanik et al, 2013). Clinical studies are now investigating repetitive TMS (rTMS) as a tool to change drug-craving and drug-taking behavior.…”