Chronic cocaine disrupts mesocortical learning mechanisms

Abstract

The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extra-synaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts.

Effects of muscarinic M1receptor stimulation on reinforcing and neurochemical effects of cocaine in rats

“…VU0364572 treatment significantly blunted the cocaine-stimulated increase in extracellular NAc dopamine in both cocaine-naïve [F(1,10]=62.9, p<0.0001] and cocaine-experienced [F(1,10]=6.13, p=0.03] rats, but with different efficacy. In the cocaine-naïve animals, prior VU0364572 treatment completely blocked the dopamine increase, while the cocaine-experienced animals still showed a significant dopamine increase [F (7,35)=6.98, p<0.0001]. Fig.…”

“…Acute cocaine administration increased NAc glutamate levels in vehicle-and VU0364572treated cocaine-naïve rats ([F (7,35)=5.91, p=0.0001] and [F (7,35)=4.07, p=0.002], respectively) and in vehicle-treated cocaine-experienced rats [F(7,35)=2.59, p=0.03], but the increase was completely abolished in the VU0364572-treated cocaine-experienced rats (Fig. 4J).…”

Restoration of Kv7 channel mediated inhibition reduces cued-reinstatement of cocaine seeking

“…Dopamine's role in drug reward processing appears to facilitate the encoding of reward prediction, imprinting incentive value to reinforcers (energizing approach behavior) and facilitating learning of reward associations (conditioning) through its modulation of subcortical (including the nucleus accumbens) and cortical brain regions (Di Chiara, 1999;Schultz, 1999;Waelti et al, 2001;Schultz, 2002;Redish, 2004;Steinberg et al, 2013). Cellular adaptations in dopaminergic signaling contribute to relapse to drug seeking (Hyman et al, 2006), in part by disrupting transmission in the prefrontal cortex (Anderson and Pierce, 2005;Dong et al, 2005a;Huang et al, 2007;Sidiropoulou et al, 2009;Buchta and Riegel, 2015). In tissue from rats with a history of repeated coca-SA training, we observed a decreased ability of dopamine to alter firing and I Kv7 in a subpopulation of cells, which may reflect prior sensitization or overactivation in this neuronal population.…”

Dynamic CRMP2 regulation of CaV2.2 in the prefrontal cortex contributes to the reinstatement of cocaine seeking

“…A prevailing hypothesis is that this behavior reflects a drug-induced maladaptive rewiring of cortical-striatal circuitry in the medial prefrontal cortex (mPFC) and nucleus accumbens regions [19; 20]. The persistence of this plasticity and related behaviors may involve neuroadaptations in synaptic strength [9] and gene expression [14; 40], as well as cytoskeletal re-arrangement [13]. Conversely, disrupting these adaptations reduces drug-induced alterations in excitability and associated behaviors [38].…”