Intermittent but not continuous access to cocaine produces individual variability in addiction susceptibility in rats.

Drug addiction is a chronic disease defined by a complex set of characteristics, including loss of control over drug intake and persistent drug craving, which primarily affects a small percentage of people who try drugs. Although many models have been developed to study individual aspects of drug use, there is great translational value in having an animal model that encompasses multiple aspects of the human disease, including the variation in severity observed in humans. Here, we describe an intermittent access model of cocaine self-administration that produces a subset of rats that display many of the core features of addiction, including escalation of drug intake, a binge-like pattern of drug use, robust locomotor sensitization, and high levels of drug-seeking during cue-induced reinstatement. This group is compared with rats that have the same drug history but do not develop this pattern of drug-taking and drug-seeking, as well as rats that undergo a traditional continuous access paradigm. Finally, we observe that high levels of cocaine consumption produce long-term changes in intracellular calcium signaling in the dorsomedial striatum.

The ins and outs of the striatum: role in drug addiction.

Addiction is a chronic relapsing disorder characterized by the loss of control over drug intake, high motivation to obtain the drug, and a persistent craving for the drug. Accumulating evidence implicates cellular and molecular alterations within cortico-basal ganglia-thalamic circuitry in the development and persistence of this disease. The striatum is a heterogeneous structure that sits at the interface of this circuit, receiving input from a variety of brain regions (e.g., prefrontal cortex, ventral tegmental area) to guide behavioral output, including motor planning, decision-making, motivation and reward. However, the vast interconnectivity of this circuit has made it difficult to isolate how individual projections and cellular subtypes within this circuit modulate each of the facets of addiction. Here, we review the use of new technologies, including optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), in unraveling the role of the striatum in addiction. In particular, we focus on the role of striatal cell populations (i.e., direct and indirect pathway medium spiny neurons) and striatal dopaminergic and glutamatergic afferents in addiction-related plasticity and behaviors.

Impact of medial orbital cortex and medial subthalamic nucleus inactivation, individually and together, on the maintenance of cocaine self-administration behavior in rats.

A reversible neuronal inactivation procedure was used to study the role of the medial orbital cortex (MO) and medial tip of the subthalamic nucleus (mSTN) in maintenance of cocaine self-administration studied under a second-order schedule of drug and cue presentation. Lidocaine or vehicle was infused 5-min before 1-h self-administration test sessions, using bilateral, asymmetric or unilateral manipulations. The results demonstrated that whether the MO was inactivated bilaterally, unilaterally or asymmetrically (with contralateral mSTN inactivation), cocaine seeking and cocaine intake were reduced. In contrast, bilateral mSTN inactivation did not impact cocaine seeking or cocaine intake, suggesting that the reductions in these measures following asymmetric inactivation may have been due to a unilateral influence of lidocaine in MO. Expression of c-Fos protein was measured in sites downstream of the STN to ensure that the lidocaine inactivation procedure was effective in selectively altering activity of neurons in mSTN. Cocaine-induced c-Fos protein expression was augmented only in the ipsilateral nucleus accumbens core after mSTN lidocaine pretreatment, consistent with the expectation that inactivation of mSTN would disinhibit nucleus accumbens core, but not shell, activity. The present investigation shows the critical importance of the MO for maintaining cocaine seeking and cocaine intake in rats, though its projections to mSTN appear to be unimportant for this purpose. Because cocaine seeking was impacted to such a great extent (45% of baseline, on average), it is likely that MO inactivation exerts its influence on maintenance of cocaine self-administration by interfering primarily with cue-controlled behavior rather than by modifying the reinforcing effects of cocaine.