Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues

Abstract

Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experienceinduced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S−) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S− was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S−). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.context cues | neuroplasticity | drug addiction P reventing or reducing the incidence of relapse remains the major challenge for the treatment of addiction, as recidivism rates can range as high as 90%. Both preclinical (1) and human addiction studies (2) have demonstrated that following repeated pairings with drug administration, various contextual and environmental stimuli when subsequently presented alone can elicit drug-seeking and drug-taking behaviors. Further, dysregulation within specific brain circuits regulating cognitive control and/or emotional regulation (3) can amplify the perceived salience of environmental contexts and cues that provoke craving (4) and thereby enhance susceptibility to relapse (2). These observations speak to the important role of reward learning in addictive processes (5). As such, it is critical to better understand the neural mechanisms and circuitry underlying the retrieval of cue-induced memories as an important intermediary in developing more efficacious interventions to decrease recidivism.The amygdala, nucleus accumbens (NAc), and various prefrontal cortical regions respond to drug-associated cues in human cocaine addicts (6, 7). Supporting their critical roles in the neural circuitry of drug-seeking behavior, these regions have also been identified using preclinical reinstatement models (8, 9). For example, NAc neurons exhibit conditioned responses to drugassociated env...

Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers

“…Indeed, the insula is increasingly recognized as being a critical neural substrate for addiction in part by mediating interoceptive awareness of drug craving [Naqvi and Bechara, 2010]. Our results differ from those obtained in rats trained to associate odor cues with the availability of a reinforcer (intravenous cocaine/oral sucrose), which show different brain activity in NAc for cocaine than for sucrose [Liu et al, 2013]. This discrepancy might reflect differences between species (addicted humans vs. rats exposed to cocaine), the use of odors versus visual cues and confounds from the effects of anesthesia used for the rodent studies.…”

Abstinence from Cocaine and Sucrose Self-Administration Reveals Altered Mesocorticolimbic Circuit Connectivity by Resting State MRI

“…Before the rsMRI scans, animals were also presented with odor cues previously associated with or without (S + /SÀ) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans (Liu et al, 2013). Results demonstrated a learning effect distinguishing S + from SÀ in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake.…”

“…After surgery, anesthesia was switched to continuous IV infusion of propofol (35 mg/kg/h). We also conducted task-based fMRI experiments in the same cohorts of animals with contextual cues (odor) and cocaine challenge (Lu et al, 2012b(Lu et al, , 2013. Given the profound pharmacological effects of anesthetics on neurovascular coupling and brain function, we had performed pilot studies with a number of commonly used anesthetics to find the ''best'' agent.…”

Sensitive periods of substance abuse: Early risk for the transition to dependence

“…Functional MRI responses to drug-associated cues in adult rodents after chronic cocaine exposure show remarkable faithfulness to human and other primate fMRI changes, including elevated responses in the dorsal STR, NAc, mPFC, and insular cortex (Johnson et al, 2013; Liu et al, 2013). Similar changes in blood flow in response to cocaine-associated cues are found when a mechanism underlying salience (PFC D1 receptors; Sonntag et al, 2014) is increased in the PFC in young rats (Lowen et al, 2015).…”