Introduction to Cocaine Seeking

The intravenous cocaine self-administration model is widely used to characterize the neurobiology of cocaine seeking.

Moreover, disrupting TSP2-α2δ-1-mediated spinogenesis and synapse generation in NAcSh decreases cue-induced cocaine seeking after withdrawal from cocaine self-administration and cue-induced reinstatement of cocaine seeking after drug extinction.

This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking.

Additionally, priming or cue-induced reinstatement of cocaine seeking was inhibited in methAEA-infused rats.

Background Prelimbic cortical projections to the nucleus accumbens core are critical for cue-induced cocaine seeking, but the identity of the accumbens neuron(s) targeted by this projection, and the transient neuroadaptations contributing to relapse within these cells, remain unknown.

Neuropharmacological disconnection studies implicated the basolateral amygdala connection to the nucleus accumbens core in cocaine seeking.

(2021) reported that CBD prevents primingand stress-induced reinstatement of the conditioned place preference induced by cocaine in mice, suggesting that CBD could reduce cocaine seeking after a period of abstinence.

Previous studies have shown a critical role of the prelimbic cortex (PL) in cue-, cocaine priming-, and stress-induced reinstatement of cocaine seeking after extinction in rats [2].

A preclinical model of CET, cue extinction, similarly reduces cue-induced cocaine seeking in rodent self-administration models; however, those models may not capture the habitual or compulsive aspects of drug use.

Disruption of prefrontal glutamate receptor interacting protein (GRIP), which anchors GluA2‐containing AMPA receptors (AMPARs) into the synaptic membrane, potentiates cue‐induced cocaine seeking in both males and females.

—PRS Serotonin can prevent the development of compulsive cocaine seeking in mice.

Using a state-of-the-art rat model of compulsive cocaine seeking (resistance to a punishment associated with cocaine seeking), we show here that: first, subthalamic nucleus (STN) oscillatory activity during prior extended access to cocaine serves as a biomarker to predict vulnerable individuals that will compulsively seek the drug, a hallmark of addiction, and second, that in compulsive “addicted” rats, low (30 Hz) but not high (130 Hz), deep brain stimulation (DBS) of the STN efficiently reduces pathological cocaine seeking.

Using this technique, we show that cofilin in the rat nucleus accumbens undergoes S-glutathionylation during 15-minutes of cued cocaine seeking in the absence of cocaine.

Cue-induced transient excitatory synaptic potentiation (t-SP) induced in the nucleus accumbens mediates cued cocaine seeking in rat models of relapse.

These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking.

Antagonism of metabotropic glutamate receptor 5 (mGlu5) has been demonstrated to decrease cocaine seeking but may also further compromise cognitive function in long-term cocaine users.

(2021) demonstrate how cocaine induces circuit-specific changes within the VP via dopamine-receptor-D3-dependent processes to promote cocaine seeking.

In this review, we provide a brief overview of the role of astrocytes in regulating synaptic transmission and neuronal function, and discuss how cocaine influences these astrocyte-mediated mechanisms to induce persistent synaptic and circuit alterations that promote cocaine seeking and relapse.

Here, we review the mechanisms and neurocircuitry that mediate stress‐triggered and stress‐potentiated cocaine seeking.

Together, their results suggest that inhibiting CB1R activity in the BLA immediately following memory retrieval may allow the memory to be strengthened during reconsolidation, causing potentiated cocaine seeking during the retention test.

We previously established a trial-based procedure in rats to isolate DSs from context, conditioned stimuli, and other drug-associated cues during cocaine self-administration and demonstrated DS-controlled cocaine seeking up to 300 abstinence days.

The acquisition of cue-controlled cocaine seeking has been shown to depend on functional interactions between the basolateral amygdala (BLA) and the nucleus accumbens core (NAcC).

Ibudilast is a non-selective phosphodiesterase (PDE) inhibitor and glia cell modulator which has shown great promise for the treatment of drug and alcohol use disorders in recent clinical studies, but it is unknown whether and how ibudilast affects cocaine seeking behavior.

This protocol demonstrates the steps needed to use optogenetic tools to reverse cocaine-induced plasticity at thalamo-amygdala circuits to reduce subsequent cocaine seeking behaviors in the rat.

We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days.

Then, we evaluated the reinstatement of cocaine seeking induced by cues and stressful stimuli (footshock).

Compulsive-like behavior also was the best predictor of cocaine seeking responses.

Trait compulsivity also was the best predictor of cocaine seeking responses.

Animal and human studies show that cannabis or its derivatives can increase relapse to cocaine seeking following withdrawal.

Infralimbic cortical (IL) manipulations indicate that this region mediates extinction learning and suppresses cocaine seeking following cocaine self-administration.