Investigating corticostriatal pathways relevant to cocaine addiction with DREADDs

Seattle Children'S Hospital, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Cocaine addiction is a neuropsychiatric disorder characterized by an uncontrollable motivation to seek cocaine. At present, no effective treatment exists for cocaine addiction and this is in part due to our lack of understanding of the circuitry involved in the disorder. The prefrontal cortex (PFC) and the nucleus accumbens (NAC) have both been implicated in the rewarding properties of drugs of abuse. However it is still unclear how neural circuitry within and between these regions regulates behavior relevant to drug addiction. Medium spiny neurons (MSNs) within the NAC can be divided into two populations by their projection targets and gene expression, commonly known as the 'direct' and 'indirect' pathways. Previous reports have indicated that 'direct' and 'indirect' pathway neurons play differential roles in drug reward and sensitization, however it has yet to be examined how these pathways in the NAC influence cocaine taking and cocaine seeking within a self-administration model. Thus, my first goal is to examine the role of the direct and indirect pathways within the NAC using DREADDs selective for the direct and indirect pathways in cocaine self-administration measures modeling drug motivation and relapse. Further, it has been suggested that a loss of top-down control from the PFC to the basal ganglia is related to the chronic nature of drug addiction. The PFC sends a major glutamatergic input to the NAC, however the NAC also receives input from the amygdala and thalamus and it is unknown if the input from the PFC to the NAC is the critical pathway for regulating addiction processes. Thus, our second goal is to examine the role of the input from the PFC to the NAC in regulating operant behavior for cocaine. To selectively activate this circuit, I will utilize Cre-recombinase dependent Gi/o DREADD FLEX vector technology to express DREADDs only in mPFC neurons that project to the NAC. Transient activation of these designer receptors during operant behavior will reveal the role of the mPFC-NAC pathway in motivation for cocaine. These experiments will help to elucidate the role of the direct and indirect NAC cell populations in the control of motivation for drugs of abuse, as well as how loss of top down control from cortical inputs into the NAC contributes to these behaviors that underlie a transition to addiction. By unraveling this complex circuitry, this work could help steer the development of treatments of drug addiction toward novel therapies that selectively target subcomponents of the cortico-basal ganglia system.