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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    014—Cocaine: Neural Mechanisms of Addiction I

    Saturday, November 09, 2013, 1:00 pm - 4:15 pm

    14.06: Viral-mediated transfer of DREADDs reveals a differential role of the corticostriatal pathway in cocaine taking and cocaine seeking behavior

    Location: 33C

    1CIBR, Seattle Children's Res. Inst., Seattle, WA; 2Dept. of Pharmacol., 3Dept. of Psychiatry and Behavioral Sci., Univ. of Washington, Seattle, WA

    Abstract Body: Motivation for drug intake and relapse to drug seeking are two behavioral components of drug dependence that can be modeled in rats using cocaine self-administration measures. Previous cocaine self-administration studies have shown that medial prefrontal cortex (mPFC) and nucleus accumbens (NA) are involved in motivation for cocaine intake and cocaine seeking. We propose that the glutamatergic input the NA receives from the mPFC is critical for guiding motivation for cocaine during Progression Ratio (PR) and Reinstatement procedures. We utilized a Cre recombinase-dependent viral vector based flip-excision (FLEX) switch system to express engineered DREADD (Designer Receptors Exclusively Activated by Designer Drugs) receptors in neurons of the mPFC that project to the NA of male Long Evans rats. An AAV FLEX construct containing an inverted form of the Gi/o DREADD receptor (hM4Di) was infused into the mPFC and a CAV Cre-recombinase viral vector (CAV-Cre) was infused into the NA of the same rats. The CAV is retrogradely transported to neuronal cell bodies, thus, only neurons that project from the mPFC to the NA express hM4Di receptors. Activation of hM4Di receptors by the otherwise pharmacologically inert synthetic ligand clozapine-N-oxide (CNO) increases Gi/o-mediated signaling, which results in a transient reduction of neuronal excitability. CNO (3 mg/kg, i.p.) was administered 20-min prior to behavioral testing. After viral expression, rats were trained to self-administer cocaine (.75/mg/kg/inf) and then switched to a PR schedule of cocaine self-administration for testing. Compared to vehicle, CNO treatment significantly increased break points and cocaine intake. Following PR testing rats underwent extinction of operant behavior followed by cocaine primed (10 mg/kg i.p.) reinstatement testing. Compared to days in which the rats received vehicle, CNO significantly decreased responding on the lever that previously delivered cocaine. These findings suggest that the glutamatergic input from the mPFC to the NA guides behavior depending the phase of drug use. During drug intake (PR), decreased input lead to an increase in motivation for cocaine, however after two weeks of abstinence decreasing mPFC-NA input lead to decreased cocaine seeking or “relapse” behavior. The opposite effects of our manipulation may be due to differential expression of AMPA/NMDA receptors in the NA during drug intake and drug abstinence.

    Lay Language Summary: Our research indicates that the input of the cingulate cortex into the nucleus accumbens controls motivation for cocaine. In rats, this circuit alters motivation for cocaine in a phase dependent manner. While taking cocaine, inactivation of this circuit increases drug intake. However, during abstinence from cocaine, inactivation of this circuit reduces drug seeking.
    Cocaine dependence is a chronic neuropsychiatric disorder characterized by an uncontrollable motivation to seek cocaine, coupled with a persistent craving for drug even after prolonged periods of drug abstinence. We hypothesize that this disorder is in part controlled by inputs from the cortex into the striatum, specifically the nucleus accumbens.
    In the present study, we utilized a Cre-dependent viral vector based FLEX switch system. Cre dependent Gi/o DREADDs (Designer Receptors Exclusivity Activated by Designer Drugs) were infused into the cingulate cortex. Canine adenovirus 2 (CAV 2) Cre viral vectors were infused into the nucleus accumbens of the same rats, this virus retrogradely transports to neuronal cell bodies. Thus, only neurons from the cingulate cortex that innervate the nucleus accumbens show expression Gi/o DREADDs. This technique was utilized to achieve selective modulation of the cingulate cortex-nucleus accumbens pathway. In conjunction with this manipulation, we utilized cocaine self-administration measures to assess the impact of this pathway on motivation and “relapse” behavior.
    Our research indicates that the glutamatergic input from the cingulate cortex into the nucleus accumbens plays a role in drug taking and drug seeking behavior. While rats are continuously taking cocaine, inactivating this circuit via the otherwise pharmacologically inert synthetic ligand clozapine-N-oxide (CNO) “releases the brake” on motivation for the drug - leading to an increase in cocaine intake. However, after a period of cocaine abstinence, inactivating this circuit reduces responding for cocaine in our model of cocaine primed “relapse”. This suggests that the glutamatergic input from the cingulate cortex to the nucleus accumbens controls motivation for cocaine in a phase dependent manner. These findings are in agreement with Stefanik et al. (2012), which found that optical inhibition of the prelimbic fibers in the nucleus accumbens core inhibits reinstatement of cocaine seeking.
    These experiments may provide insight into how loss of top down control from cortical inputs into the nucleus accumbens contributes to 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. Future studies will use flex DREADDs combined with novel retrograde viruses to selectively target dynorphin or enkephalin expressing neurons in the cortico-striatal pathway.