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

    350—Cocaine: Neural Mechanisms of Addiction II

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    350.02: Inhibiting the expression of SAP97, which transports GluA1-containing AMPA receptors to synapses, in the accumbens shell blocks the reinstatement of cocaine seeking

    Location: Halls B-H

    *S. L. WHITE1, P. ORTINSKI1, S. H. FRIEDMAN1, H. D. SCHMIDT1, R. G. KALB2, C. PIERCE1;
    1Psychiatry, Univ. of Pennsylvania, PHILADELPHIA, PA; 2Neurol., Univ. of Pennsylvania, Philadelphia, PA

    Abstract Body: A growing body of evidence indicates that the transport and stabilization of GluA1-containing AMPA glutamate receptors to synapses in the accumbens is associated with the reinstatement of cocaine seeking. However, the specific mechanisms of underlying the trafficking of GluA1-containing AMPA receptors to synapses in accumbens subregions during the reinstatement of cocaine seeking remains unclear. Here, herpes simplex viral vectors (HSV) were employed to modulate GluA1 subunit function in the nucleus accumbens core or shell prior to cocaine priming-induced reinstatement of cocaine seeking. HSV GluA1-Q582E was used to express “pore-dead” dominant-negative GluA1 subunits that are ion impermeable. Viral-mediated expression of pore-dead GluA1 subunits in the accumbens core and shell attenuated the reinstatement of cocaine seeking. Consistent with these results, over-expression of wild-type GluA1 subunits (via HSV GluA1-WT) in the shell enhanced the reinstatement of cocaine seeking. SAP97 plays an important role in the transport of GluA1-containing AMPA receptors to synapses. HSV miSAP97 (miSAP) expresses a microRNA sequence that reduces SAP97 protein expression. Expression of miSAP in the accumbens shell attenuated cocaine seeking. In all cases, virus expression had no influence on the reinstatement of food seeking. Viral expression and function were characterized by immunofluorescence and whole-cell patch clamp. Taken together, these results provide further evidence that GluA1-containing AMPA receptors in the nucleus accumbens play a critical role in the reinstatement of cocaine seeking. Moreover, SAP97-mediated trafficking of GluA1-containing AMPA receptors to synapses in the accumbens shell is necessary for cocaine reinstatement. These results support investigation into GluA1 subunit accessory proteins as potential novel targets for pharmacotherapeutic intervention in cocaine craving and addiction.

    Lay Language Summary: Lay Summary:
    Our research indicates that inhibiting the activity of a protein that modulates excitatory neurotransmission in the brain attenuates the reinstatement of cocaine seeking, an animal model of relapse. Synapse-associated protein 97 (SAP97) normally facilitates excitatory transmission through calcium-permeable AMPA receptors (CP-AMPARs), which play a critical role in the development of addiction. Disrupting the interaction between SAP97 and CP-AMPARs in the nucleus accumbens shell attenuated the reinstatement of cocaine seeking in rodents. These findings suggest that developing drug treatments that modulate SAP97 might offer a novel therapy to prevent cocaine relapse in humans.
    The United States spends approximately 181 million dollars annually to combat the use of illicit drugs, including cocaine. Cocaine use is involved in almost 500,000 emergency room visits annually, and over 600,000 people begin using cocaine each year. Unfortunately, cocaine abuse is also associated with a high rate of relapse to drug taking following periods of abstinence, making cocaine addiction a continuing public health concern. Unlike nicotine, alcohol, or heroin there are no FDA-approved prescription drug interventions for cocaine addiction, leaving time-consuming behavioral therapies like cognitive behavioral therapy as the only alternatives. Consequently, the implications of identifying a novel target in the brain to develop drug therapies to combat cocaine relapse are considerable.
    Our experiments employed a well-established rat model of human cocaine addiction (cocaine self-administration) and relapse (cocaine reinstatement). We first illustrated that a toxin that blocks the signaling of CP-AMPA receptors, Naspm, also reduces cocaine-seeking behavior when injected into the nucleus accumbens. Interestingly, blocking these receptors in the shell subregion only reduced cocaine seeking whereas the same manipulation in the core subregion of the accumbens also reduced food-seeking behavior. This suggests that signaling by these receptors in the shell specifically processes cocaine reward, while the receptors are involved in more global reward processing in the core subregion.
    We then used viral vector technology to temporarily genetically manipulate CP-AMPA receptors and SAP97 in the nucleus accumbens, particularly focusing on the shell subregion. We used a virus that reduced the expression of CP-AMPARs in the accumbens shell, which significantly decreased the reinstatement of cocaine-seeking behavior. Conversely, we found that a virus that enhanced the contribution CP-AMPARs in the shell promoted the reinstatement of cocaine-seeking behavior. Finally, we used a virus that decreased the levels of SAP97 in the shell subregion of the nucleus accumbens, because SAP97 interaction with AMPA receptor GluA1 subunits has been associated with the successful function of GluA1-containing CP-receptors. Reduction of SAP97 in the accumbens shell caused a significant reduction of cocaine-seeking behavior without altering food-seeking behavior.
    Though we found that reducing signaling through CP-receptors that contain GluA1 subunits in the accumbens shell subregion is sufficient to reduce rodent cocaine reinstatement, a human model of relapse, these receptors are necessary in other brain regions for additional aspects of cognition like learning and memory. Currently, any drug therapy that impairs the function of CP-receptors would do so throughout the brain, which could lead to dramatic side effects in addition to preventing cocaine relapse. We showed that reducing SAP97 interactions with GluA1 subunits in the shell reduces cocaine reinstatement, but GluA1 subunits have other helper proteins in addition to SAP97 that assist the function of CP-receptors. It is possible that novel therapeutics targeted at SAP97 could prevent human cocaine relapse with fewer adverse side effects due to compensation by other helper proteins.