Estimates indicate that addiction cost the U.S. economy neariy one half-trillion dollars per year. The mechanisms driving this behavior are unclear, but involve drug-conditioned cues. In animal models this is attributed to an interaction between dopamine and glutamate neurons In the prefrontal cortex (PFC). However, there remains a lack of understanding ofthe cellular mechanism underiying this interaction. This hampers the development of effective pharmacological treatment strategies for addiction. The long-term objective of this proposal is to identify cellular abnormalities in the PFC that may provide effective therapeutic targets to restore function and thereby prevent relapse to drug seeking. In pyramidal neurons, firing patterns during drug self-administration are regulated in part by dopamine activation of beta-adrenergic receptors (?- AR), which increase intracellular calcium. This activates KCNQ channels to control spike frequency adaptation, which limits the frequency of action potential firing. The central hypothesis of this proposal Is that the ?-AR -signaling cascade is upregulated by chronic cocaine self-administration and depresses KCNQ- mediated inhibition during cue-induced reinstatement of cocaine seeking. To explore the interaction between dopamine and KCNQ-inhibition in PFC neurons, we will record currents mediated by KCNQ that are coupled to of ?-ARs. Patch-clamp recordings will be performed in acute brain slices from rats trained to self- administer cocaine and control (yoked saline) rats, before or after cue-induced reinstatement. The mechanism and functional impact ofthe dopamine-suppressed KCNQ signal on reinstatement is unknown and will be examined in the first two specific aims of this proposal. While activation ofthe prelimbic PFC (PL) initiates cocaine seeking, the projection from the infralimbic PFC (IL) inhibits cocaine seeking. Thus, Aim-2 will examine whether dopamine-suppressed KCNQ signaling is specific to the PL, or also occurs in the IL.
Aim -3 will evaluate if manipulation of ?-AR signaling normalizes the KCNQ adaptation during relapse. The results of the proposed experiments are expected to positively influence human health because they should identify novel cellular targets for development of improved therapies to treat drug-seeking behaviors.
Substance abuse costs the U.S. neariy one half-trillion dollars annually (NIDA), and pharmacological treatment can help reduce these costs. At present, there are no effective pharmacotherapeutic interventions for cocaine addiction. Identification ofthe KCNQ-mediated neuroadaptations in glutamate transmission in cortical neurons after cocaine self-administration is expected to reveal novel cellular targets for therapeutic development and therebv lead to a better understanding of. and treatment for, relaose to drug seeking.
|Mulholland, Patrick J; Chandler, L Judson; Kalivas, Peter W (2016) Signals from the Fourth Dimension Regulate Drug Relapse. Trends Neurosci 39:472-85|
|Garcia-Keller, C; Kupchik, Y M; Gipson, C D et al. (2016) Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration. Mol Psychiatry 21:1063-9|
|Go, Bok Soon; Barry, Sarah M; McGinty, Jacqueline F (2016) Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking. Eur Neuropsychopharmacol 26:1989-1999|
|Scofield, Michael D; Li, Hao; Siemsen, Benjamin M et al. (2016) Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core. Biol Psychiatry 80:207-15|
|Augur, Isabel F; Wyckoff, Andrew R; Aston-Jones, Gary et al. (2016) Chemogenetic Activation of an Extinction Neural Circuit Reduces Cue-Induced Reinstatement of Cocaine Seeking. J Neurosci 36:10174-80|
|McGlinchey, Ellen M; James, Morgan H; Mahler, Stephen V et al. (2016) Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking. J Neurosci 36:8700-11|
|Stefanik, Michael T; Kupchik, Yonatan M; Kalivas, Peter W (2016) Optogenetic inhibition of cortical afferents in the nucleus accumbens simultaneously prevents cue-induced transient synaptic potentiation and cocaine-seeking behavior. Brain Struct Funct 221:1681-9|
|Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2016) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry :|
|Scofield, M D; Heinsbroek, J A; Gipson, C D et al. (2016) The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis. Pharmacol Rev 68:816-71|
|Back, Sudie E; McCauley, Jenna L; Korte, Kristina J et al. (2016) A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans With Posttraumatic Stress Disorder and Substance Use Disorders. J Clin Psychiatry :|
Showing the most recent 10 out of 155 publications