A treatment for cocaine addiction remains elusive due to incomplete knowledge of the circuitry controlling the overwhelming desire to relapse to drug use. Using the cue-induced reinstatement rodent model of relapse, synaptic changes that are necessary for reinstating cocaine seeking have been discovered in the circuit containing glutamatergic inputs to the core of the nucleus accumbens (NAcore) and GABAergic inputs from the NAcore to the dorsolateral ventral pallidum (dlVP). The overarching hypothesis of this renewal application continues to be that relapse depends on synaptic plasticity produced by cocaine use at excitatory synapses in NAcore and GABAergic synapses in dlVP. A critical gap in our understanding is the relative roles played by the two distinct classes of NAcore D1- and D2-expressing medium spiny neurons (MSNs). The development of transgenic D1 and D2 Cre mice and optogenetic strategies provides the necessary technology to determine how these MSN populations regulate relapse. Our preliminary data show that the classic direct and indirect basal ganglia circuits do not apply to NAcore D1 MSNs, in that the indirect projection to dlVP contains substantial inputs from both D1 and D2 MSNs.
In Aim 1 we will characterize this aberration from classical dogma, and determine if any specificity exists regarding D1 and D2 synapses on dlVP neurons projecting to distinct subcortical target regions. We will also determine which D1/D2 cell group and dlVP efferent is necessary for reinstated cocaine seeking.
Aim 2 focuses on discoveries that cued reinstatement produces transient potentiation at glutamatergic synapses on NAcore MSNs that is necessary for cue-induced reinstatement, and will determine which glutamatergic afferent and which MSN cell type (D1 or D2) harbors the molecular, morphological and electrophysiological markers of reinstatement-induced synaptic potentiation.
Aim 3 focuses on how neuropeptides co- localized in D1 vs D2 MSNs regulate GABA synapses in dlVP and how cocaine changes this regulation in a manner necessary for cues to reinstate cocaine seeking. Together, these experiments will provide a comprehensive understanding of the circuitry and synaptic plasticity mediating cue-induced relapse to cocaine seeking.
Drug addiction is a major neuropsychiatric disease in the USA. The proposed research continues our study into a brain circuit that mediates relapse to using addictive drugs. We will determine which cell groups in the circuit underpin the uncontrollable urge to take drug, and identify cellular pathologies in these cells that mediate relapse and may harbor new targets for small molecule interventions to treat drug addiction.
| Roberts-Wolfe, Douglas; Bobadilla, Ana-Clara; Heinsbroek, Jasper A et al. (2018) Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons. J Neurosci 38:7100-7107 |
| Spencer, Sade; Neuhofer, Daniela; Chioma, Vivian C et al. (2018) A Model of ?9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens. Biol Psychiatry 84:601-610 |
| Neuhofer, Daniela; Kalivas, Peter (2018) Metaplasticity at the addicted tetrapartite synapse: A common denominator of drug induced adaptations and potential treatment target for addiction. Neurobiol Learn Mem 154:97-111 |
| Bobadilla, Ana-Clara; Heinsbroek, Jasper A; Gipson, Cassandra D et al. (2017) Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior. Prog Brain Res 235:93-112 |
| Spencer, Sade; Kalivas, Peter W (2017) Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse. Int J Neuropsychopharmacol 20:797-812 |
| Kupchik, Yonatan M; Kalivas, Peter W (2017) The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think. Neuropsychopharmacology 42:369-370 |
| Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756 |
| Brown, Robyn Mary; Kupchik, Yonatan Michael; Spencer, Sade et al. (2017) Addiction-like Synaptic Impairments in Diet-Induced Obesity. Biol Psychiatry 81:797-806 |
| Bobadilla, Ana-Clara; Garcia-Keller, Constanza; Heinsbroek, Jasper A et al. (2017) Accumbens Mechanisms for Cued Sucrose Seeking. Neuropsychopharmacology 42:2377-2386 |
| Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2017) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 81:616-624 |
Showing the most recent 10 out of 86 publications
