Drug addiction is a behavioral pathology associated with impairments at excitatory synapses in the nucleus accumbens. The continuing premise of this proposal is that it is possible to pharmacologically repair this impairment(s) and thereby ameliorate the vulnerability to relapse. The possibility that enduring drug-induced changes in accumbens excitatory synapses can be biomarkers for drug addiction has attracted substantial experimental attention over the last 15 years. However, although the behavioral criteria defining drug dependence are shared, including an enduring vulnerability to relapse, many enduring neuroadaptations are not recapitulated between different chemical classes addictive drug. We have explored an approach that drug- induced cellular neuroadaptations shared in common between distinct classes of addictive drug, but not sucrose, may be strong candidate pathologies underpinning the shared behavioral symptoms of addiction. During the previous funding period we and others demonstrated that a shared characteristic between cocaine, heroin, nicotine and alcohol, but not sucrose, is the down-regulation of glial glutamate transport in the core of the nucleus accumbens (NAcore). We also recently discovered that the resulting spillover of synaptic glutamate during reinstated drug seeking initiates transient long-term potentiation (t-LTP) at glutamatergic synapses in NAcore, and this process is regulated by activating matrix metalloprotease-9 (MMP-9) in heroin, cocaine- and nicotine-, but not sucrose-trained rats. MMP-9 is an inducible metalloproteinase that degrades the extracellular matrix (ECM) and thereby signals synaptic plasticity at glutamatergic synapses, such as changes in spine morphology and amplitude of AMPA- mediated currents. The primary experimental goals in continuing this project are to identify the signaling and pathophysiological mechanisms in NAcore that link synaptic glutamate spillover and activating MMP-9 to the subsequent t-LTP that is necessary for reinstating drug seeking. To support the possibility that this sequence of cellula events is a mediator of relapse, we will determine if the signaling mechanisms are shared by animals trained to self-administer heroin and cocaine, but not sucrose.
Drug addiction is a major neuropsychiatric disease in the USA. The proposed research continues our study into the changes in brain cells that cause relapse to using addictive drugs. We will determine which cell groups and the molecular sequence of events that are altered by addictive drugs, and in doing so, we endeavor to identify 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 |
| 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 |
| Taniguchi, Makoto; Carreira, Maria B; Cooper, Yonatan A et al. (2017) HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. Neuron 96:130-144.e6 |
| 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 |
| Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin 3rd, William C et al. (2017) Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking. J Neurosci 37:757-767 |
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