Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons

Autor: Daniela Neuhofer, Ana-Clara Bobadilla, Douglas Roberts-Wolfe, Jasper A. Heinsbroek, Peter W. Kalivas
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
media_common.quotation_subject
Drug-Seeking Behavior
Mice
Transgenic
Self Administration
Context (language use)
AMPA receptor
Nucleus accumbens
Biology
Medium spiny neuron
Receptors
N-Methyl-D-Aspartate
Nucleus Accumbens
Extinction
Psychological
Receptors
Dopamine
Rats
Sprague-Dawley
Cocaine-Related Disorders
Mice
03 medical and health sciences
Glutamatergic
0302 clinical medicine
Cocaine
Genes
Reporter
Animals
Receptors
AMPA
Promoter Regions
Genetic
Research Articles
media_common
Receptors
Dopamine D2
Dopaminergic Neurons
Receptors
Dopamine D1
General Neuroscience
Addiction
Excitatory Postsynaptic Potentials
Long-term potentiation
Rats
Substance Withdrawal Syndrome
030104 developmental biology
nervous system
Synapses
Conditioning
Operant
NMDA receptor
Cues
Neuroscience
030217 neurology & neurosurgery
Zdroj: The Journal of Neuroscience. 38:7100-7107
ISSN: 1529-2401
0270-6474
DOI: 10.1523/jneurosci.0791-18.2018
Popis: Cocaine-associated cues and contexts can precipitate drug seeking in humans and in experimental animals. Glutamatergic synapses in the core subcompartment of the nucleus accumbens (NAcore) undergo transient potentiation in response to presenting drug-associated cues. The NAcore contains two populations of medium spiny neurons (MSNs) that differentially express D1 or D2 dopamine receptors. By recording the ratio of AMPA and NMDA glutamate receptor currents (AMPA/NMDA ratio) from MSNs in NAcore tissue slices, we endeavored to understand which subpopulation of MSNs was undergoing transient potentiation. Transgenic female and male mice differentially expressing fluorescent reporters in D1 or D2 MSNs were withdrawn for 2-3 weeks after being trained to self-administer cocaine. In some mice, discrete cocaine-conditioned cues were isolated from the drug-associated context via extinction training, which causes rodents to refrain from drug seeking in the extinguished context. By measuring AMPA/NMDA ratios in the drug context with or without contextual or discrete cues, and with or without extinction training, we made the following three discoveries: (1) mice refraining from cocaine seeking in the extinguished context showed selective elevation in AMPA/NMDA ratios in D2 MSNs; (2) without extinction training, the drug-associated context selectively increased AMPA/NMDA ratios in D1 MSNs; (3) mice undergoing cue-induced cocaine seeking after extinction training in the drug-associated context showed AMPA/NMDA ratio increases in both D1 and D2 MSNs. These findings reveal that the NAcore codes drug seeking through transient potentiation of D1 MSNs, and that refraining from cocaine seeking in an extinguished context is coded through transient potentiation of D2 MSNs.SIGNIFICANCE STATEMENT Relapse is a primary symptom of addiction that can involve competition between the desire to use drugs and the desire to refrain from using drugs. Drug-associated cues induce relapse, which is correlated with transiently potentiated glutamatergic synapses in the nucleus accumbens core. We determined which of two cell populations in the accumbens core, D1-expressing or D2-expressing neurons, undergo transient synaptic potentiation. After being trained to self-administer cocaine, mice underwent withdrawal, some with and others without extinguishing responding in the drug-associated context. Extinguished mice showed transient potentiation in D2-expressing neurons in the extinguished environment, and all mice engaged in context-induced or cue-induced drug seeking showed transient potentiation of D1-expressing neurons. A simple binary engram in accumbens for seeking drugs and refraining from drugs offers opportunities for cell-specific therapies.
Databáze: OpenAIRE
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