Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward

• Published in: Cell reports (Cambridge) Vol. 40; no. 13; p. 111440
• Main Authors: Dai, Kathy Z., Choi, In Bae, Levitt, Ryan, Blegen, Mariah B., Kaplan, Alanna R., Matsui, Aya, Shin, J. Hoon, Bocarsly, Miriam E., Simpson, Eleanor H., Kellendonk, Christoph, Alvarez, Veronica A., Dobbs, Lauren K.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 27-09-2022
• Subjects: addiction; cocaine; D2-receptor; dopamine; enkephalin; GABA; reward; striatum; synaptic; withdrawal; reward; enkephalin; striatum; D2-receptor; cocaine; CP: Neuroscience; addiction; GABA; withdrawal; dopamine; synaptic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111440

Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse.
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•Dopamine D2Rs bidirectionally regulate striatal enkephalin expression•Endogenous enkephalin suppresses intra-striatal GABA transmission•Heightened striatal enkephalin levels potentiate cocaine reward in wild-type mice•Opioid receptor antagonists attenuate cocaine reward in wild-type mice
Low striatal D2 receptor levels are associated with cocaine abuse. Dai et al. bidirectionally alter striatal D2 receptor levels to probe the downstream mechanisms underlying this abuse liability. They provide evidence that enhanced enkephalin tone resulting from low D2 receptors is associated with suppressed intra-striatal GABA and potentiated cocaine reward.