Abstract
Dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP32) is a signaling molecule that could serve as a molecular switch, promoting or restraining sucrose seeking. We measured DARPP32 and pThr34 DARPP32 in the brains of male Long-Evans rats with a history of sucrose self-administration followed by 1 or 30 days of abstinence and exposure to either overnight (acute) or one month (chronic) environmental enrichment (EE). Brains were extracted following a 1 h cue reactivity test or no exposure to the test environment. Micropunches (prelimbic, infralimbic, and anterior cingulate areas of the medial prefrontal cortex, orbitofrontal cortex, dorsal striatum, nucleus accumbens, and ventral tegmental area) were then processed using Western blot. Abstinence increased, while EE decreased, sucrose seeking. DARPP32 and pThr34 DARPP32 levels were affected by testing, abstinence, and/or EE in most regions. Especially salient results were observed in the nucleus accumbens core, a region associated with relapse behaviors. Both acute and chronic EE reduced DARPP32 in the nucleus accumbens core and acute EE increased the ratio of phosphorylated to total DARPP32. Degree of DARPP32 phosphorylation negatively correlated with sucrose seeking. These findings demonstrate a potential role for DARPP32 in mediating the “anti-craving” effect of EE.
Highlights
Dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP32) is an intracellular protein identified as a key regulator of dopamine neurotransmission and dopamine-mediated behaviors[1]
Ten subjects were removed from the study for failure to acquire reliable self-administration and 6 brains were damaged in processing leaving 126 subjects for analyses
DARPP32 and pThr[34] DARPP32 levels were associated with the abstinence and EE manipulations; effects varied by brain region examined
Summary
Dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP32) is an intracellular protein identified as a key regulator of dopamine neurotransmission and dopamine-mediated behaviors[1]. Dopamine D1 receptor agonism increases activity of protein kinase A which in turn promotes phosphorylation of DARPP32 at threonine 34. This phosphorylated DARPP32 (pThr[34] DARPP32) attenuates activity of protein phosphatase 1, thereby releasing its inhibition of the MEK/ERK pathway. Blocking D1 receptors is more effective at reducing sucrose seeking after one day versus one month of abstinence[6]. Sucrose seeking markedly reduced by exposure to environmental enrichment (EE) was restored with a D1 agonist[7] These changes in sensitivity to D1 antagonist and agonist could relate to altered intracellular signaling via DARPP32. Nucleus accumbens core and shell sub-regions were examined, as were seven other brain regions including regions of medial prefrontal cortex (mPFC), orbitofrontal cortex, striatum, and midbrain
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