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

Area of Science:

• Neuroscience
• Neuropharmacology
• Addiction Research

Background:

• Low striatal dopamine D2 receptor (D2R) availability is linked to cocaine abuse vulnerability.
• The precise mechanisms by which low D2Rs facilitate cocaine reward remain unclear.

Purpose of the Study:

• To investigate the role of striatal D2R availability in modulating cocaine reward pathways.
• To elucidate the neurochemical mechanisms, particularly involving enkephalin and GABA, that mediate cocaine reward under conditions of low D2R availability.

Main Methods:

• Utilized mouse models with varying striatal D2R availability.
• Measured striatal Penk mRNA levels and enkephalin peptide tone.
• Assessed intra-striatal GABA transmission in brain slices.
• Employed place conditioning paradigms with and without pharmacological interventions (met-enkephalin, mu-opioid receptor antagonist).

Main Results:

• Low striatal D2Rs increase striatal Penk mRNA and enkephalin peptide tone.
• Enkephalin suppresses intra-striatal GABA transmission.
• Cocaine paired with intra-accumbens met-enkephalin enhances place preference acquisition in wild-type mice.
• Mu-opioid receptor antagonists block this potentiation in wild-type mice but not in mice with low striatal D2Rs.

Conclusions:

• Heightened striatal enkephalin potentiates cocaine reward by reducing GABAergic inhibition, thereby enhancing striatal output.
• The lack of blockade by mu-opioid antagonists in low D2R mice suggests involvement of other opioid receptor systems in cocaine reward.
• D2R activity bidirectionally regulates enkephalin, offering insights into cocaine abuse vulnerability.