Allopregnanolone Regulation of Phasic Dopamine Release and Motivated Behavior.

Abstract

Allopregnanolone, an endogenous neurosteroid that is a potent, positive allosteric modulator of γ-aminobutyric acid type A (GABA_A) receptors, has emerged as a compound with considerable potential in the treatment of psychiatric disorders, including substance use disorders and postpartum depression. We previously demonstrated that allopregnanolone dose- and sex-dependently reduced electrically evoked dopamine release in the nucleus accumbens (NAc) of anesthetized male and female rats, which could indicate negative effects on motivation and reward processing. The present study investigated the effects of allopregnanolone on dopamine release and motivated behaviors in awake rats. Using fast-scan cyclic voltammetry, we found that 15 mg/kg allopregnanolone (IP) reduced the frequency of spontaneous dopamine transients in the NAc of freely moving male and female rats. Next, we observed that allopregnanolone (15 mg/kg, IP) produced a robust conditioned place preference in males and females, indicating that allopregnanolone's effects are not aversive despite fewer dopamine transients. Finally, using a sucrose self-administration task, we found that allopregnanolone (7.5 and 15 mg/kg, IP) did not significantly alter response rate, intertrial and interpress intervals, or trial latency in either sex, suggesting that allopregnanolone does not alter motivation or fast motor actions. These results clarify the regulation of dopamine neurotransmission and motivated behavior by allopregnanolone, which has clinical implications for its use as a therapeutic agent to treat various psychiatric disorders.