Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ-tetrahydrocannabinol, cocaine and morphine

Rationale: The neuroactive steroid, 3 alpha-hydroxy-5 alpha-pregane-20-one ( allopregnanolone) is a potent modulator of GABA(A) receptor function. Moreover, pharmacologically relevant concentrations of allopregnanolone are found in brain during physiological conditions ( stress, pregnancy and menstrual cycle) and pharmacological challenge ( ethanol, fluoxetine, olanzapine). Enhanced levels of neurosteroids are thought to contribute to the therapeutic effects of fluoxetine and various effects of ethanol via GABAA receptors. Moreover, neurosteroids influence rewarding effects of ethanol in some models and modulate activation of the hypothalamic pituitary adrenal (HPA) axis. Thus, it is possible that enhanced allopregnanolone levels are involved in the effects of abused drugs. Objectives: To determine if other abused drugs elicit alterations in brain neurosteroid levels, Delta 9-tetrahydrocannabinol (Delta 9-THC), cocaine and morphine were administered to male rats. Methods: Cortical brain tissue and plasma were collected and analyzed for steroid concentrations using radioimmunoassays. Results: Delta 9-THC (5 mg/kg, IP) elevated cortical allopregnanolone levels to pharmacologically active levels, while morphine ( 15 mg/kg, SC) produced a small but significant increase. Cocaine ( 30 mg/kg, IP) did not alter allopregnanolone levels, nor did lower doses of Delta 9-THC or morphine. Plasma progesterone levels were elevated in both Delta 9-THC and cocaine-treated animals. Conclusions: Some, but not all, drugs of abuse produce increases in cortical allopregnanolone levels. In addition, increases in plasma steroid precursor levels do not always translate into increases in brain allopregnanolone levels.