Cortical 3 alpha-hydroxy-5 alpha-pregnan-20-one levels after acute administration of Delta 9-tetrahydrocannabinol, cocaine and morphine.
BACKGROUND
The neuroactive steroid, 3alpha-hydroxy-5alpha-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 GABA(A) 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.


OBJECTIVE
To determine if other abused drugs elicit alterations in brain neurosteroid levels, Delta9-tetrahydrocannabinol (Delta9-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
Delta9-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 Delta9-THC or morphine. Plasma progesterone levels were elevated in both Delta9-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.
Grobin
A Chistina
AC
Department of Psychiatry, University of North Carolina at Chapel Hill, CB#7160, Chapel Hill, NC 27599-7178, USA. grobinac@med.unc.edu
VanDoren
Margaret J
MJ
Porrino
Linda J
LJ
Morrow
A Leslie
AL
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D011280:Pregnanolone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009020:Morphine; D013759:Dronabinol; D011280:Pregnanolone; D003042:Cocaine