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Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine

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Abstract

Rationale

The neuroactive steroid, 3α-hydroxy-5α-pregane-20-one (allopregnanolone) is a potent modulator of GABAA 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, Δ9-tetrahydrocannabinol (Δ9-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

Δ9-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 Δ9-THC or morphine. Plasma progesterone levels were elevated in both Δ9-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.

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Acknowledgements

The authors wish to thank Tejas Patel and Todd O’Buckley for excellent technical assistance. This work was supported by NIAAA grants AA10564 (A.L.M.) and AA09291 and DA006634 (L.J.P.) and a NRSA award (to M.J.V.).

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Authors and Affiliations

  1. Department of Psychiatry, University of North Carolina at Chapel Hill, CB#7160, Chapel Hill, NC, 27599-7178, USA

    A. Chistina Grobin, Margaret J. VanDoren & A. Leslie Morrow

  2. Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Linda J. Porrino

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  1. A. Chistina Grobin
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  2. Margaret J. VanDoren
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  3. Linda J. Porrino
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  4. A. Leslie Morrow
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Correspondence to A. Chistina Grobin.

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Grobin, A.C., VanDoren, M.J., Porrino, L.J. et al. Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine. Psychopharmacology 179, 544–550 (2005). https://doi.org/10.1007/s00213-004-2084-3

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