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Neurosteroids in nicotine and morphine dependence

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Abstract

Rationale

Neurosteroids are implicated in various stages of drug dependence, including the acquisition phase, tolerance, and withdrawal. The neurosteroid allopregnanolone is also able to substitute for drugs with abuse potential and possesses reinforcing properties.

Objectives

The effects of acute treatment with, and discontinuation of, chronic exposure to nicotine or morphine on the concentrations of allopregnanolone and its precursors, pregnenolone and progesterone, in the cerebral cortex and plasma of rats were investigated. The role of the hypothalamic–pituitary–adrenal (HPA) axis in, and the development of tolerance to, such effects were also examined.

Methods

Nicotine or morphine was administered acutely or chronically, and withdrawal syndrome was induced by spontaneous discontinuation of drug treatment or by administration of a corresponding receptor antagonist (mecamylamine and naloxone, respectively). Neurosteroids were extracted from the cerebral cortex and plasma, fractionated by high-performance liquid chromatography, and quantitated by radioimmunoassay.

Results

Acute intraperitoneal administration of nicotine (0.3–2 mg kg−1) or morphine (5–30 mg kg−1) induced dose- and time-dependent increases in the cerebrocortical and plasma concentrations of pregnenolone, progesterone, and allopregnanolone. The effects of both drugs were abolished by adrenalectomy–orchiectomy. Spontaneous or naloxone-precipitated morphine withdrawal and mecamylamine-precipitated (but not spontaneous) nicotine withdrawal also increased neurosteroid concentrations in the brain and plasma. A challenge dose of nicotine or morphine, administered 14 or 24 h after the last drug injection in chronic ally treated rats, failed to increase cerebrocortical neurosteroid concentrations.

Conclusions

Changes in neurosteroid concentrations mediated by activation of the HPA axis may both contribute to the early acquisition phase of nicotine or morphine addiction and serve to counteract the anxiety-like behavior associated with nicotine or morphine withdrawal. However, the evidence that nicotine withdrawal did not increase neurosteroids, unless precipitated by mecamylamine, suggests that the role of these neurosteroids in spontaneous nicotine withdrawal may not be clear.

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Acknowledgements

This research was supported by grant CE00042735 (Project Center of Excellence for the Neurobiology of Dependence, D.M. 21 January 2001), and PRIN grants 2003057334 from the Ministry of Instruction, Universities, and Research, Italy; by the Sardinian Health Ministry; and in part by the GIO.I.A. Foundation (Pisa).

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Authors and Affiliations

  1. Department of Experimental Biology, Center of Excellence for Neurobiology of Dependence, University of Cagliari, Cagliari, Italy

    Alessandra Concas, Cristiana Sogliano, Patrizia Porcu, Carla Marra, Andrea Brundu & Giovanni Biggio

  2. CNR Institute for Neuroscience, Unit of Neuropsychopharmacology, Cagliari, Italy

    Alessandra Concas & Giovanni Biggio

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  1. Alessandra Concas
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  2. Cristiana Sogliano
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  3. Patrizia Porcu
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  4. Carla Marra
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  5. Andrea Brundu
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  6. Giovanni Biggio
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Correspondence to Alessandra Concas.

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Concas, A., Sogliano, C., Porcu, P. et al. Neurosteroids in nicotine and morphine dependence. Psychopharmacology 186, 281–292 (2006). https://doi.org/10.1007/s00213-005-0111-7

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