Neurosteroids in nicotine and morphine dependence

Area of Science:

• Neuroscience
• Endocrinology
• Pharmacology

Background:

• Neurosteroids, such as allopregnanolone, play a role in drug dependence, including acquisition, tolerance, and withdrawal.
• Allopregnanolone can substitute for drugs of abuse and exhibits reinforcing properties.

Purpose of the Study:

• To investigate the effects of acute nicotine/morphine and chronic exposure/discontinuation on allopregnanolone, pregnenolone, and progesterone levels in rat brain and plasma.
• To examine the involvement of the hypothalamic-pituitary-adrenal (HPA) axis and the development of tolerance to these neurosteroid changes.

Main Methods:

• Rats received acute or chronic nicotine or morphine administration.
• Withdrawal was induced spontaneously or via receptor antagonists (mecamylamine, naloxone).
• Neurosteroids were quantified in cerebral cortex and plasma using radioimmunoassay after HPLC fractionation.

Main Results:

• Acute nicotine and morphine increased brain and plasma levels of pregnenolone, progesterone, and allopregnanolone in a dose- and time-dependent manner.
• These increases were dependent on the adrenal and testes/ovaries.
• Withdrawal from morphine and precipitated nicotine withdrawal increased neurosteroid concentrations, but chronic treatment led to tolerance to these effects.

Conclusions:

• HPA axis-mediated neurosteroid changes may contribute to the acquisition of nicotine/morphine addiction and mitigate withdrawal anxiety.
• The unclear role of neurosteroids in spontaneous nicotine withdrawal suggests further investigation is needed.