Clinical Trial: Neurosteroids and Acute Alcohol Intoxication in Humans

Study Status: Completed
Recruit Status: Unknown status
Study Type: Interventional

Official Title: Neurosteroids and Acute Alcohol Intoxication in Humans

Brief Summary:

1. The major aims are to assess: (1) the relationship of basal and alcohol-induced neurosteroid and GABA levels to the degree of acute alcohol intoxication in healthy male and female volunteers; and (2) the effect of acute pregnenolone administration on the degree of acute alcohol intoxication in these same volunteers. Specific hypotheses are:

  • Baseline serum levels of pregnenolone, pregnenolone sulfate (PS), dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) will be inversely correlated with the magnitude of acute behavioral responses to alcohol (sedation, anxiolysis, amnesia, psychomotor impairment and intoxication). That is, higher baseline levels of these neurosteroids will be associated with lessened behavioral responses to alcohol.
  • Baseline serum levels of allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), androstanediol, androsterone and GABA will be directly correlated with the magnitude of acute behavioral responses to alcohol. That is, higher baseline levels of these substances will be associated with heightened behavioral responses to alcohol.
  • Acute alcohol ingestion, compared to placebo ingestion, will increase serum levels of allopregnanolone and THDOC and plasma levels of GABA and will decrease plasma levels of PS. (Effects on levels of other neurosteroids are not specifically predicted based on animal data but will be examined in an exploratory manner.)
  • Acute alcohol-induced increases in serum levels of allopregnanolone and THDOC and in plasma levels of GABA will be directly correlated with the magnitude of acute behavioral responses to alcohol. Acute alcohol-induced decreases in serum levels of PS will be directly correlated with the magnitude of acute behavioral responses to alcohol. Correlations between alcoho

    Detailed Summary:

    2. BACKGROUND Neurosteroid Responses to Alcohol Administration: Alcohol likely interacts with the brain GABA-A receptor complex via two distinct manners: a direct effect (Grobin et al 1998), and an indirect effect, which is secondary to alterations in levels of endogenous GABA-A receptor-active neurosteroids or in levels of GABA itself (Morrow et al 1999). Indeed, alcohol's effects on neurosteroid and GABA levels may represent a novel and important mechanism of alcohol's actions (Morrow et al 1999). Acute alcohol administration significantly increases cerebral cortex (700%) and circulating (600%) levels of allopregnanolone, a potent GABA-A receptor agonist neurosteroid, in male rats (Morrow et al 1999). The magnitude of the observed alcohol-induced increase in allopregnanolone levels is sufficient to enhance GABA'ergic neurotransmission and to exert anxiolytic, sedative and anticonvulsant effects. Indeed, alcohol-induced increases in cerebral cortex allopregnanolone levels are significantly correlated with alcohol's hypnotic effects in rats (VanDoren et al 2000), and the time course of alcohol-induced increases in cerebral cortex allopregnanolone levels correlates well with many of alcohol's behavioral effects (VanDoren et al 2000); (Morrow et al 1999). Alcohol's effects on other neurosteroids have been poorly studied, although preliminary data suggest that alcohol dramatically lowers brain levels of PS (a GABA-A receptor antagonist neurosteroid) (Corpechot et al 1983) and increases brain levels of THDOC (a GABA-A receptor agonist neurosteroid) (Barbaccia et al 1999) in rats. In the latter study, THDOC and allopregnanolone levels were increased to a significantly greater extent in alcohol-preferring, compared to non-preferring rats, supporting a role of these neurosteroids in modulating alcohol's reinforcing effects (Barbaccia et al 1999) and in determining individual susceptibility to alcoholism. Regarding levels of GAB
    Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

    Current Primary Outcome: Behavioural Measures of Alcohol Intoxication, such as the Weingartner Verbal Memory Test, and the BVMT-R Visual Memory Test. [ Time Frame: Behavioural measures are assessed within 2 hours of alcohol administration. ]

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    Original Secondary Outcome:

    Information By: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

    Dates:
    Date Received: January 26, 2008
    Date Started: May 2004
    Date Completion: March 2009
    Last Updated: December 18, 2008
    Last Verified: December 2008