The molecular basis of ethanol action involves the production of GABAergic neuroactive steroids, including 3a-hydroxy-5a-pregnan-20-one (3a,5a-THP) and 3a,21-dihydroxy-5a-pregnan-20-one (3a,5a-THDOC). Ethanol elevates brain levels of these steroids in rodents to enhance GABA-A receptor activity. Neuroactive steroids modulate anticonvulsant effects, sedation, impairment of spatial memory, anxiolytic-like, antidepressant-like and reinforcing properties of ethanol. Each of these responses is inhibited by pretreatment with the biosynthesis inhibitor finasteride and/or prior adrenalectomy. These studies suggest that neuroactive steroids are responsible for many of the GABAergic effects of ethanol in vivo and the elevation of neuroactive steroids may determine sensitivity to the behavioral effects of ethanol. The effects of ethanol on 3a,5a-THP levels are dependent upon de novo synthesis of steroidogenic acute regulatory protein in the adrenals to produce the precursor pregnenolone. Low sensitivity to the behavioral effects of ethanol is a risk factor for development of alcoholism. Moreover, individuals with the GABRA2 polymorphism linked to alcoholism exhibit blunted sensitivity to subjective effects of ethanol and insensitivity to finasteride. Alcoholic subjects show blunted activation of the HPA axis and this may lead to dysregulation of neurosteroid levels that would normally contribute to alcohol sensitivity. Hence, neurosteroid production in response to physiological challenge may be protective against the development of alcoholism. GABAergic neuroactive steroids may be therapeutic for alcoholism since they are known to substitute for ethanol in discrimination studies, increase alcohol sensitivity, reduce ethanol consumption using various drinking paradigms, reduce ethanol withdrawal anxiety and seizure susceptibility, restore physiological responses to stress challenges, prevent neurotoxicity and promote neurogenesis.
Neurosteroids mediate alcohol sensitivity: mechanisms and therapeutic relevance
Porcu P
2008
Abstract
The molecular basis of ethanol action involves the production of GABAergic neuroactive steroids, including 3a-hydroxy-5a-pregnan-20-one (3a,5a-THP) and 3a,21-dihydroxy-5a-pregnan-20-one (3a,5a-THDOC). Ethanol elevates brain levels of these steroids in rodents to enhance GABA-A receptor activity. Neuroactive steroids modulate anticonvulsant effects, sedation, impairment of spatial memory, anxiolytic-like, antidepressant-like and reinforcing properties of ethanol. Each of these responses is inhibited by pretreatment with the biosynthesis inhibitor finasteride and/or prior adrenalectomy. These studies suggest that neuroactive steroids are responsible for many of the GABAergic effects of ethanol in vivo and the elevation of neuroactive steroids may determine sensitivity to the behavioral effects of ethanol. The effects of ethanol on 3a,5a-THP levels are dependent upon de novo synthesis of steroidogenic acute regulatory protein in the adrenals to produce the precursor pregnenolone. Low sensitivity to the behavioral effects of ethanol is a risk factor for development of alcoholism. Moreover, individuals with the GABRA2 polymorphism linked to alcoholism exhibit blunted sensitivity to subjective effects of ethanol and insensitivity to finasteride. Alcoholic subjects show blunted activation of the HPA axis and this may lead to dysregulation of neurosteroid levels that would normally contribute to alcohol sensitivity. Hence, neurosteroid production in response to physiological challenge may be protective against the development of alcoholism. GABAergic neuroactive steroids may be therapeutic for alcoholism since they are known to substitute for ethanol in discrimination studies, increase alcohol sensitivity, reduce ethanol consumption using various drinking paradigms, reduce ethanol withdrawal anxiety and seizure susceptibility, restore physiological responses to stress challenges, prevent neurotoxicity and promote neurogenesis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
