Caffeine-induced increases in the brain and plasma concentrations on neuroactive steroids in the rat

The effects of caffeine, a naturally occurring stimulant, on the brain and plasma concentrations of neuroactive steroids were examined in the rat. A single intraperitoneal injection of caffeine induced dose- and time-dependent increases in the concentrations of pregnenolone, progesterone, and 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in the cerebral cortex. The increases were significant at a caffeine dose of 25 mg/kg and greatest (+188, +388, and +71%, respectively) at a dose of 100 mg/kg in rats killed 30 min after caffeine administration. Caffeine also increased the plasma concentrations of pregnenolone and progesterone with a dose-response relation similar to that observed in the brain, whereas the caffeine-induced increase in the plasma concentration of allopregnanolone was maximal at a dose of 50 mg/kg. Caffeine increased the plasma concentration of corticosterone, but it had no effect on the brain or plasma concentrations of 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one and dehydroepiandrosterone. Moreover, the brain and plasma concentrations of pregnenolone, progesterone, and allopregnanolone were not affected by caffeine in adrenalectomized-orchiectomized rats. These results suggest that neuroactive steroids may modulate the stimulant and anxiogenic effects of caffeine. (C) 2000 Elsevier Science Inc

Neurosteroids in nicotine and morphine dependence

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. 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. 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. 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. 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

Long-term administration with levonorgestrel decreases allopregnanolone levels and alters GABAA receptor subunit expression and anxiety-like behavior

Fluctuations in the concentrations of the neuroactive steroid allopregnanolone are thought to influence γ-amino-butyric acid type A (GABAA) receptor gene expression and function. Long-termtreatment with ethinyl estradiol (EE) plus levonorgestrel (LNG), two of the most widely used steroids in the hormonal contraceptive pill, decreases allopregnanolone levels in rat cerebral cortex and plasma, alters GABAA receptor expression and induces anxiety-like behavior. We evaluated which component of the hormonal contraceptive pill is responsible for the aforementioned changes. Female rats were injected subcutaneously (s.c.) with EE (0.030 mg) or LNG (0.125 mg) once a day for 4 weeks. Compared to the respective vehicle-treated control groups, EE decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 76, 72 and 33%, respectively and hippocampal levels by 52, 56 and 50%, respectively. Likewise, LNG decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 75, 68 and 33%, respectively, and hippocampal levels by 55, 65 and 60%, respectively. Administration of LNG, but not EE, increased the abundance of the γ2 subunit peptide in cerebral cortex and hippocampus by 38 and 59%, respectively. Further, LNG, but not EE, decreased the time spent and the number of entries into the open arms of the elevated plus maze by 56 and 43%, respectively, an index of anxiety-like behavior. These results suggest that alterations in GABAA receptor subunit expression and anxiety-like behavior induced by long-term treatment with combined EE/LNG appear to be caused by LNG. Given that both EE and LNG decrease allopregnanolone levels in a similar manner, these results further suggest that changes in allopregnanolone levels are not associated with GABAA receptor expression

Neonatal exposure to estradiol in rats influences neuroactive steroid concentrations, GABA(A) receptor expression, and behavioral sensitivity to anxiolytic drugs

Gonadal steroids, in particular estradiol, exert important actions during pre- and perinatal periods in the regulation of sexual dimorphism and development of the nervous system. We have now examined the effects of neonatal estradiol administration in female rats on brain concentrations of the neuroactive steroids allopregnanolone and tetrahydrodeoxycorticosterone, expression of GABA(A) receptor subunits, and behavioral sensitivity to benzodiazepines and allopregnanolone. Administration of beta-estradiol 3-benzoate on the day of birth resulted in marked decreases in the concentrations of progesterone and allopregnanolone in the cerebral cortex at 21, 60, and 180 days after birth. The concentrations of tetrahydrodeoxycorticosterone, 17beta-estradiol, and dehydroepiandrosterone in the brain at 60 days were not affected by such treatment. Neonatal administration of beta-estradiol 3-benzoate also increased the cerebrocortical abundance of alpha(1), alpha(2), and gamma(2) subunits of the GABA(A) receptor without affecting that of alpha(3), alpha(4), alpha(5), or delta subunits. Diazepam induced a greater reduction in locomotor activity as well as a more pronounced anxiolytic-like effect in the elevated plus-maze test in rats subjected to neonatal treatment with beta-estradiol 3-benzoate than in vehicle-treated controls, while allopregnanolone induced a similar effect in both groups. These effects of estradiol suggest that it plays a major role in regulation both of GABAergic transmission and of the abundance of endogenous modulators of such transmission during development of the central nervous system

Fluctuations in brain concentrations of neurosteroids are not associated to changes in gephyrin levels

Neurosteroids play a crucial role in stress, alcohol dependence and withdrawal, and other physiological and pharmacological actions by potentiating or inhibiting neurotransmitter action. This review article focuses on data showing that the interaction among stress, ethanol, and neuroactive steroids may result in plastic molecular and functional changes of GABAergic inhibitory neurotransmission. The molecular mechanisms by which stress–ethanol–neuroactive steroids interactions can produce plastic changes in GABAA receptors have been studied using different experimental models in vivo and in vitro in order to provide useful evidence and new insights into the mechanisms through which acute and chronic ethanol and stress exposure modulate the activity of GABAergic synapses. We show detailed data on a) the effect of acute and chronic stress on peripheral and brain neurosteroid levels and GABAA receptor gene expression and function; b) ethanol-stimulated brain steroidogenesis; c) plasticity of GABAA receptor after acute and chronic ethanol exposure. The implications of these new mechanistic insights to our understanding of the effects of ethanol during stress are also discussed. The understanding of these neurochemical and molecular mechanisms may shed new light on the physiopathology of diseases, such as anxiety, in which GABAergic transmission plays a pivotal role. These data may also lead to the need for new anxiolytic, hypnotic and anticonvulsant selective drugs devoid of side effects