Inhibition of basal and stress-induced dopamine release in the cerebral cortex and nucleus accumbens of freely moving rats by the neurosteroid allopregnanolone

Abstract

The neurosteroid allopregnanolone is a potent and efficacious modulator of γ-aminobutyric acid (GABA) type A receptors. The effects of intracerebroventricular injection of allopregnanolone (5 to 15 μg in 5 μl) on basal and stress-induced changes in the extracellular concentrations of dopamine were investigated by microdialysis in various brain areas of freely moving rats and compared with those of the benzodiazepine midazolam (1 to 10 μg in 5 μl). Allopregnanolone reduced (by a maximum of 65 to 75%) basal dopamine content in the prefrontal cortex and nucleus accumbens in a dose-dependent manner, but had no effect on dopamine output in the striatum. Allopregnanolone (10 to 15 μg) also completely prevented the increase in extracellular dopamine concentrations in the nucleus accumbens and cerebral cortex induced by foot-shock stress. Midazolam reduced basal dopamine content in all three brain regions studied as well as the stress- induced increase in dopamine content in the nucleus accumbens and cerebral cortex with a greater potency than allopregnanolone. These results suggest that endogenous neurosteroids may participate in the GABAergic modulation of dopaminergic transmission in the rat cerebral cortex and nucleus accumbens, two brain areas which are important in the regulation of emotional processes. These agents do not appear to affect striatal dopaminergic transmission which modulates motor function.

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

“…A recent clinical report also demonstrated that the ALLO concentrations stemming from 30 mg progesterone, but not 0, 60 or 200 mg were associated with enhanced negative mood scores in postmenopausal women [1]. Lastly, administration of 100 pmol ALLO into the lateral ventricle was found to elevate extracellular dopamine content in the NAc [32] whereas 45 nmol ALLO suppressed this measure [24]. Notably, ALLO's peak effect (50 ng; equivalent to 150 pmol) on bout micro-architecture in the present study closely resembled the concentration and route of ALLO administration (100 pmol; ICV) that led to enhanced dopamine content in the NAc.…”

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

“…Specifically, allopregnanolone decreases stress-induced dopamine release in rodent cerebral cortex and nucleus accumbens (Motzo et al, 1996) and influences dopamine-mediated rodent behaviors (Khisti et al, 2002). The GABAergic neuroactive steroid 3a,21-dihydroxy-5a-pregnan-20-one (THDOC) also decreases stress-induced prefrontal cortical dopamine release (Grobin et al, 1992).…”

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

“…Olanzapine is known to block dopamine receptors with relatively weaker potency and the blockade of receptors, other than D 2 , is thought to be responsible for its atypical antipsychotic profile (Bymaster et al, 1999). Moreover, ALLO represents the most potent positive modulator of GABA A receptor and is known to diminish basal and stress-induced dopaminergic transmission in the brain by its action on GABA A receptors (Motzo et al, 1996). Our observation that bicuculline pretreatment antagonized the effects of olanzapine on CAR-and apomorphineinduced climbing behaviors suggests that the antipsychoticlike action of olanzapine could be mediated via activation of GABA A receptors.…”

“…Our observation that bicuculline pretreatment antagonized the effects of olanzapine on CAR-and apomorphineinduced climbing behaviors suggests that the antipsychoticlike action of olanzapine could be mediated via activation of GABA A receptors. Consequently it may be speculated that the influence of ALLO on dopaminergic neurotransmission might be mediated via GABA A receptors (Motzo et al, 1996;Khisti et al, 2002) perhaps through modulation of intracellular signaling mechanisms like protein kinase C (PKC) (Brunig et al, 1999;Brussard et al, 2000;Liu et al, 2000). That the activation or inhibition of PKC increases or decreases, respectively, dopamine release in striatum has already been demonstrated (Gimbalvo, 1988).…”

“…ALLO increases the GABA-mediated chloride ion (Cl À ) flux through GABA A receptors and is 20-fold more potent than benzodiazepines and 200-fold more potent than barbiturates (Majewska et al, 1986;Morrow et al, 1987Morrow et al, , 1990. High doses of ALLO increase GABAergic tone leading to suppression of dopaminergic transmission (Motzo et al, 1996;Van Kammen, 1977;Khisti et al, 1998) and elicit a behavioral profile similar to that of the D 2 -receptor antagonist haloperidol . ALLO exerts multiple effects in CNS including anxiolysis (Wieland et al, 1991), antistress (Zimmerberg and Blaskey, 1998), antidepressant , and anticonvulsant activity (Frye, 1995), in addition to its neuroleptic-like activity .…”