Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus.

Abstract

N-Methyl-D-aspartate (NMDA, 200 pzM) evokes the release of [3H]norepinephrine ([3H]NE) from preloaded hippocampal slices. This effect is potentiated by dehydroepiandrosterone sulfate (DHEA S), whereas it is inhibited by pregnenolone sulfate (PREG S) and the highaffinity r inverse agonist 1,3-di(2-tolyl)guanidine, at concentrations of .100 nM. Neither 3a-hydroxy-5a-pregnan-20-one nor its sulfate ester modified NMDA-evoked [3H] NE overflow. Eighty-four female Sprague-Dawley rats (180-225 g), purchased from Iffa Credo, were kept at 21°C on a 12 hr:12 hr light/dark cycle with free access to water and Purina chow. At least 4 weeks prior to the release experiments, rats were anesthetized under ether and bilateral ovariectomy was carried out by lateral access. In a subgroup of 16 rats, anesthetized with chloral hydrate (400 mg/kg, i.p.) 3-11 days prior to the experiments, PTX (1 ,g/2 ,ul of physiological saline) was injected (using a 10-uAl Hamilton syringe) bilaterally into the dorsal hippocampus at A: 4.5, L: 4, and D: 4, according to the atlas of Paxinos and Watson (25) as described (3). Twelve control rats received an equal volume of the vehicle. When appropriate, the rats were killed by decapitation and their brains were rapidly dissected. Coronal slices (0.4-mm thick) of the hippocampus were prepared with a McIlwain tissue chopper. The slices were incubated in Krebs' solution containing[3H]NE (0.1 ,uM) and bubbled with a mixture of 95% 02/5% CO2 at 37°C for 30 min. The composition of the Krebs' solution (in mM) was NaCl 118, KCl 4.7, CaCl2 1.3, MgCl2 1.2, NaH2PO4 1, NaHCO3 25, glucose 11.1, Na2EDTA 0.04, and ascorbic acid 0.06. At the end of the incubation period, each glass chamber received two slices that were superfused continuously at a rate of 0.5 ml/min with oxygenated Mg2+-free Krebs' solution at 37°C for 68 min. As indicated in Results, one steroid and/or one of the cr ligands DTG, haloperidol, BD-1063, or spiperone were added in Mg2+-free Krebs' solution throughout the superfusion period. The prototypic a-ligand DTG was chosen since it acts on both a-i and o'2 receptors (3, 26). The universal o-antagonist haloperidol also binds to dopaminergic, serotoninergic, adrenergic, and cholinergic sites Abbreviations: 3a,5a-THP, 3a-hydroxy-Sa-pregnan-20-one; CNS, central nervous system; DHEA, dehydroepiandrosterone; DTG, 1,3-di(2-tolyl)guanidine; Gi/o protein, guanine nucleotide-binding pro-

Antipsychotic-Like Properties of 5-α-Reductase Inhibitors

“…This possibility is supported by the notion that environmental stress, a major factor in the etiology of psychosis (Howes et al, 2004), has been shown to affect the metabolism of several NSs (Barbaccia et al, 2001). Moreover, NSs influence the function of all the major key substrates involved in the pathophysiology of psychotic disorders, such as the dopaminergic mesolimbic system (Barrot et al, 1999;Jaworska-Feil et al, 1998;Rouge-Pont et al, 2002), as well as the N-methyl-d-aspartate (NMDA) glutamate receptor (Monnet et al, 1995).…”

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

“…DHEAS is more soluble in water than DHEA, is converted to DHEA in the cerebral tissue (Kroboth et al, 1999), and is reported to affect the brain neurotransmitter receptors (GABA A R, NMDAR, s1R) in the same mode as DHEA (Majewska, 1992;Monnet et al, 1995;Urani et al, 2001). Therefore, DHEAS was used for the direct intrabrain administration.…”

“…DHEA may act through the neurotransmitter receptors GABA A R, s1R and NMDAR (Majewska et al, 1990;Monnet et al, 1995;Urani et al, 2001). A role in depression for s1R Figure 4 Immobility of saline, DHEA, and muscimol-treated FSL rats in the swim test.…”

σ1 Receptor Ligands and Related Neuroactive Steroids Interfere with the Cocaine-Induced State of Memory

“…These steroids are synthesized in the periphery or centrally in the brain by glial cells and neurons, and modulate the brain activity through both genomic and nongenomic rapid neuromodulatory actions affecting several neurotransmitters and second messenger systems (Baulieu, 1981;Paul and Purdy, 1992). In vitro and in vivo pharmacological tests, as well as behavioral studies, demonstrated that pregnenolone, DHEA, and their sulfate esters act as s 1 receptor agonists, whereas progesterone acts as a potent antagonist (Monnet et al, 1995;Bergeron et al, 1996;. These steroids also interact with excitatory and inhibitory neurotransmitter receptors.…”

“…In addition, cocaine interacts with the s 1 receptor at a similar dose range as observed for the dopamine transporter (Sharkey et al, 1988), and the s 1 receptor is implicated in several of cocaine's effects such as locomotor stimulation, sensitization, acquisition and reactivation of conditioned place preference, convulsions, and lethality (Reith et al, 1986;Menkel et al, 1991;Ujike et al, 1992;Ritz and George, 1993;Romieu et al, 2000Romieu et al, , 2002Romieu et al, , 2003Romieu et al, , 2004; for a review, see Maurice et al, 2002). This intracellular protein sharing some characteristics of neuromodulatory receptors is also a target for several neuroactive steroids, including pregnenolone, dehydroepiandrosterone (3b-hydroxy-5a-androsten-17-one (DHEA)), their sulfate esters, or progesterone, but not pregnanolone or allopregnanolone (Su et al, 1988;Monnet et al, 1995;Bergeron et al, 1996;Maurice et al, 1999).…”