Ovarian steroids modify the behavioral and neurochemical responses of the central benzodiazepine receptor

Abstract

The effect of ovarian steroids on the benzodiazepine receptor was assessed in the elevated plus-maze and, after restraint stress, in benzodiazepine receptor binding assays. Vehicle-treated proestrous rats displayed anxiolytic behavior, relative to diestrus or estrous rats. Anxiolytic behavior was observed after 1 or 2 mg/kg diazepam in diestrus and estrus. However, whereas 4 mg/kg increased open arm exploration in diestrus, a decrease in the same measure was found at estrus. At proestrus, a decrease in anxiolytic behavior was observed after 2 and 4 mg/kg. In ovariectomized vehicle-treated rats, restraint stress increased NaCl-induced potentiation of 3H-flunitrazepam binding in cortical and cerebellar, but not in hippocampal membranes. Estradiol benzoate (2 micrograms) prevented the potentiation of flunitrazepam binding by NaCl in nonstressed and stressed animals, whereas progesterone (0.5 mg) increased the NaCl-induced potentiation of flunitrazepam binding in both nonstressed and stressed animals. Combined estradiol benzoate and progesterone treatment produced effects that were intermediate to those seen after injection of either steroid alone. The potentiation of flunitrazepam binding by NaCl observed in vehicle-treated stressed or progesterone-treated nonstressed animals was mimicked in vitro by addition to reaction test tubes of the neuroactive metabolite of progesterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone). These results point to a significant role of ovarian hormones in modifying the stress response of the benzodiazepine receptor.

Withdrawal from 3α-OH-5α-Pregnan-20-One Using a Pseudopregnancy Model Alters the Kinetics of Hippocampal GABAA-Gated Current and Increases the GABAAReceptor α4 Subunit in Association with Increased Anxiety

“…Altered response to BDZs is also observed across the estrous cycle or after ovariectomy (Fernandez-Guasti and Picazo, 1990;Bitran et al, 1991b;Wilson, 1992;Bitran and Dowd, 1996). Additional evidence for crosstolerance of BDZs with neuroactive steroids is provided by behavioral studies, which demonstrate that 3␣,5␣-THP can substitute for several BDZs in a drug discrimination task (Ator et al, 1993).…”

“…The maze was wiped clean with 70% ethanol after testing each rat. Anxiogenic effects of progesterone withdrawal were assessed based on the frequency of open arm entries versus closed entries as well as the time spent in the open arms (Pellow and File, 1985;Bitran and Dowd, 1996;Moran et al, 1996). Decreased time spent on the open arms and a low frequency of open arm entries relative to control animals is consistent with an increase in anxious behavior (Pellow and File, 1985).…”

Diazepam Increases the Number of Punished Responses in a Conflict-Operant Paradigm during Late Proestrus and Estrus in the Wistar Rat

“…Several behavioral findings suggest that anxiety-like behaviors decrease during late proestrus [1,2]. The low anxiety-like behaviors occurring during late proestrus have been attributed to the presence of increased levels of progesterone [3] occurring during late proestrus [4].…”

Progesterone and Testosterone Modulate the Convulsant Actions of Pentylenetetrazol and Strychnine in Mice

“…Testosterone has more inconsistent actions, since it is metabolized to oestradiol, which can exacerbate seizures, and dihydrotestosterone, which inhibits NMDA-type glutamate transmission and may have antiseizure effects (Herzog 1999a). On the other hand, ovarian steroids modify the behavioural response to activation of the benzodiazepine receptor, reducing withdrawal anxiety and hyperactivity in mice (Bitran & Dowd 1996;Reddy & Kulkarni 1997). The number of seizures occurring during the benzodiazepine withdrawal syndrome is significantly less in prooestrus-oestrus, where progesterone Author for correspondence: M. E. Pesce, University of Santiago de Chile, Alameda 3363, P.O.…”