Benzodiazepines (BZD) are used widely, and abused, as minor tranquilizers in our society. They are also prescribed as muscle relaxants and are standard treatment for generalized status epilepticus. Naturally occurring metabolites of steroid hormones affect BZD binding; steroid hormones affect the severity of seizures and an endogenous BZD inhibitor, extracted from bovine cerebral cortex shows specific saturable binding to the type I BZD receptor. The lateral vestibular nucleus (LVN) has high concentrations of type I receptors and is the presumptive site of action for diazepam-induced muscle relaxation in response to cutaneous inputs. One proposed model for studying interactions of BZD and steroids include reproductive behaviors in female rats. The hormone-dependent lordosis reflex is executed by back and neck muscles and is elicited by stimulation of the skin by the male during mounting. LVN facilitates lordosis. Aggressive postures such as rearing and boxing also involve the axial muscles. A multiple assay of reproductive behaviors will measure the effect of microinjections of BZD into LVN and into the gigantocellular reticular nucleus (Gi) in females with different hormone treatments. Responsivity, proceptivity and the disposition to sociosexual interactions will be evaluated in an apparatus that allows the female to pace copulation. In acute experiments, BZD will be applied from a cannula to which a stimulating electrode is attached, and back and neck muscle EMG will measure the effect of microinjections of agonists and antagonists on the descending excitatory drive from LVN and Gi to axial motoneurons. Then, retrograde tracer from the same cannula will label afferents to sites effective vs ineffective for BZD modulation of axial EMG. The behavioral model contains elements relevant to BZD action: sex hormones, cutaneous inputs, back muscles and the disposition to engage in social interactions. In humans, back muscles are also involved in hormone modulated behaviors such as labor and delivery; low back pain associated with menses, labor, and stress; and neck tension related to stress. By studying the potential of steroid hormones to modulate specific classes of BZD, the relative potency of these drugs and presumptive endogenous ligands during the various stages of reproductive and post reproductive life will be better understood.
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| McCarthy, M M; Kaufman, L C; Brooks, P J et al. (1995) Estrogen modulation of mRNA levels for the two forms of glutamic acid decarboxylase (GAD) in female rat brain. J Comp Neurol 360:685-97 |
