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      Sexually Dimorphic Ontogeny of GABAergic Influences on Periventricular Somatostatin Neurons

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          The biosynthesis and secretion of somatostatin (SRIH) within the hypothalamic periventricular-median eminence (PeN-ME) pathway follows a sexually differentiated developmental pattern beginning in the early neonatal period. It is generally accepted that testosterone plays a role in these processes, but the mechanisms underlying the age and sex differences are poorly understood. The present study sought to investigate the hypothesis that γ-aminobutyric acid (GABA) may play a role in determining sex differences in SRIH neuronal activity. Using an in vitro hypothalamic preparation where more than 97% of the immunoreactive SRIH is contained within the PeN-ME pathway, peptide release in response to the GABA<sub>A</sub> receptor antagonist, bicuculline, was followed through development. In the male a stimulatory response, indicative of an inhibitory GABAergic tone on SRIH secretion, was observed as early as postnatal day (P) 5. This persisted throughout juvenile development (P10, P17) and was present also in the adult male (P75), but in the peripubertal period the response to bicuculline was first lost (P25) and then reversed to an inhibition (P40), suggesting a transient switch to an apparent stimulatory GABAergic tone on SRIH release. By contrast, in the female, no bicuculline responsiveness was seen until P25 when it caused a decrease in SRIH release which persisted into adulthood. Using in situ hybridization studies we found no evidence to support the view that these age- and sex-dependent differences were due to changes in the expression of GABA<sub>A</sub> receptor α-subunits (α<sub>1</sub> and α<sub>2</sub>) which are colocalised in the PeN SRIH neurons. Following adult gonadectomy, the bicuculline response was abolished in the male, whereas, in the female it was reversed and identical in magnitude to the response in the intact male. These results demonstrate marked sex differences in GABA<sub>A</sub>-receptor-mediated influences on SRIH release which develop soon after birth and, in the adult, depend on gonadal factors. In the male these factors activate a primarily inhibitory influence, whereas in the female they facilitate an apparently stimulatory tone of GABA on SRIH secretion via the GABA<sub>A</sub> receptor. Our findings thus support the view that GABAergic transmission may play a key role in generating sex differences in the mode of SRIH secretion from the hypothalamus which has been shown to be a major factor in determining the sexually dimorphic patterns of growth hormone secretion.

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          Most cited references 8

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          GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity.

          Mammals manifest circadian behaviour timed by an endogenous clock in the hypothalamic suprachiasmatic nucleus (SCN). Considerable progress has been made in identifying the molecular basis of the circadian clock, but the mechanisms by which it is translated into cyclic firing activity, high during the day and low at night, are still poorly understood. GABA (gamma-aminobutyric acid), a common inhibitory neurotransmitter in the central nervous system, is particularly densely distributed within the SCN, where it is located in the majority of neuronal somata and synaptic terminals. Using an in vitro brain-slice technique, we have now studied the effect of bath-applied GABA on adult SCN neurons at various times of the day. We find that GABA acts as an inhibitory neurotransmitter at night, decreasing the firing frequency; but during the day GABA acts as an excitatory neurotransmitter, increasing the firing frequency. We show that this dual effect, which is mediated by GABA(A) receptors, may be attributed to an oscillation in intracellular chloride concentration. A likely explanation is that the amplitude of the oscillation in firing rate, displayed by individual neurons, is amplified by the dual effect of GABA in the SCN's GABAergic network.
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            Expression of glutamic acid decarboxylase messenger RNA in rat medial preoptic area neurones during the oestrous cycle and after ovariectomy

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              Sex differences in the response of rats to drugs affecting GABAergic transmission.

               H Manev,  D Pericić,  N Lakić (1985)
              The administration of diazepam 1.0 mg/kg decreased the level of plasma corticosterone in female but not in male Wistar rats. Picrotoxin, another drug affecting GABAergic transmission, also brought about an increase of plasma corticosterone in both sexes. However, in order to achieve a plasma corticosterone increase of similar magnitude (more than 500%) a threefold higher dose of picrotoxin had to be given to males. When the convulsive properties of picrotoxin were tested, it became evident that the dose of picrotoxin (2.5 mg/kg) which was subconvulsive in male was almost 100% convulsive in female rats. The existing sex differences in the response of rats to drugs affecting GABAergic transmission might have possible implications in the treatment of GABA system dysfunction.

                Author and article information

                S. Karger AG
                December 1999
                24 December 1999
                : 70
                : 6
                : 384-391
                aDepartment of Neuroendocrinology, Division of Neuroscience, Imperial College School of Medicine, London, bLaboratory of Neuroendocrinology, Babraham Institute, Cambridge, and cDepartment of Cell Biology, Neurobiology and Anatomy, Loyola University of Chicago, Ill., USA
                54500 Neuroendocrinology 1999;70:384–391
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 51, Pages: 8
                Regulation of Hypothalamic Neurons


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