Xihua Chen

Interleukin-1β fever in rats: gender difference and estrous cycle influence

Evidence exists to support the concept of sex difference in immune system activation by pyrogenic cytokines. In this study, fever development was monitored to analyze the effect of peripheral administration of interleukin (IL)-1beta (1 microgram/kg) in adult male and cycling or ovariectomized female rats with or without ovarian hormonal replacement. In male and randomly cycling female rats, a similar increase in body temperature occurred after intraperitoneal IL-1beta injection. Two representative stages of estrus with higher and lower levels of ovarian hormones (proestrus and diestrus, respectively) were chosen for study of the febrile response induced by IL-1beta. The fever induced by IL-1beta was found to be significantly higher and more prolonged in females at proestrus than at diestrus. The differential fever response seems to be mainly linked to the ovarian hormonal levels because bilaterally ovariectomized females, supplemented with sequential injections of estradiol 17beta and progesterone, showed a significantly higher IL-1beta fever than did ovariectomized rats receiving estradiol 17beta only. These results indicate that gonadal hormones can influence fever development and raise the possibility of interaction between sex hormones and thermogenesis in females during the estrous cycle.

Dopamine depresses glutamatergic synaptic transmission in the rat parabrachial nucleus in vitro.

Nystatin-perforated patch recordings were made from rat parabrachial neurons in an in vitro slice preparation to examine the effect of dopamine on parabrachial cells and on excitatory synaptic transmission in this nucleus. In current clamp mode, dopamine reduced the amplitude of the evoked excitatory postsynaptic potential without significant change in membrane potential. In cells voltage-clamped at -65 mV, dopamine dose dependently and reversibly decreased evoked, pharmacologically isolated, excitatory postsynaptic currents with an EC50 of 31 microM. The reduction in excitatory postsynaptic current was accompanied by an increase in paired pulse ratio (a protocol used to detect presynaptic site of action) with no change in the holding current or in the decay of the evoked excitatory postsynaptic currents. In addition, dopamine altered neither postsynaptic (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate-induced currents, nor steady-state current voltage curves. Miniature excitatory postsynaptic current analysis revealed that dopamine caused a rightward shift of the frequency-distribution curve with no change in the amplitude-distribution curve, which is consistent with a presynaptic mechanism. The dopamine-induced attenuation of the excitatory postsynaptic current was almost completely blocked by the D1-like receptor antagonist SCH23390 (10 microM), although the D2-like antagonist sulpiride (10 microM) also partially blocked it. Combined application of both antagonists blocked all dopamine-induced synaptic effects. The synaptic effect of dopamine was mimicked by the D1-like agonist SKF38393 (50 microM), but the D2-1ike agonist quinpirole (50 microM) also had a small effect. Combined application of both agonists did not produce potentiated responses. Dopamines effect on the excitatory postsynaptic current was independent of serotonin, GABA and adenosine receptors, but may have some interactions with adrenergic receptors. These results suggest that dopamine directly modulates excitatory synaptic events in the parabrachial nucleus predominantly via presynaptic D1-like receptors.

Suppression of PGE(2) fever at near term: reduced thermogenesis but not enhanced vasopressin antipyresis.

Fevers are known to be suppressed near term in the mother, but the mechanism responsible for this phenomenon is not understood. We tested the hypothesis that the suppression of fever at term is a result of enhanced vasopressin-induced antipyresis. Effects of intracerebroventricular prostaglandin E(2) (PGE(2)) were examined in rats at gestational days 16-17 and 19-20 (near term) and days 1-2 postpartum. PGE(2) (50 ng) elevated body and interscapular brown adipose tissue (iBAT) temperatures and increased sympathetic nerve activity to the iBAT. PGE(2)-induced changes in iBAT temperature and nerve activity, as well as in rectal temperature, were reduced or eliminated near term, and responses were recovered in the postpartum period. Blood pressure and heart rate changes induced by central PGE(2) were also decreased at near term. Coinfusion of Manning compound, a V(1) vasopressin receptor antagonist, with PGE(2) throughout the peripartum period did not reverse the suppressed iBAT temperature and nerve activity or body temperature responses to PGE(2). Microdialysis experiments revealed unchanged terminal release of vasopressin in the ventral septal area after PGE(2) infusion in either pregnant or parturient rats. These results suggest that fever reduction at near term is not associated with enhanced vasopressin antipyresis, but may be a result of reduced sympathetic tone and in particular a reduced sympathetic drive to the iBAT. This finding may reflect a generalized reduction in autonomic output around the time of parturition.Fevers are known to be suppressed near term in the mother, but the mechanism responsible for this phenomenon is not understood. We tested the hypothesis that the suppression of fever at term is a result of enhanced vasopressin-induced antipyresis. Effects of intracerebroventricular prostaglandin E2(PGE2) were examined in rats at gestational days 16-17 and 19-20 (near term) and days 1-2 postpartum. PGE2 (50 ng) elevated body and interscapular brown adipose tissue (iBAT) temperatures and increased sympathetic nerve activity to the iBAT. PGE2-induced changes in iBAT temperature and nerve activity, as well as in rectal temperature, were reduced or eliminated near term, and responses were recovered in the postpartum period. Blood pressure and heart rate changes induced by central PGE2 were also decreased at near term. Coinfusion of Manning compound, a V1 vasopressin receptor antagonist, with PGE2 throughout the peripartum period did not reverse the suppressed iBAT temperature and nerve activity or body temperature responses to PGE2. Microdialysis experiments revealed unchanged terminal release of vasopressin in the ventral septal area after PGE2 infusion in either pregnant or parturient rats. These results suggest that fever reduction at near term is not associated with enhanced vasopressin antipyresis, but may be a result of reduced sympathetic tone and in particular a reduced sympathetic drive to the iBAT. This finding may reflect a generalized reduction in autonomic output around the time of parturition.

Ibogaine and a total alkaloidal extract of Voacanga africana modulate neuronal excitability and synaptic transmission in the rat parabrachial nucleus in vitro

Ibogaine is a natural alkaloid of Voacanga africana that is effective in the treatment of withdrawal symptoms and craving in drug addicts. As the synaptic and cellular basis of ibogaines actions are not well understood, this study tested the hypothesis that ibogaine and Voacanga africana extract modulate neuronal excitability and synaptic transmission in the parabrachial nucleus using the nystatin perforated patch-recording technique. Ibogaine and Voacanga africana extract dose dependently, reversibly, and consistently attenuate evoked excitatory synaptic currents recorded in parabrachial neurons. The ED50 of ibogaines effect is 5 microM, while that of Voacanga africana extract is 170 micrograms/ml. At higher concentrations, ibogaine and Voacanga africana extract induce inward currents or depolarization that are accompanied by increases in evoked and spontaneous firing rate. The depolarization or inward current is also accompanied by an increase in input resistance and reverses polarity around 0 mV. The depolarization and synaptic depression were blocked by the dopamine receptor antagonist haloperidol. These results indicate that ibogaine and Voacanga africana extract 1) depolarize parabrachial neurons with increased excitability and firing rate; 2) depress non-NMDA receptor-mediated fast synaptic transmission; 3) involve dopamine receptor activation in their actions. These results further reveal that the Voacanga africana extract has one-hundredth the activity of ibogaine in depressing synaptic responses. Thus, ibogaine and Voacanga africana extract may produce their central effects by altering dopaminergic and glutamatergic processes.

Electrophysiological studies of neurohypophysial neurons and peptides.

We have used hypothalamic slices of the supraoptic nucleus (SON) to investigate synaptic control of magnocellular vasopressinergic and oxytocinergic neurons. With the use of perforated patch recording techniques we identified and isolated excitatory or inhibitory postsynaptic currents elicited by electrical stimulation of afferent fibers. Both inhibitory and excitatory afferent fibers displayed presynaptic GABAB receptors; the GABAB agonist, baclofen caused a dose-dependent suppression of the evoked potentials in the absence of any effects on postsynaptic input resistance. Further evidence for a presynaptic locus included an increase in paired pulse ratio and a lack of effect on currents elicited by exogenously applied muscimol (a GABAA receptor agonist) or AMPA (a glutamate agonist). With the use of an GABAB receptor antagonist we demonstrated an action of endogenously released GABA, acting at GABAB receptors on excitatory terminals, to reduce excitatory transmission. In addition to presynaptic modulation by GABA of afferent inputs, we also observed actions of vasopressin and oxytocin, released from dendrites of magnocellular SON neurons, to gate afferent, excitatory transmission in the SON. Exogenously applied vasopressin and oxytocin, or these peptides when released by depolarizing stimuli of magnocellular neurons, reduced the size of evoked excitatory postsynaptic potentials at a presynaptic locus. We have also observed actions of arginine vasopressin to modulate the action of glutamate in slices of the ventral septal area and to attenuate a glutamate-mediated excitatory postsynaptic current in slices of the parabrachial nucleus.