Neuroscience
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Environmental synchronization of the endogenous mammalian circadian rhythm involves glutamatergic and GABAergic neurotransmission within the hypothalamic suprachiasmatic nucleus (SCN). The neuropeptide nociceptin/orphanin FQ (N/OFQ) inhibits light-induced phase shifts, evokes K(+)-currents and reduces the intracellular Ca(2+) concentration in SCN neurons. Since these effects are consistent with a modulatory role for N/OFQ on synaptic transmission in the SCN, we examined the effects of N/OFQ on evoked and spontaneous excitatory and inhibitory currents in the SCN. ⋯ However, N/OFQ had no effect on currents activated by muscimol application or on the amplitude of miniature IPSC (mIPSC) and significantly reduced the mIPSC frequency consistent with an inhibition of GABA release downstream from Ca(2+) entry. Finally, N/OFQ inhibited the paired-pulse depression observed in SCN GABAergic synapses consistent with a presynaptic mechanism of action. Together these results suggest a widespread modulatory role for N/OFQ on the synaptic transmission in the SCN.
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Although neurokinin-1 receptor (NK-1)-bearing neurons are distributed in lamina I of the trigeminal caudal nucleus (Vc) and constitute major projection neurons, little is known about their fundamental role(s) in nociceptive processing. This study examines the effect of intra cisterna magna injection of substance P (SP) conjugated to saporin (SP-Sap; 5 microM, 5 microl) [with/without systemic administration of bicuculline] on c-Fos expression in the trigeminal sensory nucleus (TSN) induced 2 h after 10 min repetitive electrical stimulation of the trigeminal ganglion (TG) at high intensity (1.0 mA, 5 Hz, 5 ms) in the urethane-anesthetized rat. In the SP-Sap-treated rats, the numbers of NK-1-immunopositive neurons in laminae I and III of the Vc decreased compared with rats similarly pretreated with saline (Sal; 5 microl) or blank-saporin (Bl-Sap; 5 microM, 5 microl). ⋯ In contrast, high intensity stimulation induced less c-Fos-immunopositive neurons in the VcI/II and Vo of rats treated with SP-Sap compared with those in Sal- or Bl-Sap-treated controls. In SP-Sap-treated rats preadministered with bicuculline, the numbers of c-Fos-immunopositive neurons in the VcI/II and Vo were increased compared with the SP-Sap-treated rats preadministered with Sal. These results suggest that NK-1-immunopositive neurons in laminae I and III of Vc play a pivotal role in the nociceptive specific processing in the TSN through GABA(A) receptors.
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It is unknown whether the amyloid beta-peptide (Abeta), a principal component found in extracellular neuritic plaques in the brain of patients with Alzheimer's disease (AD), is capable of altering adenylyl cyclase (AC) activity and the somatostatin (SRIF) receptor-effector system in the cerebral cortex of the patients. Therefore, the objective of this study was to investigate the effect of the beta fragment, beta (25-35), on AC activity and the somatostatinergic system in the rat frontoparietal cortex. A single dose of beta (25-35) (10microg) injected intracerebroventricularly significantly decreased the density of SRIF receptors (27.4%) and increased their affinity (32.2%) in the frontoparietal cortex. ⋯ Continuous infusion of Abeta (25-35) had no effect on Gialpha1, Gialpha2 or Gialpha3 levels in membranes from frontal and parietal cortex. However, this treatment caused a decrease in SRIF-like immunoreactivity content in the parietal (38.9%) and frontal (20.4%) cortex. These results suggest that Abeta might be involved in the alterations of somatostatinergic system reported in AD.
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Epilepsy may result from altered transmission of the principal inhibitory transmitter GABA in the brain. Using in situ hybridization in two animal models of epileptogenesis, we investigated changes in the expression of nine major GABA(A) receptor subunits (alpha1, alpha2, alpha4, alpha5, beta1-beta3, gamma2 and delta) and of the GABA(B) receptor species GABA(B)R1a, GABA(B)R1b and GABA(B)R2 in 1) hippocampal kindling and 2) epilepsy following electrically-induced status epilepticus (SE). Hippocampal kindling triggers a decrease in seizure threshold without producing spontaneous seizures and hippocampal damage, whereas the SE model is characterized by spontaneous seizures and hippocampal damage. ⋯ The observed changes suggest substantial and cell specific rearrangement of GABA receptors. Lasting downregulation of subunits delta and alpha5 in granule cells and transient decreases in subunit alpha2 and beta1-3 mRNA levels in cornu ammonis 3 pyramidal cells are suggestive of impaired GABA(A) receptor-mediated inhibition. Persistent upregulation of subunits beta1-3 and gamma2 of the GABA(A) receptor and of GABA(B)R2 mRNA in granule cells, however, may result in activation of compensatory anticonvulsant mechanisms.
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These experiments explore the role of 5-HT1A receptors in the regulation of cell proliferation in the dentate gyrus of the intact and adrenalectomized adult rat. Depleting 5-HT with p-chlorophenylalanine (300 mg/kg initially followed by 100 mg/kg/day) or stimulating 5-HT1A receptors with 8-OH-DPAT (1 mg/kg or 2 mg/kg, s.c. injections twice daily) for 14 days had no effect on cell proliferation as measured by Ki-67 or BrdU (5-bromo-3-deoxyuridine) immunocytochemistry in the dentate gyrus. However, combined treatment with p-chlorophenylalanine followed by 8-OH-DPAT significantly increased cell proliferation compared with p-chlorophenylalanine alone. ⋯ The 5-HT1A antagonist WAY-100635 (1.5 mg/kg/day also delivered by osmotic pump) by itself did not alter cell proliferation, confirming that reduced serotonin activity does not change proliferation, but blocked the effect of 8-OH-DPAT. However, WAY-100635 could not block the stimulating action of adrenalectomy cell proliferation. 5-HT1A mRNA expression was not altered in the hippocampus by adrenalectomy. Thus, the effect of adrenalectomy on cell proliferation and survival is not 5-HT1A dependent, despite the interaction between 5-HT1A and corticosterone.