Neuropharmacology
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Comparative Study
Chronic DHEAS administration facilitates hippocampal long-term potentiation via an amplification of Src-dependent NMDA receptor signaling.
Dehydroepiandrosterone sulfate (DHEAS) has well characterized effects on memory and cognitive performances. Recently we have reported that repetitive administration of DHEAS lowers the threshold pulse number in inducing activity-dependent long-term potentiation (LTP) in rat hippocampal Schaffer collateral-CA1 synapses, in which a sub-threshold high frequency stimulation (HFS, 30 pulses at 100 Hz) for normal rats could induce robust LTP in DHEAS-treated rats (Chen et al., 2006). Here we report that the sub-threshold HFS could trigger the phosphorylation of Src and ERK2 in the DHEAS-treated rats, but not in control rats. ⋯ These findings suggest that the chronic administration of DHEAS brings the NMDA receptor (NMDAr) to a potentiated state that causes an enough level of [Ca2+]i increase for LTP induction even by the sub-threshold HFS. The potentiated [Ca2+]i transient by the sub-threshold HFS may trigger the Src phosphorylation that will further potentiate NMDAr followed by an activation of ERK2 and LTP induction. This novel postsynaptic NMDAr/Src-mediated signal amplification through "NMDAr-Ca2+-->Src-->NMDAr-Ca2+" cycle may play a pivotal role in the DHEAS-facilitated LTP induction.
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Although most commonly associated with actions at cannabinoid CB1 receptors on the extracellular surface of the plasma membrane, the endocannabinoid anandamide (AEA) is also transported into the cell, by the putative anandamide membrane transporter (AMT), and activates the vanilloid receptor 1 (TRPV1) at an intracellular site. AEA is then inactivated by fatty acid amide hydrolase (FAAH). As systemic administration of TRPV1 ligands reduces locomotor activity in normal rodents, we hypothesised that activation of TRPV1 by endocannabinoids could play a role in the control of voluntary movement and that such actions could be regulated by AMT and FAAH. ⋯ Horizontal activity was attenuated by capsaicin (1 mg/kg, -60%), but not by URB597 (10 mg/kg) or OMDM-2 (5 mg/kg). Vertical activity was attenuated by capsaicin (1 mg/kg, -61%) and by URB597 (10 mg/kg, -54%), but not by OMDM-2. These data suggest that activation of the TRPV1 system can suppress spontaneous locomotion in normal animals and modulates several L-DOPA-induced behaviours in reserpine-treated rats.
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Comparative Study
Interactions between CB1 cannabinoid and mu opioid receptors mediating inhibition of neurotransmitter release in rat nucleus accumbens core.
We examined the occurrence of functional interactions between CB1 cannabinoid and mu opioid receptors in the core of rat nucleus accumbens (NAc core). To that end, receptor-mediated inhibition of depolarization (4-aminopyridine)-induced [3H]glutamate release and glutamate (NMDA) receptor-stimulated [14C]acetylcholine (ACh) and [3H]GABA release was studied in superfused NAc core slices. The inhibitory effects of the mu receptor agonist morphine and the CB1 receptor agonist HU210 on the release of these neurotransmitters were selectively antagonized by the mu receptor antagonist naloxone and the CB1 receptor antagonist SR141716A, respectively. ⋯ Finally, the apparent allosteric interaction between antagonists was also observed regarding the effects of other receptor-selective agonists and antagonists at mu opioid and CB1 cannabinoid receptors (mediating inhibition of NMDA-induced [3H]GABA release) and must therefore be a unique property of the receptors involved. These data suggest the existence of physically associated mu opioid and CB1 cannabinoid receptors, whereby activation of these receptors results in either a non-additive (glutamate release) or a synergistic (GABA release) effect. It is proposed that these allosterically interacting mu and CB1 receptors in the NAc core may represent G-protein coupled heterodimeric receptor complexes.
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Comparative Study
Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats.
Epileptogenesis, i.e. the process leading to epilepsy with spontaneous recurrent seizures, can be initiated by a number of brain damaging insults, including traumatic brain injury, status epilepticus (SE), and stroke. Such acquired epilepsy is often associated with memory impairment and behavioral problems. There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection and prevention or modification of epileptogenesis induced by such brain insults. ⋯ However, treatment with VPA after SE prevented the hyperexcitability and locomotor hyperactivity observed in vehicle-treated epileptic rats. Furthermore, VPA completely counteracted the neuronal damage in the hippocampal formation, including the dentate hilus. The data demonstrate that, although VPA does not prevent the occurrence of spontaneous seizures after SE, it exerts powerful neuroprotective effects and prevents part of the behavioral alterations, demonstrating that administration of VPA immediately after SE exerts a favorable effect on long-term functional outcome.