Journal of neurochemistry
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Journal of neurochemistry · Jan 2010
Modifications in DARPP-32 phosphorylation pattern after repeated palatable food consumption undergo rapid habituation in the nucleus accumbens shell of non-food-deprived rats.
In non-food-deprived rats a palatable meal induces a transient increase in dopamine output in the prefrontal cortex and nucleus accumbens shell and core; habituation to this response develops with a second palatable meal, selectively in the shell, unless animals are food-deprived. A palatable meal also induces time-dependent modifications in the dopamine and cAMP-regulated phosphoprotein of Mr 32 000 (DARPP-32) phosphorylation pattern that are prevented when SCH 23390, a selective dopamine D(1) receptor antagonist, is administered shortly after the meal. This study investigated whether dopaminergic habituation in the shell had a counterpart in DARPP-32 phosphorylation changes. ⋯ In food-deprived rats two consecutive meals also induced similar phosphorylation changes in the shell. Finally, SCH 23390 administered shortly after the first palatable meal in non-food-deprived rats inhibited DARPP-32 phosphorylation changes in response to the first meal, and prevented the habituation to a second meal in terms of dopaminergic response and DARPP-32 phosphorylation changes. Thus, dopamine D(1) receptor stimulation plays a role in the development of habituation.
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Journal of neurochemistry · Jan 2010
Inhibition of NAALADase by 2-PMPA attenuates cocaine-induced relapse in rats: a NAAG-mGluR2/3-mediated mechanism.
Pharmacological activation of group II metabotropic glutamate receptors (mGluR2/3) inhibits cocaine self-administration and reinstatement of drug-seeking behavior, suggesting a possible use of mGluR2/3 agonists in the treatment of cocaine dependence. In this study, we investigated whether elevation of the endogenous mGluR2/3 ligand N-acetyl-aspartatylglutamate (NAAG) levels by the N-acetylated-alpha-linked-acidic dipeptidase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) attenuates cocaine self-administration and cocaine-induced reinstatement of drug seeking. N-acetylated-alpha-linked-acidic dipeptidase is a NAAG degradation enzyme that hydrolyzes NAAG to N-acetylaspartate and glutamate. ⋯ Finally, pre-treatment with 2-PMPA partially attenuated cocaine-enhanced extracellular NAc DA, while completely blocking cocaine-enhanced extracellular NAc glutamate in rats during reinstatement testing. Intra-NAc perfusion of LY341495 blocked 2-PMPA-induced reductions in cocaine-enhanced extracellular NAc glutamate, but not DA. These findings suggest that 2-PMPA is effective in attenuating cocaine-induced reinstatement of drug-seeking behavior, likely by attenuating cocaine-induced increases in NAc DA and glutamate via pre-synaptic mGluR2/3s.
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Journal of neurochemistry · Jan 2010
Comparative StudyRegulation of increased glutamatergic input to spinal dorsal horn neurons by mGluR5 in diabetic neuropathic pain.
Diabetic neuropathic pain is associated with increased glutamatergic input in the spinal dorsal horn. Group I metabotropic glutamate receptors (mGluRs) are involved in the control of neuronal excitability, but their role in the regulation of synaptic transmission in diabetic neuropathy remains poorly understood. Here we studied the role of spinal mGluR5 and mGluR1 in controlling glutamatergic input in a rat model of painful diabetic neuropathy induced by streptozotocin. ⋯ The mGluR5 protein level in the dorsal root ganglion, but not in the dorsal spinal cord, was significantly increased in diabetic rats compared with that in control rats. Furthermore, intrathecal administration of MPEP significantly increased the nociceptive pressure threshold only in diabetic rats. These findings suggest that increased mGluR5 expression on primary afferent neurons contributes to increased glutamatergic input to spinal dorsal horn neurons and nociceptive transmission in diabetic neuropathic pain.
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Journal of neurochemistry · Jan 2010
Comparative StudyN-acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy.
Several studies have indicated the involvement of oxidative stress in the development of diabetic neuropathy. In the present study, we have targeted oxidative stress mediated nerve damage in diabetic neuropathy using N-acetyl-l-cysteine (NAC), a potent antioxidant. After 8 weeks, streptozotocin-induced diabetic rats developed neuropathy which was evident from decreased tail-flick latency (thermal hyperalgesia). ⋯ Electron microscopy revealed demyelination, Wallerian degeneration and onion-bulb formation in sciatic nerve of diabetic rats. NAC on the other hand was able to reverse structural deficits observed in sciatic nerve of diabetic rats. Our results clearly demonstrate protective effect of NAC is mediated through attenuation of oxidative stress and apoptosis, and suggest therapeutic potential of NAC in attenuation of diabetic neuropathy.
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Journal of neurochemistry · Jan 2010
Comparative StudyACh receptors link two signaling pathways to neuroprotection against glutamate-induced excitotoxicity in isolated RGCs.
Previous studies have reported that activation of nicotinic acetylcholine (ACh) receptors (nAChRs) on cultured pig retinal ganglion cells (RGCs) has a neuroprotective effect against glutamate-induced excitotoxicity. However, the mechanism linking nAChRs to neuroprotection is unknown. Here, we tested the hypothesis that signaling cascades involving p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) --> Akt are involved in linking activation of nAChRs to neuroprotection in isolated pig RGCs. ⋯ The p38 MAPK inhibitor significantly decreased the number of RGCs that died by glutamate-induced excitotoxicity but had no effect on the number of cells that survived because of ACh-induced neuroprotection. PI3K inhibitors significantly decreased cell survival caused by ACh-induced neuroprotection but had no effect on cell death caused by glutamate-induced excitotoxicity. These results demonstrate that glutamate mediates excitotoxicity through the p38 MAPK signaling pathway and that ACh provides neuroprotection by stimulating the PI3K --> Akt --> Bcl-2 signaling pathway and inhibiting the p38 MAPK --> Bcl-2 pathway.