ABSTRACT
Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hyperactivity disorder (ADHD), triggers alterations of reward-based behavior paralleled by persistent and plastic synaptic changes of neuronal and glial markers within key areas of the reward circuits. By immunohistochemistry, we observe a marked increase of glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expression and a down-regulation of glial glutamate transporter GLAST in dorso-lateral and ventro-medial striatum. Using electron microscopy, we find in the prefrontal cortex a significant reduction of the synaptic active zone length, paralleled by an increase of dendritic spines. We demonstrate that in limbic areas the MPH-induced reactive astrocytosis affects the glial glutamatergic uptake system that in turn could determine glutamate receptor sensitization. These processes could be sustained by NO production and synaptic rearrangement and contribute to MPH neuroglial induced rewiring.
Subject(s)
Brain/drug effects , Central Nervous System Stimulants/pharmacology , Methylphenidate/pharmacology , Nerve Net/drug effects , Neuroglia/drug effects , Neurons/drug effects , Animals , Brain/metabolism , Choice Behavior/drug effects , Conditioning, Operant/drug effects , Glial Fibrillary Acidic Protein/metabolism , Nerve Net/metabolism , Neuroglia/metabolism , Neurons/metabolism , Nitric Oxide Synthase Type I/metabolism , Rats , Rats, Wistar , RewardABSTRACT
Nerve growth factor (NGF), an essential peptide for sensory neurons, seems to have opposite effects when administered peripherally or directly to the central nervous system. We investigated the effects of 7-days intrathecal (i.t.) infusion of NGF on neuronal and glial spinal markers relevant to neuropathic behavior induced by chronic constriction injury (CCI) of the sciatic nerve. Allodynic and hyperalgesic behaviors were investigated by Von Frey and thermal Plantar tests, respectively. NGF-treated animals showed reduced allodynia and thermal hyperalgesia, compared to control animals. We evaluated on lumbar spinal cord the expression of microglial (ED-1), astrocytic (GFAP and S-100beta), and C- and Adelta-fibers (SubP, IB-4 and Cb) markers. I.t. NGF treatment reduced reactive astrocytosis and the density of SubP, IB4 and Cb positive fibers in the dorsal horn of injured animals. Morphometric parameters of proximal sciatic nerve stump fibers and cells in DRG were also analyzed in CCI rats: myelin thickness was reduced and DRG neurons and satellite cells appeared hypertrophic. I.t. NGF treatment showed a beneficial effect in reversing these molecular and morphological alterations. Finally, we analyzed by immunohistochemistry the expression pattern of neurotrophin receptors TrkA, pTrkA, TrkB and p75(NTR). Substantial alterations in neurotrophin receptors expression were observed in the spinal cord of CCI and NGF-treated animals. Our results indicate that i.t. NGF administration reverses the neuro-glial morphomolecular changes occurring in neuropathic animals paralleled by alterations in neurotrophin receptors ratio, and suggest that NGF is effective in restoring homeostatic conditions in the spinal cord and maintaining analgesia in neuropathic pain.
Subject(s)
Gliosis/pathology , Nerve Growth Factor/administration & dosage , Nerve Growth Factor/pharmacology , Pain/metabolism , Pain/pathology , Receptors, Nerve Growth Factor/metabolism , Animals , Behavior, Animal/drug effects , Biomarkers/metabolism , Cell Count , Constriction, Pathologic , Disease Models, Animal , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Gliosis/metabolism , Immunohistochemistry , Injections, Spinal , Male , Myelin Sheath/drug effects , Myelin Sheath/pathology , Neuroglia/drug effects , Neuroglia/metabolism , Neuroglia/pathology , Rats , Rats, Sprague-Dawley , Sciatic Nerve/drug effects , Sciatic Nerve/metabolism , Sciatic Nerve/pathology , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Cord/pathologyABSTRACT
Probes for the occurrence of endogenous D-aspartic acid (D-Asp) and N-methyl-D-aspartic acid (NMDA) in the neural complex and gonads of a protochordate, the ascidian Ciona intestinalis, have confirmed the presence of these two excitatory amino acids and their involvement in hormonal activity. A hormonal pathway similar to that which occurs in vertebrates has been discovered. In the cerebral ganglion D-Asp is synthesized from L-Asp by an aspartate racemase. Then, D-Asp is transferred through the blood stream into the neural gland where it gives rise to NMDA by means of an NMDA synthase. NMDA, in turn, passes from the neuronal gland into the gonads where it induces the synthesis and release of a gonadotropin-releasing hormone (GnRH). The GnRH in turn modulates the release and synthesis of testosterone and progesterone in the gonads, which are implicated in reproduction.
