Neuroscience
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Previous human postmortem brain tissue research has implicated abnormalities of 5-HT receptor availability in depression and suicide. Although altered abundance of 5-HT 1A, 5-HT 2A, and 5-HT 2C receptors (5-HT(1A), 5-HT(2A), and 5-HT(2C)) has been reported, the causes remain obscure. This study evaluated the availability of these three receptor subtypes in postmortem brain tissue specimens from persons with a history of major depression (MDD) and normal controls and tested the relationships to protein kinases A and C (PKA, PKC). ⋯ Basal and cyclic AMP-stimulated PKA activity was also reduced in the depressed sample; PKC activity was not different between groups. 5-HT(2A) receptor availability was significantly inversely correlated with PKC activity in controls, but with PKA activity in the depressed sample. Increased 5-HT(2A) receptor abundance and decreased PKA activity in the depressed sample are consistent with prior reports. The correlation of 5-HT(2A) receptor levels with PKA activity in the depressed group suggests that abnormalities of 5-HT(2A) receptor abundance may depend on receptor uncoupling and heterologous regulation by PKA.
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Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glutamate release, glutamate elimination by glutamate transporters and diffusion, and negative feedback on synaptic release via metabotropic glutamate receptors (mGluR2/3). ⋯ By using experimental values for cocaine-induced reductions in cystine-glutamate exchange and mGluR2/3 signaling, and by predicting the down-regulation of glutamate transporters, the computational model successfully represented the experimentally observed increase in glutamate that is seen in rats during cocaine-seeking. This model provides a mathematical framework for describing how pharmacological or pathological conditions influence glutamate transmission measured by microdialysis.
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Infants who are passively exposed to morphine or heroin through their addicted mothers usually develop neurobiological changes. The postsynaptic density 95 (PSD-95) protein, a submembranous cytoskeletal specialization, is dynamically linked with N-methyl-d-aspartate receptors (NMDARs) to form a synaptic complex in postsynaptic neurons. This complex serves important neurobiological functions, including mammalian learning and memory. ⋯ Furthermore, the protein interaction of the synaptic complex between the PSD-95 and NMDAR subunit, as indicated by coimmunoprecipitation, was less in prenatal morphine samples than in vehicle controls (P14 and P45). The prenatal morphine group also showed poorer performance for an eight-arm radial maze task than the vehicle-control group. These results are particularly important for a better understanding of certain opioid-mediated neurobehavioral cognitive changes in offspring associated with altered protein interaction between PSD-95 and NMDAR subunits within the developing brain.
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Although previous studies have shown pointing errors and abnormal multijoint coordination in seated subjects with Parkinson's disease (PD) who cannot view their arm, the extent to which subjects with PD have problems using proprioception to coordinate equilibrium maintenance and goal-oriented task execution has not been adequately investigated. If a common motor program controls voluntary arm pointing movements and the accompanying postural adjustments, then impairments of proprioceptive integration in subjects with PD should have similar effects on pointing and body center of mass (CoM) control with eyes closed. Ten standing subjects with PD (OFF-medication) and 10 age-matched control (CTR) subjects pointed to a target with their eyes closed and open. ⋯ This poor coupling with eyes closed could be related to the PD subjects' increased jerkiness of CoM displacements. The different effects of eye closure between CTR and PD subjects on the CoM displacements, but not pointing accuracy, are consistent with separate motor programs for the pointing and postural components of this task. Furthermore, the decoupling between the two movement components in subjects with PD when they could not use vision, suggests that the basal ganglia are involved in the integration of proprioceptive information for posture-movement coordination.
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We investigated the systemic and site-specific actions of a selective CB(2) receptor agonist, A-836339 on mechanically evoked (10 g von Frey hair) and spontaneous firing of spinal wide dynamic range (WDR) neurons in neuropathic (L5 and L6 ligations) and sham rats. Systemic administration of A-836339 (0.3-3 micromol/kg, i.v.) reduced both evoked and spontaneous WDR neuronal activity in neuropathic, but not sham rats. The effects in neuropathic rats were blocked by pre-administration of a CB(2), but not a CB(1), receptor antagonist. ⋯ Pre-administration of a CB(1) receptor antagonist did not alter the site-specific effects of A-836339. Injection of A-836339 (300 nmol) into the neuronal receptive field on the ipsilateral hind paw did not affect evoked or spontaneous firing of WDR neurons. Thus, the current data demonstrate that modulation of spinal neuronal activity by a CB(2) receptor agonist is enhanced following peripheral nerve injury, and further delineate the contribution of spinal and peripheral CB(2) receptors to this modulation.