Neuroscience
-
In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. ⋯ These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex.
-
Methamphetamine (METH) abuse is personally and socially devastating. Although effects of METH on dopamine (DA) systems likely contribute to its highly addictive nature, no medications are approved to treat METH dependence. Thus, we and others have studied the METH-induced responses of neurotensin (NT) systems. ⋯ We also found that nucleus accumbens NT levels were elevated via a D1 mechanism after five sessions in rats self-administering METH (SAM), with a lesser effect in corresponding yoked rats. Extended (15 daily sessions) exposure to METH SA manifested similar NT responses; however, more detailed analyses revealed (i) 15 days of METH SA significantly elevated NT levels in the nucleus accumbens shell and dorsal striatum, but not the nucleus accumbens core, with a lesser effect in the corresponding yoked METH rats; (ii) the elevation of NT in both the nucleus accumbens shell and dorsal striatum significantly correlated with the total amount of METH received in the self-administering, but not the corresponding yoked METH rats; and (iii) an NT agonist blocked, but an NT antagonist did not alter, lever-pressing behavior on day 15 in SAM rats. After 5 days in SAM animals, NT levels were also elevated in the ventral tegmental area, but not frontal cortex of rats self-administering METH.
-
Agonists for the cannabinoid CB2 receptor are antinociceptive in several rodent models and several reports have suggested that the target for these drugs is CB2 expressed in the spinal cord pain pathway. After confirming the efficacy of a systemically delivered CB2-selective agonist, GW405833, we tested this hypothesis by administering the CB2 agonists GW405833 and JWH-133, via intrathecal cannulation, to the lumbar spinal cord of rats that had undergone chronic constriction injury to induce mechanical allodynia. We found that although the non-selective CB1/CB2 cannabinoid receptor agonist WIN55,212-2 reversed mechanical allodynia in both ipsilateral and contralateral hind paws, neither GW405833 nor JWH-133 reversed mechanical allodynia. ⋯ Although protein-based analysis of CB2 partially matched the results of earlier studies using the same antibody, we found evidence that this antibody may be insufficiently specific for the detection of CB2 in native tissue. Using [(35)S]GTPγS binding assays, we found no evidence of functional CB2 in the spinal cord, in sham or surgery-treated tissue. However, WIN55,212-2 stimulated [(35)S]GTPγS binding showed clear evidence of functional CB1 receptors consistent with the known distribution of elements of the pain pathway, and we concluded that spinal CB2 receptors are not a likely target for cannabinoid-mediated antinociception in this model.
-
Repeated injections of psychostimulants, such as D-amphetamine (D-AMPH), provide a well-validated model of progressive cellular and systems-level alterations in brain function and behavior associated with addiction. The present study employed quantitative measures of both power spectral density and synchrony from local field potentials (LFPs) recorded simultaneously from the prefrontal cortex (PFC), parietal cortex (PAR), and hippocampus (HPC) in awake, behaving rats to assess changes in oscillations during different stages of D-AMPH-induced sensitization. The induction and development of sensitization altered the power of multiple frequency bands in a brain region-specific manner, whereas no changes were observed in animals treated with chronic saline. ⋯ Sensitization was also related to increased theta coherence between the PFC and HPC, along with suppression of cross-frequency correlations between theta and fast-gamma (65-100 Hz) in both the HPC and the PFC. Collectively, the present findings indicated the induction of a state in which the timing and synchronizing effects of oscillations are altered by sensitization to D-AMPH and are especially pronounced in the PFC. Furthermore, numerous LFP-derived measures were characterized that may serve as objective physiological correlates of pathological states observed in addiction.
-
Substance P by acting on its preferred receptor neurokinin 1 (NK1) in the amygdala appears to be critically involved in the modulation of fear and anxiety. The present study was undertaken to identify neurochemically specific subpopulations of neuron expressing NK1 receptors in the lateral amygdaloid nucleus (LA), a key site for regulating these behaviors. We also analyzed the sources of glutamatergic inputs to these neurons. ⋯ The remaining ~25% were immunoreactive for the vesicular glutamate transporter 2 (VGluT2), and may then originate from subcortical areas. On the other hand, we could not detect VGluT2-containing inputs onto NK1/PV immunopositive neurons. Our data add to previous localization studies by describing an unexpected variation between LA and basal nucleus of the amygdala (BA) in the neurochemical phenotype of NK1-expressing neurons and reveal the relative source of glutamatergic inputs that may activate these neurons, which in turn regulate fear and anxiety responses.