Neuroscience
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Recent studies have demonstrated nicotinamide (NAM), a soluble B-group vitamin, to be an effective treatment in experimental models of traumatic brain injury (TBI). However, research on this compound has been limited to administration regimens starting shortly after injury. This study was conducted to establish the window of opportunity for NAM administration following controlled cortical impact (CCI) injury to the frontal cortex. ⋯ In the working memory task both the 15-min and 4-h groups also improved working memory compared with saline treatment. The window of opportunity for NAM treatment is task-dependent and extends to 8 h for the sensorimotor tests but only extends to 4 h post-injury in the cognitive tests. These results suggest that a 50 mg/kg treatment regimen starting at the clinically relevant time point of 4 h may result in attenuated injury severity in the human TBI population.
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It is unclear which nicotinic acetylcholine receptor (nAChR) subtypes are involved in the nicotinic activation of cells in the subfornical organ (SFO). We investigated the nAChR subtype using molecular biological, electrophysiological, pharmacological and immunohistochemical techniques. The use of reverse transcription-polymerase chain reaction in rats demonstrated the presence of mRNAs for the alpha2, alpha3, alpha4, alpha6, alpha7, beta2 and beta4 subunits in the SFO. ⋯ Methyllycaconitine at 10 nM (a selective alpha7-nAChR antagonist) reduced the nicotine-induced current significantly, but to a lesser extent. Fluorescence-labeled alpha-bungarotoxin (a homomeric alpha7 subtype selective binding drug) binding and immunofluorescence for the alpha7 subunit showed that positive images almost overlapped with those immunopositive for an astrocyte marker. These results suggest that the alpha4beta2 subtype is the main functional receptor in SFO neurons while alpha2, alpha3, alpha6, and beta4 subunits have some effect, and homomeric the alpha7 subtype exists in SFO astrocytes.
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Mechanisms underlying cold hypersensitivity in neuropathic states are unclear. Recent data indicate both transient receptor potential (TRP) M8 and TRPA1 play a role. In relation to TRPA1, there are reported increases in mRNA. ⋯ In contrast, compared with naive rats, mechanical thresholds of the Adelta-fibers in SNL rats are significantly decreased, the proportion of cold-sensitive and MO-sensitive Adelta-fibers is significantly increased and the response magnitude of Adelta-fibers to MO is significantly increased. MO-induced activity in Adelta-fibers is significantly reduced by Ruthenium Red (TRPA1 receptor antagonist). These results demonstrate that TRPA1 is expressed on peripheral nociceptors, and they are up-regulated on intact Adelta-fibers following nerve injury, contributing to cold hypersensitivity.
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Sensorimotor gating as measured by prepulse inhibition (PPI) to startle-evoking auditory stimulation (AS) is disrupted in schizophrenia and in rodents receiving systemic administration of apomorphine, a dopamine D1/D2 receptor agonist, or MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. The functional analogies and our prior results showing apomorphine- and AS-induced relocation of the dopamine D1 receptor (D1R) in the nucleus accumbens (Acb) shell suggest that apomorphine and AS may affect the subcellular distribution of the NMDA receptor NR1 subunit, a protein that forms protein-protein interactions with the D1R. We quantitatively compared the electron microscopic immunogold labeling for NR1 in dendritic profiles distinguished with respect to presence of D1R immunoreactivity and location in the Acb shell or core of rats receiving a single s.c. injection of vehicle (VEH) or apomorphine (APO) alone, or combined with AS (VEH+AS, APO+AS). ⋯ D1R-containing small dendrites in the Acb shell of the APO+AS group also showed a significantly higher density of plasmalemmal and a lower density of cytoplasmic NR1 immunogold particles compared with VEH or APO groups. In the Acb core, the APO+AS group had significantly fewer dendritic spines co-expressing NR1 and D1R compared with VEH or VEH+AS groups. These results, together with our earlier findings, suggest that NMDA receptors are preferentially mobilized in D1R-containing Acb neurons of rats showing apomorphine-induced disruption of PPI in a paradigm using acoustic stimulation.
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Reinstatement of previously extinguished instrumental responding for drug-related cues has been used as an animal model for relapse of drug abuse, and is differentially affected by inactivation of the core and shell subregions of the nucleus accumbens (NAc). To compare the roles of these subregions in reinstatement induced by cues associated with natural and drug rewards, the present study assessed the effects of inactivation of the NAc core and shell on cue-induced reinstatement of food-seeking behavior. Rats acquired a lever pressing response for food reward paired with a light/tone conditioned stimulus (CS). ⋯ The core enables reward-related stimuli to bias the direction and vigor of instrumental responding. In contrast, the shell facilitates alterations in behavior in response to changes in the incentive value of conditioned stimuli. The fact that the NAc core appears to play a similar role in cue-induced reinstatement induced by both natural and drug rewards suggests that this region of the ventral striatum may be a final common pathway through which both drug- and food-associated stimuli may influence the direction and magnitude of ongoing behavior.