Neuroscience
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To investigate the role of neurotransmitter secretion in the development and stabilization of synapses, the innervation of the diaphragm and intercostal muscles was studied in munc18-1 null mutant mice, which lack regulated secretion. We found that this mutant is completely devoid of both spontaneous and evoked neuromuscular transmission throughout embryonic development. At embryonic day (E) 14, axonal targeting and main branching of the phrenic nerve were normal in this mutant, but tertiary branches were elongated and no terminal branches were observed at this stage, in contrast to control littermates. ⋯ In contrast, sensory ganglia in the dorsal root showed no obvious degeneration. These data suggest that regulated secretion is not essential for initial axon path finding, clustering of acetylcholine receptors, acetylcholinesterase or the formation of synapses. However, in the absence of regulated secretion, the maintenance of the motor neuronal system, organization of nerve terminal branches and stabilization of synapses is impaired and a-neural postsynaptic elements persist.
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The effect of the i.c.v. administration of antisense oligodeoxynucleotides directed against the alpha subunit of different Gi-proteins (anti-Gialpha(1), anti-Gialpha(2), anti-Gialpha(3), anti-Goalpha(1), anti-Goalpha(2)) on the amnesia induced by the H(1)-antihistamine diphenhydramine (20 mg kg(-1) s.c.) was evaluated in the mouse passive avoidance test. Pretreatment with anti-Gialpha(1) (12.5-25 microg per mouse i.c.v.) and anti-Gialpha(2) (25 microg per mouse i.c.v.), administered 24 and 18 h before test, prevented antihistamine-induced amnesia. ⋯ At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest the important role played by the Gi(1)- and Gi(2)-protein pathway in the transduction mechanism involved in the impairment of memory processes produced by the H(1)-antihistamine diphenhydramine.
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This study examined the role of spinal GABAergic, serotoninergic and alpha(2) adrenergic receptors in the antinociception produced by the microinjection of equi-antinociceptive doses of selective opioid receptor agonists in the nucleus raphe magnus (NRM) or the nucleus reticularis gigantocellularis pars alpha (NGCpalpha) of the rat. Rats were pretreated with intrathecal administration of either the GABA(A) receptor antagonist bicuculline, the GABA(B) receptor antagonist CGP35348, the serotonin(1/2) receptor antagonist methysergide, the alpha(2) adrenergic receptor antagonist yohimbine or saline. Ten minutes later, either the delta(1) opioid receptor agonist [D-Pen(2,5)]enkephalin (DPDPE), delta(2) opioid receptor agonist [D-Ala(2),Glu(4)]deltorphin (DELT) or mu opioid receptor agonist [D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO) was microinjected into the NRM, NGCpalpha or sites in the medulla outside these two regions. ⋯ Intrathecal pretreatment with methysergide or bicuculline did not antagonize the antinociception produced by microinjection of DELT into either the NRM or the NGCpalpha. The increase in tail-flick latency produced by microinjection of DAMGO in the NRM was antagonized by intrathecal pretreatment with methysergide or CGP35348, but not by bicuculline or yohimbine. Taken together, these results support the hypothesis that the antinociception produced by activation of delta(1), delta(2) or mu opioid receptors in the rostral ventromedial medulla is mediated by different neural substrates.
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Previously, we demonstrated that stress-induced self-grooming behaviour in rats predicted an enhanced motivation to self-administer cocaine as determined under a progressive ratio schedule of reinforcement. The enhanced motivation of high grooming (HG) rats was associated with a reduced reactivity of dopaminergic neurons in the medial prefrontal cortex and amygdala, but not nucleus accumbens. In the present study, we studied the effect of cocaine and saline self-administration on these pre-existing differences in neurochemical profile by determining the electrically evoked release of [3H]dopamine and [14C]acetylcholine from superfused slices of the nucleus accumbens shell and core, medial prefrontal cortex and amygdala of HG and low grooming (LG) rats. ⋯ Differences in depolarisation-induced dopamine and acetylcholine release were maintained in the medial prefrontal cortex, emerged in the nucleus accumbens and dissipated in the amygdala. These results indicate that altered reactivity of mesocorticolimbic dopaminergic and cholinergic neurons due to exposure to cocaine and environmental stimuli (saline) is dependent on pre-existing neurochemical differences and displays region-specificity. These pre-existing differences and the cocaine- and environmental-induced neuroadaptations seem to act in concert to produce an enhanced motivational state to self-administer cocaine.
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We monitored survival of Purkinje cells in rat cerebellar slices to test the hypothesis that isoflurane preconditioning reduces ischemia-induced neuronal death. Preconditioning the brain slices with isoflurane, a volatile anesthetic commonly used in clinical practice, at 1-4% for 15 min at 37 degrees C significantly decreased Purkinje cell injury and death caused by a 20-min ischemia (simulated by oxygen-glucose deprivation, OGD). The effective concentration for half of the maximal effect (EC(50)) for this isoflurane preconditioning-induced neuroprotection was 1.17+/-0.31% and the maximal protective effects were achieved at 3% or higher concentrations of isoflurane. ⋯ Our results suggest that isoflurane preconditioning is neuroprotective. The isoflurane concentrations and times needed for the preconditioning to be neuroprotective are clinically relevant. The mechanisms of this protection seem to involve modulation of glutamate transporter activity.