Neuroscience
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We investigated interactions of an anesthetic barbiturate, pentobarbital, with non-ligand gated channels and identified inhibitory synaptic transmission in thalamic neurons. Using whole cell voltage-clamp, current-clamp and single channel recording techniques in rat ventrobasal neurons of slices and dispersed preparations, we determined the mechanisms of pentobarbital actions on ionic currents and inhibitory postsynaptic currents (IPSCs), mediated by aminobutyric acid (GABA). We investigated pentobarbital effects on intrinsic currents using hyperpolarizing voltage commands from rest and tetrodotoxin blockade of action potentials. ⋯ The concentration-response relationships for pentobarbital effects on the intrinsic currents and IPSCs overlapped, implying multiple sites of action and possible redundancy in anesthetic mechanisms. This is the first study to show that an i.v. anesthetic modulates the intrinsic currents, Ih, IKir, and Ileak, as well as IPSC time course in the same neurons. These effects likely underlie inhibition in thalamocortical neurons during pentobarbital anesthesia.
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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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In previous studies electrically-evoked release of acetylcholine in septal slices was demonstrated. The present experiment aimed at verifying if this release involved intrinsic neurons bearing p75(NTR) receptors. Long-Evans rats sustained injections of 192 IgG-saporin into the medial septum/diagonal band of Broca (0.8 microg). ⋯ Our data exclude that a major part of the acetylcholine released by MS and DBB slices derived from intrinsic neurons bearing p75(NTR) receptors. In the LS, part of the released acetylcholine might be from projections of such neurons located in the LS, MS and/or DBB. These data also suggest that the MS and the DBB may be the target of extrinsic cholinergic innervation that does not bear p75(NTR) receptors.
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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.