1,721,079 research outputs found
Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol
No full textProlonged exposure of the brain to ethanol is a prerequisite for developing ethanol dependence, but the underlying neural adaptations are unknown. Here we demonstrate that rats subjected to repeated cycles of intoxication and withdrawal develop a marked and long-lasting increase in voluntary ethanol intake. Exposure-induced but not spontaneous alcohol intake is antagonized by acamprosate, a compound clinically effective in human alcoholism. Expression analysis of cingulate cortex and amygdala reveals a set of long-term up-regulated transcripts in this model. These include members of pathways previously implicated in alcohol dependence (glutamatergic, endocannabinoid, and monoaminergic neurotransmission), as well as pathways not previously thought to be involved in this disorder (e.g., members of the mitogen-activated protein kinase pathway). Thus, alternating periods of ethanol intoxication and withdrawal are sufficient to induce an altered functional brain state, which is likely to be encoded by long-term changes in gene expression. These observations may have important implications for how alcoholism is managed clinically. Novel clinically effective treatments may be possible to develop by targeting the products of genes found to be regulated in our model. - Rimondini, R., Arlinde, C., Sommer, W., Heilig, M. Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol
Multiple intramembrane receptor-receptor interactions in the regulation of striatal dopamine D2 receptors
No full textAdenosine A(2A), group I mGlu and neurotensin receptors have been previously found to modulate the binding characteristics of dopamine D2 receptors in membrane preparations from rat striatum. In the present study it is shown that stimulation of different combinations of striatal A(2A), group I mGlu and neurotensin receptors induce different effects on the modulation of D2 receptor binding to those obtained when they are separately stimulated using maximal effective concentrations. In competitive inhibition experiments of dopamine versus the D2 receptor antagonist [3H]raclopride the addition of the A(2A) receptor agonist CGS 21680, the group I mGlu receptor agonist DHPG or neurotensin induced a decrease in the affinity of the high affinity state of the dopamine D2 receptors for dopamine. When added together CGS 21680 plus neurotensin induced the same effect as when administered alone, CGS 21680 plus DHPG induced a synergistic effect and DHPG plus neurotensin lost their modulating effect on D2 receptor binding. These results demonstrate the existence of multiple intramembrane receptor-receptor interactions in the regulation of striatal D2 receptors
Effects of competitive and non-competitive NMDA receptor antagonists on behavioral responses induced by 7-OH-DPAT and quinpirole in rats
No full textThe administration of dizocilpine (0.06 mg kg-1), but not of CGP 43487 (0.75 mg kg-1), counteracted the hypolocomotion induced in the rat by low doses (5-80 μg kg-1) of the putative D3 dopamine agonist 7-OH-DPAT. Both NMDA antagonists did not change the reduced locomotion due to the administration of low doses (12.5-50 μg kg-1) of the D2 agonist quinpirole. In spite of the lack of effect of either NMDA receptor antagonist on D2 or D3 recognition sites, as shown by our radioligand binding studies, the behavioural findings suggest that the non-competitive, but not the competitive, NMDA receptor antagonist physiologically antagonizes dopamine D3 receptor mediated mechanisms. Both NMDA receptor antagonists failed to modify the hyperlocomotion induced by high doses (160 and 320 μg kg-1) of 7-OH-DPAT, whereas they inhibited the same behavioural response produced by high doses of quinpirole (150 and 300 μg kg-1). The different effect of the NMDA receptor antagonists on the behavioural responses induced by the dopaminergic agonists could be explained by the different activity of 7-OH-DPAT and quinpirole on D3/D2 receptors. Either dizocilpine or CGP 43487 induced stereotyped responses to high doses of 7-OH-DPAT. This suggests that both NMDA receptor antagonists could potentiate dopaminergic function in the striatum, a region critically involved in the generation of stereotyped behaviour
Effects of tiagabine and diazepam on operant ethanol self-administration in the rat
No full textObjective: Benzodiazepines (BDZ) are widely used in the treatment of anxiety and ethanol withdrawal. It has been suggested that this class of compounds may increase the reinforcing value of ethanol; however, the literature is scarce. Tiagabine has recently been introduced into clinical use as an anti-epileptic drug. It acts through inhibiting γ-aminobutyric acid (GABA) reuptake, and thus represents a pharmacodynamically novel principle for potentiating GABAergic transmission. The objective of the present study was to examine whether these two manners of modulating GABAergic transmission would affect ethanol self-administration in rats. Method: Rats were trained on an operant oral ethanol self-administration task in a two-lever free-choice paradigm. When trained, subjects were treated with tiagabine (2, 6 and 18 mg/kg, intraperitoneally [i.p.]) or diazepam (0.5, 1.5 and 4.5 mg/kg, i.p.). Postsession blood alcohol concentrations and locomotor activity measures also were obtained. Results: At nonsedating doses, neither tiagabine nor diazepam affected operant ethanol self-administration. At the highest doses (18 and 4.5 mg/kg, respectively), both drugs suppressed ethanol self-administration but also induced significant suppression of locomotion, indicative of sedation. Conclusions: Systemic administration of either the GABA-uptake blocker, tiagabine, or the GABA/BDZ agonist, diazepam, at nonsedating doses does not seem to affect oral ethanol self-administration
The competitive NMDA antagonists CGP 43487 and APV potentiate dopaminergic function
No full textThe administration to rats of different doses of the non competitive NMDA receptor blocker MK-801 (0.03-1 mg/kg IP) induced stimulation or reduction of locomotor activity, depending on the dose, whereas the competitive NMDA antagonists CGP 43487 (0.188-6 mg/kg IP) and APV (2.5-20 μg/rat ICV) inhibited locomotion at the highest doses. Unlike MK-801 and APV treatment, the administration of CGP 43487 did not induce impairment of rota-rod test performance. Both competitive and non-competitive NMDA antagonists, at doses devoid of any behavioral effect per se, potentiated the responses elicited by apomorphine (0.25 mg/kg SC). In particular, the occurrence of episodes of licking was weakly affected by MK-801 administration, but significantly increased by CGP 43487 and APV treatment; the presence of gnawing was augmented by all the pretreatments; sniffing, locomotion, grooming and rearing occurrence were not affected by the administration of NMDA antagonists. The results suggest that the competitive antagonists which facilitated dopaminergic function without causing motor impairment could be useful supplements in the treatment of Parkinson's disease. © 1995 Springer-Verlag
Altered gene expression of Na+/Ca2+ exchanger isoforms NCX1, NCX2 and NCX3 in chronic ischemic rat brain
No full textTo investigate the effect of chronic global cerebral ischemia on gene expression of Na+/Ca2+ exchanger isoforms NCX1, NCX2 and NCX3 in rat brain. Chronic global cerebral ischemia was induced by bilateral common carotid artery ligation (BCAL) in rats for 1 week, 2 weeks and 4 weeks, respectively. Morris water maze was applied to demonstrate the credibility of BCAL models. After BCAL for 4 weeks, there was learning and memory deficiency that the latency and distance of BCAL group were longer than those of sham group from the second trial to tenth trial in hidden platform trials. Reverse transcription-polymerase chain reaction was used to assess the gene expression of Na+/Ca2+ exchanger isoforms at mRNA level in cerebral cortex and hippocampus. For NCX1, its expression was decreased by 35%, 54% and 27% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively; For NCX2, its expression was decreased by 41%, 29% and 12% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively; For NCX3, its expression was decreased by 29%, 27% and 12% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively. However, in hippocampus, the expressions of NCX1 and NCX3 did not change significantly in different BCAL groups. NCX2 was increased by 60% in BCAL for 1 week only, but did not change significantly in BCAL for 2 weeks or 4 weeks. The study indicated that brain ischemia regulated gene expression levels of Na+/Ca2+ exchanger isoforms especially in cerebral cortex. © 2002 Elsevier Science Ireland Ltd. All rights reserved
D-Cycloserine decreases both D1 and D2 dopamine receptors number and their function in rat brain
No full textTwenty-four hours after the implantation of the transstriatal probe D-cycloserine (3 mg/kg IP), a partial agonist of the strychnine-insensitive NMDA-associated glycine recognition site failed to change DA and DOPAC extracellular output in rat striatal dialysates. In extensively washed synaptic plasma membranes prepared both from cortices or striata of rats treated with D-cycloserine [3H]-MK 801 specific binding was increased. In contrast, in striatal membranes the Bmax values of both [3H]-SCH 23390 and [3H]-spiroperidol bindings to D1 and D2 dopamine receptors were decreased. Parallel decreases both of grooming behavior induced by the D1 agonist SKF 38393 (10 mg/kg IP) and of the hyperactivity elicited by the D2 agonist LY 171555 (0.3 mg/kg IP) in rat were observed. © 1994
The NMDA positive modulator d-cycloserine inhibits dopamine-mediated behaviors in the rat
No full textThe NMDA positive modulator d-cycloserine (DCS), which failed to modify rat spontaneous behavior, inhibited the hypermotility induced by the dopamine releaser methamphetamine as well as the behavioral responses to the selective stimulation of D1 or D2 dopamine receptors (SKF 38393 induced grooming and LY 171555 elicited hyperactivity, respectively). In contrast, behavioral responses to different doses of apomorphine (hypermotility and stereotypies) were not modified by the administration of DCS. No change in apomorphine-induced stereotyped behavior was observed during DCS repeated treatment (21 days), but an antagonism of dopaminergic stimulation occurred when DCS was repeatedly administered together with low doses of D1 and D2 dopamine receptor blockers [SCH 23390 and (-)-sulpiride]. Five days following the combined repeated treatment, behavioral dopaminergic supersensitivity was observed. The results are consistent with the view that an increase in glutamatergic function could decrease the response to dopaminergic stimulation. © 1994
Effect of NMDA receptor antagonists on D1, D2 and D1/D2 mediated behaviors in intact rats
No full textThe effect of treatment with the competitive (CGP 43487) and non-competitive (MK-801) NMDA antagonists on behaviors induced by the stimulation of D1 (SKF 38393 induced grooming), D2 (LY 171555 elicited hypermotility) or D1/D2 (apomorphine induced locomotion and stereotypies) was observed in intact rats. The administration of low doses of MK-801 (0.03 and 0.06 mg/kg) or CGP 43487 (0.375 and 0.75 mg/kg), which were without effect by themselves on animal locomotion, reduced the hyperactivity induced by LY 171555 (0.15 mg/ kg) and did not change the stimulating motor effect of a low dose of apomorphine (0.15 mg/kg). Spontaneous grooming behavior was inhibited by both NMDA antagonists, whereas the administration of CGP 43487 but not of MK-801 potentiated grooming response to SKF 38393 (10 mg/kg). Both antagonists increased stereotyped behavior induced by 0.25 mg/kg apomorphine. The results, according to those obtained by other authors in DA depleted/lesioned animals, support the view of interaction between NMDA/D1,D2 receptors in intact rats
Mechanical nociception in mice and rats: Measurement with automated von frey equipment
No full textvon Frey hairs are important tools for the study of mechanisms of cutaneous stimulation-induced sensory input. Mechanical force is exerted via application of a particular hair to the cutaneous receptive field until buckling of the hair occurs. The most commonly used von Frey filaments are productive in evaluating behavioral responses of neuropathic pain in preclinical and clinical research. To reduce the potential experimenter bias, automated instruments are being developed for behavioral assessment
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