sch-23390 and Alcoholism

Topics: Administration, Oral; Alcoholism; Animals; Benzazepines; Bepridil; Calcium, Dietary; Conditioning, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Humans; Locomotion; Male; Mice; Mice, Inbred DBA; Motor Activity; Time Factors; Treatment Outcome

Environmental contexts associated with drug use can trigger craving in humans and the renewal of drug-seeking behaviors in animals. Here, we tested the hypothesis that context-induced renewal of Pavlovian-conditioned alcohol-seeking is mediated by dopamine.. Male, Long-Evans rats were trained to discriminate between two, 10-second, auditory conditioned stimuli. One stimulus (CS+) was consistently paired with 15% ethanol (EtOH) (v/v, 0.2 ml per CS+) and the second stimulus (CS-) was not. Each CS occurred 16 times per session, and entries into a fluid port where EtOH was delivered were measured. Pavlovian discrimination training (PDT) occurred in a distinctive context, referred to as Context A. Subsequently, behavior was extinguished by presenting both cues without EtOH in a different context (Context B). At test, rats were injected with a dopamine D1-like receptor antagonist (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0, 3.33, 10 μg/kg; 1 ml/kg; s.c.) and presented with the CS+ and CS- without EtOH in the prior PDT context (Context A).. Across training, rats developed higher response levels to the alcohol-predictive CS+, compared with the CS-. Port entries during the CS+ decreased across extinction. At test, placement into the alcohol-associated context triggered a selective increase in CS+ responses after saline, which was significantly reduced by SCH 23390 pretreatment. In separate studies, SCH 23390 did not affect lever-pressing for sucrose under reinforced or extinction conditions, but decreased port entries relative to saline in both cases.. These data indicate that dopamine is required for context-induced renewal of Pavlovian-conditioned alcohol-seeking and may also be necessary for preparatory conditioned approach behaviors.

Topics: Alcohol Drinking; Alcoholism; Animals; Behavior, Animal; Benzazepines; Conditioning, Classical; Discrimination Learning; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Extinction, Psychological; Male; Rats; Rats, Long-Evans; Receptors, Dopamine D1; Recurrence; Self Administration; Sucrose

Ryanodine receptors (RyRs) amplifying activity-dependent calcium influx via calcium-induced calcium release play an important role in central nervous system functions including learning, memory, and drug abuse. In this study, we investigated the role and the regulatory mechanisms of RyR expression under continuous exposure of mice to ethanol (EtOH) vapor for 9 days.. The model of EtOH physical dependence was prepared as follows: 8-week-old male ddY mice were exposed to EtOH vapor for 9 days. Protein and mRNA of RyR-1, RyR-2, and RyR-3 in the frontal cortex and limbic forebrain were determined by Western blot and real-time RT-PCR analysis, respectively.. Exposure of mice to EtOH vapor for 9 days induced significant withdrawal signs when estimated with withdrawal score, which was dose-dependently suppressed by intracerebroventricular administration of dantrolene, an RyR antagonist. Protein levels of RyR-1 and RyR-2 in the frontal cortex and limbic forebrain significantly increased during EtOH vapor exposure for 9 days with increased expression of their mRNA, whereas that of RyR-3 in these 2 brain regions showed no changes. Increased proteins and mRNA of RyR-1 and RyR-2 were completely abolished by SCH23390, a selective antagonist of dopamine D1 receptors (D1DRs), but not by sulpiride, a selective antagonist of D2DRs.. RyRs play a critical role in the development of EtOH physical dependence and that the up-regulation of RyRs in the brain of mouse, showing EtOH physical dependence is regulated by D1DRs.

Topics: Alcoholism; Animals; Benzazepines; Blotting, Western; Brain; Central Nervous System Depressants; Dantrolene; Disease Models, Animal; Ethanol; Frontal Lobe; Male; Mice; Prosencephalon; Receptors, Dopamine D1; Reverse Transcriptase Polymerase Chain Reaction; Ryanodine Receptor Calcium Release Channel

The authors have previously shown that high alcohol preference rats (HAP) have a significantly higher sensitivity than low alcohol preference rats (LAP) for methamphetamine (MAP). In this study, changes in dopamine and serotonin release induced by MAP (1 mg/kg, intraperitoneally) after pre-treatment with D1 and D2 receptor antagonists were examined in the striatum of rats with different alcohol preferences to elucidate differences in receptor levels between the two rat strains. D1 receptor antagonist SCH23390 or D2 receptor antagonist haloperidol were administrated intracerebroventricularly 10 min before MAP stimulation. This study investigated the effect of methamphetamine-induced dopamine and serotonin release in striatum using microdialysis of freely moving rats coupled to ECD-HPLC. With haloperidol treatment both strains of rats showed a significantly greater maximum increase on MAP-induced dopamine release compared with respective control rats. However, after SCH23390 treatment only HAP rats showed a significantly greater increase in dopamine release compared with controls. SCH23390 blocks mainly D1 receptors only in the post-synaptic membrane, whereas haloperidol blocks D2 receptors in both the pre-synaptic and post-synaptic membranes. The MAP-induced increase in dopamine release following haloperidol pre-treatment was greater than SCH23390 pre-treatment in both strains. This result indicates that D2 receptors (autoreceptors) in the pre-synaptic membrane were blocked, leading to the elimination of the feedback function that regulates dopamine release. These data suggested that alcohol preference is associated with the action of MAP, and the dopaminergic mechanism, specifically the D1 system in the striatum, might have a different pathway dependent on alcohol preference.

Topics: Alcoholism; Animals; Animals, Inbred Strains; Benzazepines; Corpus Striatum; Dopamine; Dopamine Agents; Dopamine Antagonists; Ethanol; Haloperidol; Methamphetamine; Rats; Rats, Wistar; Receptors, Dopamine; Serotonin