The present study examined the effects of the acute intraperitoneal (i.p.) administration of the selective dopamine (DA) D(3) receptor antagonist SB-277011A (10, 20 or 30 mg/kg i.p.) on the oral ...operant self-administration of alcohol in male C57BL/6N mice. These effects were compared with those of naltrexone (0.5, 1 and 2 mg/kg i.p.) and acamprosate (100, 200 and 400 mg/kg i.p.). Compared with vehicle, the acute administration of SB-277011A (10 or 20 mg/kg) did not significantly alter the operant self-administration of alcohol, whereas the 30 mg/kg dose significantly reduced alcohol intake (g/kg), the number of reinforcers, and the number of active lever presses. The oral self-administration of alcohol was not significantly altered by the acute administration of either naltrexone or acamprosate, compared with vehicle-treated mice. SB-277011A, naltrexone and acamprosate were also tested in a model of drug/cue-triggered reinstatement of alcohol-seeking behavior. In this model, neither naltrexone (2 mg/kg) nor acamprosate (400 mg/kg) prevented relapse to alcohol-seeking behavior. In contrast, SB-277011A significantly reduced reinstatement of alcohol seeking in a dose-dependent manner. Provided these results can be extrapolated to humans, they suggest that selective DA D(3) receptor antagonists may be useful in the pharmacotherapeutic management of alcohol intake and prevention of relapse to alcohol-seeking behavior.
Although an important regulatory role for serotonin (5‐HT) in seizure activation and propagation is well established, relatively little is known of the function of specific 5‐HT receptor subtypes on ...seizure modulation.
The aim of the present study was to investigate the role of 5‐HT
1A, 1B and 1D
receptors in modulating generalised seizures in the rat maximal electroshock seizure threshold (MEST) test.
The mixed 5‐HT receptor agonists SKF 99101 (5–20 mg kg
−1
i.p.) and RU 24969 (1–5 mg kg
−1
i.p.), 0.5 h pretest, both produced marked dose‐related increases in seizure threshold. These agents share high affinity for 5‐HT
1A, 1B and 1D
receptors.
Antiseizure effects induced by submaximal doses of these agonists were maintained following p‐chlorophenylalanine (150 mg kg
−1
i.p. × 3 days)‐induced 5‐HT depletion.
The anticonvulsant action of both SKF 99101 (15 mg kg
−1
i.p.) and RU 24969 (2.5 mg kg
−1
i.p.) was dose‐dependently abolished by the selective 5‐HT
1B
receptor antagonist SB‐224289 (0.1–3 mg kg
−1
p.o., 3 h pretest) but was unaffected by the selective 5‐HT
1A
receptor antagonist WAY 100635 (0.01–0.3 mg kg
−1
s.c., 1 h pretest). This indicates that 5‐HT
1B
receptors are primarily involved in mediating the anticonvulsant properties of these agents.
In addition, the ability of the 5‐HT
1B/1D
receptor antagonist GR 127935 (0.3–3 mg kg
−1
s.c., 60 min pretest) to dose‐dependently inhibit SKF 99101‐induced elevation of seizure threshold also suggests possible downstream involvement of 5‐HT
1D
receptors in the action of this agonist, although confirmation awaits the identification of a selective 5‐HT
1D
receptor antagonist.
Overall, these data demonstrate that stimulation of postsynaptic 5‐HT
1B
receptors inhibits electroshock‐induced seizure spread in rats.
British Journal of Pharmacology
(2005)
144
, 628–635. doi:
10.1038/sj.bjp.0706027
A growing body of evidence indicates that dopamine (DA) D(3) receptors are significantly involved in the control of drug-seeking behavior, and may play an important role in the pathophysiology of ...impulse control disorders and schizophrenia. This hypothesis has been difficult to test due to the lack of compounds with high selectivity for central DA D(3) receptors. Recently, however, the synthesis and characterization of new highly potent and selective DA D(3) receptor antagonists has permitted to characterize the role of the DA D(3) receptor in a wide range of preclinical animal models. Although the proof of efficacy of pharmacotherapeutic agents is to be derived ultimately from clinical trials, the preclinical findings that selective antagonism at DA D(3) receptors reduces the reinforcing efficacy of drugs of abuse, reverses cognitive deficits, and shows efficacy in animal models of schizophrenia add to an accumulating body of evidence that selective DA D(3) receptor antagonists may hold highest promise in the treatment of several neuropsychiatric diseases. The present review is aiming at describing current areas of interest and the possible future development of selective DA D(3) receptor antagonists by outlining about 40 patents and 100 publications in this research field between 2001 and 2005.
Issue Title: Theme issue on dopamine receptors Growing evidence indicates that dopamine (DA) D^sub 3^ receptors are involved in the control of drug-seeking behavior and may play an important role in ...the pathophysiology of substance use disorders. First, DA D^sub 3^ receptors are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse has been shown to produce neuroadaptations in the DA D^sub 3^ system. Third, the synthesis and characterization of highly potent and selective DA D^sub 3^ receptor antagonists has permitted to further define the role of the DA D^sub 3^ receptor in drug addiction. Provided that the available preclinical and preliminary clinical evidence can be translated into clinical proof of concept in human, selective DA D^sub 3^ receptor antagonists show promise for the treatment of substance use disorders as reflected by their potential to (1) regulate the motivation to self-administered drugs under schedules of reinforcement that require an increase in work demand and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in the reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, re-exposure to environmental cues that had been previously associated with drug-taking behavior, or stress.
There has been considerable interest in the role of dopamine D(3) receptors in appetitive conditioning but few studies have examined their role in aversive conditioning. The present study examined ...the effect of the dopamine D(3) receptor-preferring partial agonist BP 897 (1-(4-(2-naphthoyl-amino)butyl)-4-(2-methoxyhenyl)-1A-piperazine hydrochloride) and the selective dopamine D(3) receptor antagonist SB-277011A (trans-N-4-2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethylsyclohexyl4-quinolininecarboxamide) on the expression and acquisition of fear conditioning. Rats (N=143) received 3 conditioned stimulus-shock pairings and then received 15 conditioned stimulus-alone presentations (3 per day) while lever pressing for food. Response suppression was taken as the behavioral measure of fear. Rats showed strong suppression to the conditioned stimulus after it had been paired with shock and suppression progressively weakened over conditioned stimulus-alone presentations. In experiment 1, rats that received BP 897 (1.0, 2.0 mg/kg i.p.) or SB-277011A (10.0 mg/kg i.p.) prior to conditioned stimulus-alone presentation sessions showed reduced suppression to the conditioned stimulus as compared to rats that received vehicle or lower doses of drug (0, 0.1 mg/kg BP 897; 0, 0.5, 5.0 mg/kg SB-277011A). Injections of BP 897 (1.0, 2.0 mg/kg) or SB-277011A (10.0 mg/kg) prior to conditioned stimulus-shock pairings did not significantly affect subsequent response suppression. Thus, BP 897 and SB-277011A dose-dependently attenuated the expression but not the acquisition of conditioned fear. These findings suggest that BP 897 and SB-277011A reduce the control of responding by aversively conditioned stimuli.
A high performance liquid chromatography (HPLC) method based on cation exchange separation has been developed for the measurement of dopamine (DA), 5-hydroxytryptamine (5-HT) and norepinephrine (NE) ...in microdialysates. The separation conditions have been optimised for using electrochemical detection. All three bioamines were resolved in less than 22 min using isocratic conditions. The optimum oxidation potential for the three bioamines was found to be +0.4 V vs. in situ Ag/AgCl reference electrode. Linear regression analysis of HPLC-peak area as a function of concentrations in the range 1–50 ng ml
−1 gave coefficients of correlation between 0.998 and 0.999. The limit of detection for DA, 5-HT and NE was found to be between 50 and 100 pg ml
−1 with a signal to noise ratio of 3:1. The method has been applied to the simultaneous measurement of the three monoamines in microdialysates from the medial prefrontal cortex under basal conditions and following the administration of the antipsychotic drug clozapine (10 mg kg
−1 s.c.).
Over three decades of evidence indicate that dopamine (DA) D
receptors (D
R) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance ...use disorders (SUD). The expectation that a selective D
R antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, D
R are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the D
R system. Third, the synthesis and characterization of highly potent and selective D
R antagonists/partial agonists have further strengthened the role of the D
R in SUD. Based on extensive preclinical and preliminary clinical evidence, the D
R shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective D
R antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective D
R antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.
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