sb-277011 and Substance-Related-Disorders

Topics: Animals; Biological Availability; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Receptors, Dopamine D2; Receptors, Dopamine D3; Structure-Activity Relationship; Substance-Related Disorders

The behavioral and pathophysiological role of the dopamine D(3) receptor, which was deduced from anatomical, lesion and drug treatment studies in the ten years following cloning of the receptor, indicated that its functions differed from those of the D(2) receptor. There is increasingly strong evidence that D(3) receptor antagonists will be effective antipsychotic agents. In this regard, an amelioration of the negative and cognitive symptoms of schizophrenia holds the most promise for D(3) receptor antagonists, a concept currently under clinical evaluation. In addition, D(3) receptors could be involved in behavioral sensitization and the potential application of D(3) receptor antagonists in the treatment of drug abuse is undergoing intensive experimental investigation.

Topics: Animals; Dopamine Antagonists; Humans; Molecular Structure; Nitriles; Receptors, Dopamine D3; Substance-Related Disorders; Technology, Pharmaceutical; Tetrahydroisoquinolines

Topics: D-Amino-Acid Oxidase; Drugs, Investigational; Humans; Molecular Structure; Nitriles; Quinazolines; Schizophrenia; Substance-Related Disorders; Tetrahydroisoquinolines

Topics: Acetylcarnitine; Animals; Cholinesterase Inhibitors; Congresses as Topic; Dehydroepiandrosterone; Humans; Nitriles; Piperazines; Quinazolines; Rats; Societies, Scientific; Substance-Related Disorders; Tetrahydroisoquinolines

Dopamine (DA) receptors are a major target for drugs employed in the treatment of neuropsychiatric disorders such as schizophrenia and drug dependence. The D(3) subtype of the D(2) DA receptor family presents a particularly focal distribution in limbic brain areas known to be associated with cognitive and emotional functions. This study examined the modulation of brain activation induced by acute administration of amphetamine in the rat by the highly selective DA D(3) receptor antagonist SB-277011-A using relative cerebral blood volume (rCBV) pharmacological MRI (phMRI). The acute administration of D-amphetamine (1 mg/kg i.v.) produced a widespread rCBV response that was strongest in cortical regions. SB-277011-A (20 mg/kg i.p.) itself did not produce significant changes in rCBV, but potentiated the phMRI response to 1 mg/kg i.v. D-amphetamine in a regionally specific manner, involving a number of structures outside the focal distribution of the D(3) receptor. Potentiated regions included the accumbens, dorsal caudate putamen, islands of Calleja, thalamus, cingulate cortex, ventral tegmental area, dorsal Raphe nucleus, and ventral subiculum. The increased response following D(3) receptor antagonism is consistent with this receptor mediating an inhibitory action on brain activity following a dopaminergic stimulus.

Topics: Amphetamines; Animals; Brain; Cerebrovascular Circulation; Dopamine Antagonists; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Nitriles; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3; Substance-Related Disorders; Tetrahydroisoquinolines

The importance of dopamine D3 receptors in reward related processes, especially in cocaine addiction, has been investigated extensively. However, in the reported studies a combination of different experimental conditions and different ligands have been used which renders the interpretation and comparison of the diverse results extremely difficult. Here, we report one comparative study investigating a wide range of dopamine D3 receptor ligands in one model of cocaine abuse: the place conditioning paradigm in rats. Of the antagonists tested, the moderately D3 selective nafadotride and the more selective SB-277011 did not produce any place conditioning effect while U-99194A caused place-preference. The most D3 selective agonist PD-128907, the less selective 7-OH-DPAT and the moderately selective partial agonist BP-897 all caused significant place aversion. None of the compounds influenced the cocaine-induced place preference. Results suggest the D3-preferring agonists could affect the reward mechanisms of the brain, however, modulation of D3 receptor function does not appear to be a significant mechanism for modifying the place conditioning effect of cocaine.

Topics: Animals; Avoidance Learning; Benzazepines; Benzopyrans; Cocaine; Conditioning, Classical; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Haloperidol; Indans; Male; Naphthalenes; Nitriles; Oxazines; Piperazines; Pyrrolidines; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Reinforcement, Psychology; Reward; Spatial Behavior; Substance-Related Disorders; Tetrahydroisoquinolines; Tetrahydronaphthalenes

Drugs of abuse, including, nicotine have been shown to enhance brain reward functions in the mesocortico-limbic dopamine (DA) system in general, and the nucleus accumbens in particular. The latter occupies a prominent position in the ventral striatum and expresses a high density of DA D(3) receptors. As such, the present study aimed at investigating the effect of the selective D(3) receptor antagonist SB-277011-A on both the stable maintenance of intravenous nicotine self-administration and nicotine-triggered relapse to nicotine-seeking behavior in the rat. SB-277011-A (3-10 mg/kg i.p.) significantly reduced reinstatement of nicotine-seeking behavior without affecting nicotine self-administration per se. These results suggest that DA D(3) receptors are involved in the reinstatement of nicotine-seeking behavior independently of any interaction with the primary reinforcing effects of nicotine itself. These findings point toward the potential use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of relapse to drug-seeking behaviors.

Topics: Animals; Behavior, Animal; Cues; Dopamine Antagonists; Dose-Response Relationship, Drug; Food; Male; Nicotine; Nicotinic Agonists; Nitriles; Quinolines; Random Allocation; Rats; Rats, Wistar; Reinforcement, Psychology; Secondary Prevention; Self Administration; Substance-Related Disorders; Tetrahydroisoquinolines; Time Factors