nafadotride and Disease-Models--Animal

Haloperidol, a dopamine (DA) D2 receptor-preferring antagonist, produces catalepsy whereby animals maintain awkward posture for a period of time. Sub-threshold doses of haloperidol fail to produce catalepsy initially, however, when the drug is given repeatedly in the same test environment, gradual day-to-day increases in catalepsy are observed. More importantly, if sensitized rats are injected with saline instead of haloperidol they continue to be cataleptic in the test environment suggesting that environment-drug associations may play a role. DA D3 receptors have been implicated in a number of conditioned behaviors. We were interested if DA D3 receptors contribute to catalepsy sensitization and conditioning in rats. We tested this hypothesis using the DA D3 receptor-selective antagonist NGB 2904 (0.5, 1.8 mg/kg) and the DA D3 receptor-preferring antagonist nafadotride (0.1, 0.5 mg/kg). For 10 consecutive conditioning days rats were treated with one of the D3 receptor antagonists alone or in combination with haloperidol (0.25 mg/kg) and tested for catalepsy, quantified by the time a rat remained with its forepaws on a horizontal bar. On test day (day 11), rats were injected with saline or the D3 receptor antagonist and tested for conditioned catalepsy in the previously drug-paired environment. Rats treated with NGB 2904 or nafadotride alone did not develop catalepsy. Rats treated with haloperidol or haloperidol plus NGB 2904 or nafadotride developed catalepsy sensitization with repeated conditioning. When injected with saline they continued to exhibit catalepsy in the test environment--now conditioned. On the other hand, NGB 2904 (1.8 mg/kg) or nafadotride (0.5 mg/kg) given on the test day (after sensitization to haloperidol) significantly attenuated the expression of conditioned catalepsy. Our data suggest that the D3 receptor antagonist NGB 2904 (1.8 mg/kg) and nafadotride (0.5 mg/kg) significantly attenuate conditioned catalepsy in rats when given in test but not when given during sensitization. Results implicate DA D3 receptors in regulating the expression of conditioned catalepsy.

Topics: Animals; Behavior, Animal; Catalepsy; Conditioning, Classical; Disease Models, Animal; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Fluorenes; Haloperidol; Male; Motor Activity; Naphthalenes; Piperazines; Pyrrolidines; Random Allocation; Rats; Rats, Wistar; Reaction Time; Receptors, Dopamine D3; Spatial Behavior; Time Factors

All drugs abused by humans increase dopamine in the shell of nucleus accumbens, which implicate the neurons of this structure in their hedonic and reinforcing properties. Among the various dopamine receptor subtypes, the D(1) (D(1)R) and D(3) (D(3)R) receptors co-localise in accumbal shell neurons. Synergistic D(1)R/D(3)R interactions at this level were found on gene expression and during induction and expression of behavioral sensitisation to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitisation to abused drugs is a component of their long-term effects. Converging pharmacologic, human postmortem and genetic studies suggest the involvement of the D(3)R in reinforcing effects of drugs; D(3)R agonists reduced cocaine self-administration in rats, without disrupting the maintenance of self-administration. These data suggest the use of D(3)R agonists as partial substitutes to treat cocaine dependence, by affecting its reward component. However, substitution therapies maintain dependence and may be inefficient on drug craving and relapse, which are the unsolved and critical problems in the treatment of drug addiction. Recently, a highly selective and partial D(3)R agonist was shown to reduce cocaine-associated cue-controlled behaviour in rats, without having any primary intrinsic effects. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, such D(3)R agents have potential therapeutic applications.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Agonists; Dopamine Antagonists; Drug Synergism; Locomotion; Naphthalenes; Neurons; Nucleus Accumbens; Pyrrolidines; Rats; Receptors, Dopamine; Reward