The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.

No abstract

Submissive animals can be defined in a food competition test as spending significantly less time on the feeder than their dominant partners. Using observer-based scoring in the Reduction of Submissive Behavior Model, submissive behavior in rats and mice has been previously shown to be sensitive and selective to antidepressant treatment. In this paper, we report the use of automated scoring by a multiple-subject video-tracking system to record similar effects of antidepressants on rat submissive behavior. Automated scoring enabled the observation of four pairs of rats during each 5-min experimental session (one set) and immediate switching to the observation of the next four pairs of animals. Studies were conducted to confirm our previous results with imipramine and fluoxetine that were obtained with manual scoring, and to extend those results to studies with other drugs, including the antidepressant maprotiline and the delta-opioid antagonist naltrindole, which is not known to have antidepressant activity. As in previous studies, treatment of the submissive animal for 5 weeks with imipramine (20 mg/kg) or fluoxetine (10 mg/kg) significantly reduced submissive behavior, with a delayed onset of antidepressant effect that was dependent on drug dose. Maprotiline (10 and 20 mg/kg), like imipramine or fluoxetine and in contrast to naltrindole, strongly reduced rat submissive behavior, further demonstrating the selectivity of this test for antidepressant activity.

Most studies concerning the effects of oral buspirone in the rat elevated plus-maze (EPM) test, spontaneous motor activity (SMA) test, and Vogel conflict (VC) test have used Sprague-Dawley or Wistar rats. Although it has been documented that the behavior of Long-Evans rats is more sensitive to detection of anxiolytics when compared to the aforementioned strains, the effects of oral buspirone have not been fully characterized in the Long-Evans strain in the EPM and VC tests. Thus, we studied the effects of orally administered buspirone (0.03-10.0 mg/kg) in the EPM, SMA, and VC (0.3-60.0 mg/kg) tests in Long-Evans rats. In a separate experiment, brain and plasma concentrations of buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP) were determined after oral administration of buspirone (0.3 and 10 mg/kg) to relate the behavioral effects of buspirone with brain and plasma concentrations of buspirone and 1-PP. Our results showed that buspirone exhibited an inverted-U-shaped dose-response curve in both the EPM and the VC tests. In the EPM, buspirone produced anxiolytic activity in a low, narrow dose-range (0.03, 0.1, 0.3 mg/kg, p.o.) with maximum efficacy at 0.3 mg/kg, whereas in the VC test, significant anxiolytic activity was observed in a high, narrow dose-range (10, 30 mg/kg, p.o.) with maximum efficacy occurring at 10 mg/kg. In the SMA test, buspirone (10 mg/kg, p.o.) significantly decreased horizontal activity and vertical movements suggestive of sedation. Also, one hour following oral doses of buspirone (0.3 and 10 mg/kg), both buspirone and 1-PP concentrations were higher in brain when compared with those in plasma. Additionally, the concentrations of 1-PP were always higher in brain and in plasma compared with the concentrations of buspirone. Of particular interest is our finding of the shift in the dose-response curve between the EPM and VC tests. This shift in the dose-response curve is discussed in relation to brain levels of buspirone and 1-PP levels and their anxiolytic action.

No abstract

No abstract

No abstract

Synucleins are small proteins regulating the filamentous network that in turn influences the release of dopamine and glutamate neurotransmitters involved in mood and motivation processes. We have studied the pattern of synuclein expression in animal models for mania and depression. Dominant behavior, as defined in a food competition test with dyads of rats, can serve as a model of mania and submissive behavior as a model of depression. The expression of a-, b-and g -synuclein was analyzed in four regions of cortex from dominant, neutral and submissive rats using TaqMan reverse transcription-polymerase chain reaction technology. The expression levels of g -synuclein were elevated consistently in all regions of cerebral cortex of dominant rats (P < 0.05; 23.5 -1.1, normalized units) in contrast to the submissive rat group (10.3 -1.2). Neutral rats had intermediate cerebral cortex levels of g -synuclein expression (15.7 -1.4) that were significantly lower than that in dominant rats (P < 0.05). No changes in a-or b-synuclein expression were observed among the groups. These studies indicate that g -synuclein levels in the cerebral cortex were differentially associated with dominant and submissive behavior.