Oral buspirone causes a shift in the dose-response curve between the elevated-plus maze and Vogel conflict tests in Long-Evans rats: relation of brain levels of buspirone and 1-PP to anxiolytic action.

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.

Different levels of gamma-synuclein mRNA in the cerebral cortex of dominant, neutral and submissive rats selected in the competition test.

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 alpha-, beta- and gamma-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 gamma-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 gamma-synuclein expression (15.7 +/- 1.4) that were significantly lower than that in dominant rats (P <0.05). No changes in alpha- or beta-synuclein expression were observed among the groups. These studies indicate that gamma-synuclein levels in the cerebral cortex were differentially associated with dominant and submissive behavior.

Pyrazolecarboxamide human neuropeptide Y5 receptor ligands with in vivo antifeedant activity.

1-Aryl-3-carboxamido-5-alkylpyrazoles were prepared based on a hit found in high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. 1-(3-Trifluoromethylphenyl)-3-[N-(5-quinolinyl)carboxamido]-5-methylpyrazole (31) bound to the human neuropeptide Y5 receptor with a 80 nM IC(50 )and was shown to inhibit cumulative food consumption 43.2% 2-6 h after ip dosing in a fasting-induced feeding model in rats.

Peripheral serotonin is an incomplete signal for eliciting satiety in sham-feeding rats.

Peripheral administration of serotonin [5-hydroxytryptamine (5-HT)] to rats equipped with gastric cannulae reduced their 30-min consumption of sweetened milk after overnight deprivation whether the cannulae were closed (real feeding) or open (sham feeding). The anorectic action of 5-HT (1.6, 4.0, and 10.0 mumol/kg, IP) in sham feeding was dose-related, rapid in onset, and persisted during the 30-min testing session. However, 5-HT failed to elicit resting--the terminal behavioral phase of satiety--in sham-feeding rats. Direct comparison of the effects of 4.0 mumol/kg 5-HT under both feeding conditions established that this dose promoted resting only when rats fed with their cannulae closed. The actions of 5-HT on feeding and resting were behaviorally selective because serotonergic treatment did not retard the beginning of feeding, alter sham drinking of water, or reduce investigation by food-deprived rats of a novel object in an open field. Together, the results suggest that 5-HT exerts separate actions to inhibit feeding and accelerate the process of satiation as marked by resting. However, peripheral 5-HT is inadequate as a signal for modulating satiety in the absence of postingestive stimuli.

Behavioral mechanisms for the anorectic action of the serotonin (5-HT) uptake inhibitor sertraline in rats: comparison with directly acting 5-HT agonists.

The 5-HT uptake inhibitor, sertraline (5-40 mumol/kg, IP) reduced the volume of milk consumed by food-deprived rats during a 30-min test (ID50 = 12 mumol/kg). Observations using a time-sampling method revealed that sertraline shortened meal duration (ID50 = 14 mumol/kg) by decreasing feeding and increasing resting without altering nonfeeding activity or the overall sequence of behavior that characterizes normal satiety. In separate experiments, analysis of videotapes demonstrated that sertraline (10 mumol/kg) decreased not only the time that rats fed but also their actual rate of intake. In comparison, doses of the direct 5-HT agonists, mCPP (1-[3-chlorophenyl]piperazine), RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole), and DOI (1-[2,5-dimethoxy-4-iodophenyl]-2-amino-propane) that produced similar anorectic effects altered either feeding time or rate but not both. DOI also disrupted the continuity of feeding and the 5-HT agonist, 8-OH-DPAT (8-hydroxy-di-N-propylamino tetralin) produced marked stereotypy at anorectic doses. Together, these results imply that stimulating a number of different serotonergic mechanisms can reduce food intake in rats. Sertraline appears to accelerate the onset of normal satiety, presumably by enhancing physiological actions of endogenous 5-HT.

Peripherally administered alpha-methyl-5-hydroxy-tryptamine and 5-carboxamidotryptamine reduce food intake via different mechanisms in rats.

Peripherally administering the serotonin (5-HT) analogs, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT) and 5-carboxamidotryptamine (5-CT), reduced milk consumption by food-deprived rats. 5-CT decreased milk intake 100-fold more potently than alpha-Me-5-HT (ID(50)'s =.06 and 5.6µmol/kg, respectively). 5-CT also elicited drinking but alpha-Me-5-HT did not. The nonselective 5-HT antagonist, methysergide, blocked the anorectic actions of each agonist. By contrast, the 5-HT(2) antagonist, ketanserin, and the peripheral 5-HT(2) antagonist, xylamidine, only prevented anorexia due to alpha-Me-5-HT. These results suggest that stimulating either peripheral 5-HT(2) or peripheral 5-HT(1)-like receptors inhibits feeding in rats. 5-HT(1)-like sites may also mediate 5-HT-induced drinking.