ABSTRACT
Dinapsoline is a new potent, full agonist at D1 dopamine receptors with limited selectivity relative to D2 receptors. The efficacy of this compound was assessed in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, a standard rat model of Parkinson's disease. Dinapsoline produced robust contralateral rotation after either subcutaneous or oral administration. This rotational behavior was attenuated markedly by the D1 receptor antagonist SCH-23390, but not by the D2 receptor antagonist raclopride. During a chronic 14-day treatment period in which rats received dinapsoline either once or twice a day, dinapsoline did not produce tolerance (in fact, some sensitization of the rotational response was observed in one experiment). Because dinapsoline shows less D1:D2 selectivity in vitro than other D1 agonists, the contribution of D2 activity to tolerance was assessed. Chronic daily cotreatment with dinapsoline and raclopride did not enable the development of tolerance to chronic dinapsoline treatment. In contrast, when dinapsoline was administered by osmotic minipump, rapid tolerance was observed. To explore further the contribution of D1 and D2 receptors to tolerance, experiments were performed with the selective D1 agonist A-77636. Daily dosing with A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D2 agonist quinpirole plus A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D1 receptor agonists is influenced by the pattern of drug exposure but not by the D1:D2 selectivity of the agonist.
Subject(s)
Antiparkinson Agents/therapeutic use , Dopamine Agonists/therapeutic use , Isoquinolines/therapeutic use , Naphthols/therapeutic use , Parkinson Disease/drug therapy , Receptors, Dopamine D1/agonists , Animals , Chromatography, High Pressure Liquid , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Tolerance , Hydroxydopamines , Male , Neostriatum/drug effects , Neostriatum/metabolism , Quinpirole/therapeutic use , Raclopride/therapeutic use , Rats , Rats, Sprague-Dawley , Rotation , Stereotyped Behavior/drug effects , Sympathectomy, ChemicalABSTRACT
BMY-14802 (BMS-181100; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol monohydrochloride) is a sigma receptor antagonist with potential antipsychotic activity. BMY-14802 also binds to 5-HT1A receptors and is able to inhibit the firing of dorsal raphe serotonergic neurons, suggesting that this compound has 5-HT1A receptor agonist properties in vivo. In the present study, we used in vivo microdialysis to study the effects of BMY-14802 on extracellular serotonin (5-hydroxytryptamine), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the dorsal raphe and ventral hippocampus in the awake rat. Systemic injections of 5-20 mg/kg BMY-14802 induced a simultaneous dose-dependent decrease in 5-HT and markedly increased the dopamine metabolite, HVA concentrations in dialysates from dorsal raphe and hippocampus. Extracellular concentrations of the 5-HT metabolite, 5-HIAA decreased only after 20 mg/kg BMY-14802. The 5-HT decreases in dorsal raphe and hippocampus produced by BMY-14802 were completely antagonized by pretreatment with 1.0 mg/kg of the specific 5-HT1A antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). These data indicate that BMY-14802 decreases dorsal raphe and hippocampal release of 5-HT by interaction with somatodendritic 5-HT1A receptors in the raphe nuclei and suggest that this compound is a potential anxiolytic.
Subject(s)
Anti-Anxiety Agents/pharmacology , Hippocampus/metabolism , Pyrimidines/pharmacology , Raphe Nuclei/metabolism , Serotonin Receptor Agonists/pharmacology , Serotonin/metabolism , Animals , Anti-Anxiety Agents/antagonists & inhibitors , Dose-Response Relationship, Drug , Hippocampus/drug effects , Homovanillic Acid/metabolism , Hydroxyindoleacetic Acid/metabolism , Male , Microdialysis , Piperazines/pharmacology , Pyridines/pharmacology , Pyrimidines/antagonists & inhibitors , Raphe Nuclei/drug effects , Rats , Rats, Sprague-Dawley , Serotonin Antagonists/pharmacologyABSTRACT
Administration of neuropeptide Y (NPY) into hypothalamic areas or into the cerebral ventricles induces marked increases in food consumption in satiated rats. Since monoamines have been suggested to be involved in NPY-induced feeding, we investigated the effects of NPY and [D-Trp32]NPY, a putative NPY antagonist, on extracellular levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), 3,4-dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA) in the hypothalamus, including the paraventricular hypothalamic nuclei (PVN), during feeding behavior. Intracerebroventricular (i.c.v.) injections of NPY (20 microg) significantly increased extracellular NE (1.5-fold), DA (2.5-fold), DOPAC (2-fold) and HVA (3-fold), and did not change 5-HT or 5-HIAA levels. This dose of NPY significantly increased food intake over a 2 h period. The putative NPY antagonist [D-Trp32]NPY (40 microg, i.c.v.) produced similar neurochemical changes to NPY: it increased dialysate levels of NE (1.7-fold), DA (2.5-fold), DOPAC (1.6-fold) and HVA (2.2-fold) and did not change 5-HT or 5-HIAA levels. [D-Trp32]NPY also produced a significant increase in food intake. I.c.v. administration of [D-Trp32]NPY 5 min before NPY did not significantly change the increase in NE, DA, HVA and DOPAC induced by NPY. In these animals, food consumption was also significantly increased. These data indicate that NPY-induced feeding is associated with activation of the hypothalamic monoaminergic system and that [D-Trp32]NPY, at the dose given, acts as an agonist and not as an antagonist at NPY receptors in vivo.
