Fumikazu Wanibuchi

Synergistic effects between D-1 and D-2 dopamine antagonists on catalepsy in rats

The effect of selective D-1 and D-2 dopamine agonists on catalepsy induced by various dopamine antagonists was studied. A potent and selective D-2 antagonist, YM-09151 (YM-09151-2) at a dose of 1.2 mg/kg, SC and a selective D-1 antagonist, SCH 23390 at 1.0 mg/kg, SC induced catalepsy in rats. Mixed D-1/D-2 antagonists, haloperidol (HPD) and cis-flupentixol (FLU) also induced catalepsy at doses of 2.0 and 0.8 mg/kg, SC, respectively. A mixed D-1/D-2 agonist, apomorphine (1.0 mg/kg, SC), a selective D-2 agonist, bromocriptine (10 mg/kg, IP) and a muscarinic antagonist, scopolamine (1.0 mg/kg, SC), prevented or markedly reduced the incidence of catalepsy by the tested antagonists. In contrast, a selective D-1 agonist, SKF 38393 (4.0 mg/kg, SC) did not reduce the cataleptogenic effects of HPD, FLU and SCH 23390, but did reduce the effect of YM-09151. Moreover, co-administration of YM-09151 with SCH 23390 produced a marked increase in the incidence of catalepsy. The incidence seen after the combination of YM-09151 and SCH 23390 at low doses was significantly different from that seen after each drug alone at the doubled dose. Thus, D-1 and D-2 antagonists potentiated each others effect in producing catalepsy. These results suggest an important role of both D-1 and D-2 receptors in the catalepsy and the existence of synergistic effects of D-1 and D-2 receptor blockade.

Characterization of a novel muscarinic receptor agonist, YM796; comparison with cholinesterase inhibitors in in vivo pharmacological studies.

Previous reports have shown that (+/-)-YM796 (2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane) exhibits M1 agonistic activity and ameliorates cognitive impairment, and that the (-)-S isomer is active in in vitro studies. We report here the characterization of the (-)-S isomer, YM796 ((-)-(S)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane L-tartrate monohydrate), and its (+)-R isomer in in vivo pharmacological studies in comparison with the cholinesterase inhibitors tacrine, amiridine and E-2020. YM796 (0.031-0.5 mg/kg p.o.), like the racemate, reversed the cognitive impairment in passive avoidance tasks of rats with nucleus basalis magnocellularis lesions, whereas (+)-R-YM796 was ineffective in this experimental amnesia. YM796 exhibited only weak effects on mouse salivation and hypothermia, a peripheral cholinergic response and a central cholinergic response, respectively. The (+)-R isomer, however, failed to induce these cholinergic responses. YM796 also ameliorated the memory deficits induced by scopolamine in rats and electroconvulsive shock in mice. The potency of YM796 in these experimental amnesia models was over a 100 times greater than that of tacrine, over 10 times greater than that of E-2020, and 6 times greater than that of amiridine. In salivary secretion and hypothermia, YM796 was 2-4 times weaker than tacrine and E-2020, and 1-2 times stronger than amiridine. Thus, YM796s ratio of anti-amnesic effects to salivary secretion and hypothermia was much greater than that of the cholinesterase inhibitors tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological studies on novel muscarinic agonists, 1-oxa-8-azaspiro[4.5]decane derivatives, YM796 and YM954.

We have investigated the pharmacological profiles of the novel muscarinic agonists, 1-oxa-8-azaspiro[4.5]decane derivatives, YM796 (2,8-dimethyl-3-methylene) and YM954 (2-ethyl-8-methyl-3-oxo). These compounds, like the putative M1 agonists, RS86 and AF102B, inhibited [3H]pirenzepine binding to cerebral cortical membranes in the micromolar range and weakly inhibited [3H]quinuclidinyl benzylate binding to cerebellar membranes. Their (-) isomers had Hill coefficients lower than 1.0. (+/-)-YM796, (+/-)-YM954 and RS86, but not AF102B, stimulated phosphoinositide hydrolysis in hippocampal slices, an effect which is mainly linked to M1 receptors. (+/-)-YM796 (0.031 mg/kg p.o.) and (+/-)-YM954 (0.016 mg/kg p.o.) reversed the cognitive impairment in nucleus basalis magnocellularis-lesioned rats in a passive avoidance task more effectively than did RS86 and AF102B. Similar results were obtained in scopolamine-treated rats. Finally, (+/-)-YM796 was weaker than (+/-)-YM954 and RS86 in the induction of tremor, hypothermia and contraction of isolated ileum, which are mainly mediated by M2 and/or M3 receptors. These results suggest that (+/-)-YM796, (+/-)-YM954 and RS86 have M1 agonistic activity in central nervous system and that (+/-)-YM796 has relatively weak M2 and/or M3 agonistic activity.

Phencyclidine-induced abnormal behaviors in rats as measured by the hole board apparatus.

Abstract Rationale: Phencyclidine (PCP) and methamphetamine (MAP) are known as psychotomimetic agents. Both agents produce behavioral alterations in animals. Objective: The present study investigated the difference in behavioral alterations in rats induced by these two psychotomimetic agents using the hole board apparatus (HBA). In addition, mechanisms underlying PCP-induced behavioral changes were also investigated. Methods: After the administration of PCP (1–4 mg/kg SC) or MAP (1–4 mg/kg SC), locomotor activity and dipping behavior were assessed using HBA. Effect of selective NMDA antagonists, (+)MK801 and 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), on rat behaviors were also assessed. The effects of d-alanine (d-Ala), a coagonist of NMDA receptors, or neuroleptics, haloperidol, clozapine and risperidone, on PCP-induced behavioral changes were investigated. Results: PCP increased locomotor activity and decreased exploratory behaviors of rats in HBA. On the other hand, MAP increased locomotor activity but did not decrease exploratory behaviors. (+)MK-801 produced hyperactivity as well as decreased exploratory behaviors, eliciting behavioral changes very similar to those of PCP. CPP decreased the exploratory behavior but failed to produce hyperactivity. d-Ala attenuated both behavioral changes induced by PCP. Three neuroleptics tested here inhibited hyperactivity but did not attenuate decreases in exploratory behavior. Conclusion: These results suggest that PCP-induced decrease in exploratory behavior are attributable to antagonism of NMDA receptors and may not involve dopaminergic transmission via D2 receptors.

5-HT2C receptor activation is a common mechanism on proerectile effects of apomorphine, oxytocin and melanotan-II in rats

5-Hydroxytryptamine (5-HT), dopamine, oxytocin and melanocortin pathways are known to be involved in the induction of penile erections in rats. Although a dopamine-oxytocin-5-HT link in the central nervous system has been suggested to be important to the control of penile erections, the 5-HT receptor subtype that mediates dopamine-oxytocin-5-HT action and the relationship between the dopamine-oxytocin-5-HT pathway and melanocortin pathway have not been fully elucidated. In this study, in order to clarify these matters, we examined the effects of a selective 5-HT(2B)/5-HT(2C) receptors antagonist, 1-(1-methylindol-5-yl)-3-(3-pyridyl)urea (SB200646) and a selective 5-HT(2C) receptor antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline (SB242084) on penile erections induced by a dopamine receptor agonist, 10, 11-dihydroxyaporphine (apomorphine), oxytocin, or a melanocortin receptor agonist, melanotan-II (MT-II) in rats. SB200646 at 10 mg/kg and SB242084 at 3 mg/kg, these doses which completely antagonize penile erections induced by 5-HT(2C) receptor agonists, m-chlorophenylpiperazine (mCPP) and (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348), significantly inhibited penile erections elicited by apomorphine, oxytocin or MT-II. In addition, in order to clarify further the suggestion that the 5-HT pathway projecting from medulla oblongata to lumbosacral spinal site and lumbosacral 5-HT(2C) receptor are involved in the induction of penile erection, we also examined the proerectile effect of YM348 in spinal and a 5-HT depletor, p-chlorophenyl alanine (pCPA)-treated rats. YM348 induced intracavernous pressure increase in spinal and pCPA-treated rats as well as normal rats. These results suggest that 5-HT(2C) receptor in lumbosacral spinal sites mediates not only dopamine-oxytocin-5-HT action but melanocortin action on penile erections, and that the 5-HT pathway is located downstream from melanocortin pathway as well as the dopamine-oxytocin pathway.

Supraspinal influence on intracavernous pressure increase by subcutaneous injections of MCPP

554 ABNORMAL NEURAL INPUTS FROM THE MEDIAN PREOPTIC NUCLEUS TO THE HYPOTHALAMIC PARAVENTJUCULAR NUCLEUS IN SPONTANEOUSLY HYPERTENSIVE RATS JUNICHI TANAKA’, YASUSHI HAYASHI 2, KATSUHIDE KARIYA3, MASAHIKO NOMURA4 Depts. of ‘Human Dev. and 2Educ. for Handicapped Child., Naruto Univ. of Educ., Naruto, Tokushima 772-8502, 3Res. Lab., Torii & Co. Ltd., Midori-ku, Chiba 267-0056, 4Dept. of Physiol., Saitama Med. Sch., lruma-gun, Saitama, 350-0495 Extracellular single-unit activity was recorded from phasically firmg neurohypophyseal neurons tn the hypothalamic paraventricularnucleus (PVN) of male Wistar-Kyoto (WKY, 40 units) and spontaneously hypertensive rats (SHR, 38 units) under urethane anesthesia. Electrical stimulation of the median preoptic nucleus (MnPO) J)roduced orthodromic excitatton (48% in WKY rats; 51% in SHR) or inhibition (10% in WKY rats; 13% in SHR) of the activity of PVN units. No signifmant differences in the latency, duration or threshold of the MnPG stimulus-induced responses were observed between WKY and SHR. The magnitude of excitatory response, but not the inhtbitory response, much greater in SHR than m WKY rats. Local administration of angiotensin II (ANG II) into the stimulation sites enhanced the neuronal activity of units (64% in WKY rats; 67% in SHR) that displayed the excitation to electrical stimulation of the MnPO. The duration and frequency of excitatory response caused by the ANG II injection was much greater in SHR than in WKY rats. These results suggest that ANG IIsensitive MnPO efferents to the PVN act to facilitate the excitability of putative vasopressin-secreting neurons in the PVN and imply that there is the alteration between WKY and SHR in the functron of the pathways.