Showa Ueki

Effects of 5-HT1A receptor agonists on the circadian rhythm of wheel-running activity in hamsters

The effects of 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone on wheel-running activity in hamsters were investigated in comparison with those of GABAA receptor agonist muscimol and benzodiazepine triazolam. Intraperitoneal administration of 8-OH-DPAT, buspirone, ipsapirone, muscimol and triazolam at circadian time (CT) 8 (CT 12; onset of activity) induced a significant phase advance of wheel-running activity under constant light conditions. However, administration of these drugs at other CT points did not induce phase changes. The administration of trifluoromethylphenylpiperazine (TFMPP), a 5-HT1B receptor agonist, at CT8 produced a small phase advance. The phase advance induced by 8-OH-DPAT was blocked by pretreatment with (-)-pindolol, a 5-HT1A receptor antagonist. In addition, 8-OH-DPAT, buspirone and SM3997 accelerated the rate of re-entrainment to an 8-h phase advance in the light-dark cycle. These observations suggest that 5-HT1A receptors in the brain participate in the regulation of the circadian rhythm of wheel-running activity in hamsters.

Influence of excitatory amino acid receptor antagonists and of baclofen on synaptic transmission in the optic nerve to the suprachiasmatic nucleus in slices of rat hypothalamus.

Electrical stimulation of the optic nerve evoked two positive waves with short latency, followed by a large negative wave in the suprachiasmatic nucleus of slices of hypothalamus of the rat. The latency to peak of the two positive waves and the large negative wave were 2.7 +/- 0.1, 6.1 +/- 0.1 and 10.3 +/- 0.5 msec, respectively. Only the large negative wave disappeared in low calcium Ca2+-high magnesium (Mg2+) Krebs solution and with the addition of tetrodotoxin (1 microM) all the waves disappeared. Baclofen inhibited the large negative wave in a dose-dependent manner but not the two positive waves. Excitatory amino acid antagonists also inhibited only the large negative wave, i.e. it was reduced to about 70% by 1 mM glutamic acid diethyl ester and to about 50% by both 1 mM 2-amino-4-phosphonobutyric acid and 1 mM DL-2-amino adipic acid. All waves were unaffected by 0.1 mM atropine, hexamethonium and curare. These results indicate that two positive waves, induced by stimulation of the optic nerve are attributed to nerve conduction and the large negative wave to the neurons of the suprachiasmatic nucleus, and that the neuronal pathway from the optic nerve to the suprachiasmatic nucleus may include aspartate and/or glutamate as an excitatory neurotransmitter.

Localization of the site of the anticonflict action of benzodiazepines in the amygdaloid nucleus of rats

Abstract The present study was designed to identify the definitive site in the amygdala of the anticonflict action of benzodiazepines (BZD). Diazepam 20 μg/μl, chlordiazepoxide 60 μg/μl and midazolam 30 μg/μl, bilaterally injected into the central amygdaloid nucleus (ACE), significantly increased the punished responses, but BZD injected into the medial and basolateral amygdaloid nucleus did not. These results suggest that the ACE could be a potential site of antianxiety actions of BZD.

Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents

The effects of rolipram, a cAMP-specific phosphodiesterase (phosphodiesterase 4) inhibitor, on experimentally-induced amnesia were examined using a 3-panel runway paradigm in rats and a passive avoidance task in mice. Scopolamine, cerebral ischemia induced by four-vessel occlusion and electric convulsive shock impaired working memory in the 3-panel runway task. Rolipram at 0.1 mg/kg reduced the increase in errors induced by scopolamine or cerebral ischemia. Rolipram at 0.32 mg/kg also reduced the increase in errors induced by electric convulsive shock. Dibutyryl cAMP also had similar effects in 3-panel runway experiments. In the passive avoidance task, rolipram reversed the impairments of the avoidance response induced by scopolamine, cycloheximide and electric convulsive shock at 10, 10 and 3 mg/kg, respectively. These results indicate that rolipram ameliorates impairments of learning and memory in rats and mice, and suggest that rolipram might ameliorate the impairments of learning and memory by elevating cAMP levels.

Influence of environmental light-dark cycle and enucleation on activity of suprachiasmatic neurons in slice preparations

The influence of environmental light-dark cycle (LD) and bilateral enucleation on single neuronal activity in the suprachiasmatic nucleus (SCN) was examined using a hypothalamic slice preparation. Firstly, we reconfirmed previous results that the discharge rate in slices taken from animals kept on normal LD was higher during the light than during the dark period. Secondly, the day time discharge rate in the ventrolateral part of the SCN was decreased by bilateral enucleation and DD housing, while in the dorsomedial part it was unaffected. Thirdly, LL housing suppressed the discharge rates in both parts during the day and night periods. The present results suggest that the dorsomedial part of the SCN is more important in regulation of the circadian rhythm of SCN neuronal activity than the ventrolateral.

Effects of benzodiazepine and GABA antagonists on anticonflict effects of antianxiety drugs injected into the rat amygdala in a water-lick suppression test

In order to elucidate the role of the amygdala in rat conflict behavior in a water lick suppression test, we examined the effect of lesions of various nuclei of the amygdaloid complex on this behavior. An anticonflict effect was produced by a lesion of the anterior part of central and basolateral amygdala, and lesion to the posterior part of the central amygdala, but not by posterior of the basolateral amygdala or medial amygdala lesions. These results suggest that the amygdala, especially the anterior part of the central and basolateral nuclei, plays an important role in conflict behavior of rats in the water lick test. In a second experiment, the effects of benzodiazepine- and GABA-antagonists on the anticonflict action of diazepam, zopiclone, and phenobarbital injected into the anterior part of central and basolateral amygdala were examined, also using a water lick suppression test. A dose-dependent anticonflict action was produced by systemic administration as well as by intra-amygdala injection of diazepam, zopiclone, lormetazepam, flurazepam and phenobarbital. The order of potency was lormetazepam>zopiclone≧diazepam>flurazepam ≧phenobarbital for both routes of injection. The antiamygdala effects of diazepam and zopiclone injected into the amygdala were completely reversed by Ro15-1788 and β-CCM but not by bicuculline, while the anticonflict effect of phenobarbital was reversed by β-CCM but not by Ro15-1788 or bicuculline. The present results strongly suggest that the anterior nuclei of central and basolateral amygdala are important sites of action of antianxiety drugs, and that an anticonflict action produced by intra-amygdala injection of benzodiazepines or barbiturate is mediated through the different receptor mechansims.

Involvement of the dorsal hippocampus in mediation of the antianxiety action of tandospirone, a 5-hydroxytryptamine1A agonistic anxiolytic

The effect of tandospirone, a 5-hydroxytryptamine (5-HT)1A agonist/anxiolytic, injected directly into dorsal hippocampus, on Vogel-type conflict behavior in rats was investigated and the findings were compared with the effects of diazepam and zopiclone. Tandospirone (30 micrograms/2 microliters and 60 micrograms/2 microliters) and diazepam (40 micrograms/2 microliters) but not zopiclone (20 micrograms/2 microliters), produced a potent anticonflict action in rats. The anticonflict action of tandospirone (30 micrograms/2 microliters), injected into the dorsal hippocampus, was significantly blocked by (-)-propranolol (5 mg/kg i.p.). The present findings provide evidence that suggests that tandospirone has an antianxiety action, presumably by stimulating 5-HT1A receptors in the dorsal hippocampus.

The mammillary body is a potential site of antianxiety action of benzodiazepines

The present study was designed to examine the anticonflict action of benzodiazepines injected into the mammillary body (MB) using the rat conflict-punishment procedure. Diazepam 20 micrograms/microliters, chlordiazepoxide 60 micrograms/microliters and midazolam 30 micrograms/microliters, bilaterally injected into the MB, produced a significant increase in the punished responses without changes in the unpunished responses. These findings have demonstrated for the first time that the MB could be a potential site of antianxiety action of benzodiazepines.

An important role of the central amygdaloid nucleus and mammillary body in the mediation of conflict behavior in rats

The present study was designed to elucidate the functional role of central amygdaloid nucleus (ACE) and mammillary body (MB) in the mediation of behavioral suppression using rat conflict punishment procedure. Lesion of ACE produced a significant and long-lasting increase in the punished responding during the experimental period. Rats with lesion of MB also showed a significant increase in the punished response 10-14 days after brain lesioning. These results demonstrated the important role of ACE and MB in the mediation of behavioral suppression such as conflict behavior.

A selective κ-opioid agonist, U-50,488H, blocks the development of tolerance to morphine analgesia in rats

The development of tolerance to morphine analgesia was completely blocked by the coadministration of a selective kappa-opioid agonist, U-50,488H at doses of 3.2 or 10 mg/kg i.p. These doses of U-50,488H exerted no analgesic effect by themselves and did not affect the analgesia induced by 10 mg/kg of morphine. The analgesic effect of morphine was restored when 10 mg/kg of U-50,488H was coinjected in morphine-tolerant rats. These findings suggest that activation of the kappa-opioid system prevents the development of tolerance to morphine analgesia.