Dopamine D2 receptor supersensitivity in the hypothalamus of olfactory bulbectomized mice.

Olfactory bulbectomy (OBX) in rodents induces neurochemical and behavioral changes similar to those observed in individuals with depressive disorders. Our previous study suggested that OBX alters dopaminergic function in the striatum of mice; however, the effects on dopaminergic function in the hypothalamus is unknown. Therefore, in this study we examined dopaminergic system changes in the hypothalamus after OBX. Mice were administrated either the nonselective dopamine (DA) agonist apomorphine or the selective D2 agonist quinelorane, or pretreated with the selective D1 antagonist SCH23390 in combination with the selective D2 antagonist sulpiride or D3 antagonist SB277011A. Body temperature, which is regulated by the hypothalamic dopaminergic system, was monitored to evaluate changes in the dopaminergic system of the hypothalamus. DA D2 receptor (D2DR), tyrosine hydroxylase (TH), and phosphorylated (p)- DA- and cAMP-regulated phosphoprotein-32 (DARPP-32) levels in the hypothalamus were evaluated by western blotting. OBX mice exhibited significantly enhanced apomorphine-induced or quinelorane-induced hypothermia. The apomorphine-induced hypothermic response was reversed by the administration of sulpiride, but not SCH23390 or SB277011A. Moreover, TH and p-DARPP-32 levels were reduced and D2DR increased in the hypothalamus of OBX mice. These findings revealed that the OBX mice display enhanced DA receptor responsiveness associated with the hypothalamus, which may relate to some of the behavioral and neurochemical alterations reported in this animal model. Identification of changes in the hypothalamic dopaminergic system of OBX mice may provide useful information for the development of novel antidepressant treatments.

p-Hydroxyamphetamine causes prepulse inhibition disruption in mice: contribution of serotonin neurotransmission.

p-Hydroxyamphetamine (p-OHA) has been shown to have a number of pharmacological actions, including causing abnormal behaviors such as increased locomotor activity and head-twitch response in rodents. We have recently reported that intracerebroventricular (i.c.v.) administration of p-OHA dose-dependently induces prepulse inhibition (PPI) disruption in mice, which is attenuated by pretreatment with haloperidol, clozapine or several dopaminergic agents. Haloperidol and clozapine have affinities for serotonergic (especially 5-HT(2A)) receptors. To investigate the involvement of the central serotonergic systems in p-OHA-induced PPI disruption, herein we tested several serotonergic agents to determine their effects on p-OHA-induced PPI disruption. p-OHA-induced PPI disruption was attenuated by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a neurotoxin which targets serotonin-containing neurons) and p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor). p-OHA-induced PPI disruption was also attenuated by pretreatment with ketanserin (a 5-HT(2A/2C) receptor antagonist) and MDL100,907 (a selective 5-HT(2A) receptor antagonist). These data suggest that p-OHA-induced PPI disruption may involve increased serotonin release into the synaptic cleft, which then interacts with the post-synaptic 5-HT(2A) receptor.

Pharmacological characterizations of memantine-induced disruption of prepulse inhibition of the acoustic startle response in mice: involvement of dopamine D2 and 5-HT2A receptors.

It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by memantine. However, the mechanism of memantine-induced PPI disruption remains unclear. In the present study, we investigated the effects of memantine on PPI of the ASR in mice. Memantine (1.25-20mg/kg, intraperitoneally) increased the ASR and dose-dependently decreased PPI for all prepulse intensities tested. This effect of memantine on PPI was attenuated by pretreatment with the antipsychotics clozapine (3 and 6 mg/kg), risperidone (0.3mg/kg) and haloperidol (0.5mg/kg), the selective D(2) antagonist sulpiride (40 mg/kg) and 5-HT(2A/2C) antagonist ketanserin (2 and 4 mg/kg) but not with the selective D(1) antagonist SCH23390 (0.05 and 0.1mg/kg). Clozapine (6 mg/kg) and risperidone (0.3 mg/kg) significantly attenuated the increased startle amplitude in the memantine-treated groups. These results suggest that involvement of dopaminergic and/or serotonergic neurotransmission may play a crucial role in memantine-induced PPI disruption, and additionally, indicate that blockade of either the D(2) or 5-HT(2A) receptor may prevent disruption of PPI induced by memantine in mice. Conceivably, memantine may exacerbate psychotic symptoms in patients with PDD and LBD.

Behavioral and neurochemical characterization of mice deficient in the N-type Ca2+ channel alpha1B subunit.

N-type voltage-dependent calcium channels (VDCCs) play an important role in neurotransmission, synaptic plasticity, and brain development. They are composed of several subunits named alpha(1), alpha(2), delta, beta and gamma. The alpha(1) subunit is essential for channel functions and determines fundamental channel properties. Since N-type VDCC are critically involved in the release of neurotransmitters and clinical relevance, we predicted that alpha(1) subunit KO mice would show several alterations in behavior. In the present study, we investigated neuronal functions in mice lacking the alpha(1B) (Ca(V)2.2) subunit of the N-type calcium channels. Ca(V)2.2(-/-) mice exhibited a significant increase in locomotion on an activity wheel during the dark phase. Furthermore, when challenged with apomorphine, mutant mice showed enhanced locomotor activity. Cognitive functions were examined using a Y-maze task for short-term memory and a passive avoidance task for long-term memory. The Y-maze revealed no differences in spontaneous alternation behavior between mutant and wild-type mice. The passive avoidance test revealed that the latency time in mutant mice was significantly decreased. The mutant mice showed prepulse inhibition deficits reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. Decreases in baseline levels of dopamine and serotonin within the striata and frontal cortices of mutant mice were also observed. These results suggest that Ca(2+) in the central nervous system modulates various neurophysiological functions, such as locomotor activity, long-term memory, and sensorimotor gating through the alpha(1B) subunit of the N-type calcium channels.

Preventive effect of kami-untan-to on performance in the forced swimming test in thiamine-deficient mice: relationship to functions of catecholaminergic neurons.

The kampo (Japanese herbal) medicine "kami-untan-to" (KUT) has been used for a long time in the treatment of neuropsychiatric disorders. We have recently reported that mice put on a thiamine-deficient (TD) diet exhibit a depressive behavior and impairment in avoidance learning after 20 days, and that this impairment was reversed by the chronic administration of KUT. In the present study, we investigated the effect of KUT on the depressive behavior observed in TD mice by using the forced swimming test. Our results show that oral administration of KUT from the 1st day of TD feeding prevented the increased duration of immobility in TD mice. Administration of KUT from the 10th day of TD feeding also had a beneficial effect on depressive behavior. To examine the relationship between the potential effects of KUT on monoaminergic neuronal functions and the depressive behavior observed in TD mice, we measured the immunohistochemical distribution of tyrosine hydroxylase (TH) in the brain using microphotometry. The fluorescence intensity of TH decreased in the limbic cortex and brainstem in TD mice compared with pair-fed mice as the control group, while KUT treatment protected against these decreases. These results suggest that KUT treatment may prevent a sign of depressive behavior, the animal immobility time, induced by TD feeding through a mechanism that involves the decrease of TH in some brain areas of TD mice.

Effect of a nutritive-tonic drink on stress-induced serum glucocorticoid in the mouse.

We evaluated stress during "restraint with gnawing (R+G+)" and "restraint without gnawing (R+G-)" in a mouse system. R+G- induced a higher serum glucocorticoid level than R+G+. Zena F-III (a nutritive-tonic drink prescribed as "Kampo", a traditional Japanese medicine with its origin in Chinese medicine) reduced the glucocorticoid elevation in R+G+, but not in R+G-. These results support the hypotheses that (i) activity, such as gnawing, which potentially leading to escape from distress, reduces the severity of emotional distress and (ii) Zena F-III reduces the severity of mental or emotional fatigue, or increases motivation, in a stressful situation that the animal can manage itself.

Effect of nutritive and tonic crude drugs on physical fatigue-induced stress models in mice.

The present study was undertaken to investigate the acute anti-fatigue effect of a liquid nutritive and tonic crude drugs (NTDs) on stress induced in mice. After forced walking for 3 or 6h, the NTDs (applied orally, 10 ml/kg) significantly increased locomotor activity, while the administration of NTDs after rapid eye movement (REM) sleep deprivation stress and after immobilization stress did not show a specific effect, having a similar effect as the vehicle with added vitamins, taurine and caffeine. The administration of NTDs after freezing due to electric shock stress showed a specific effect which was not seen in other control groups, water, vehicle (ethanol) and vehicle including vitamins, taurine and caffeine and so resemble the specific effect of NTDs in the stress of forced walking. The present results indicate that the NTDs produced an anti-fatigue effect on the decreased locomotor activity after forced walking and immobility induced by electric stimulation. However, the crude drugs were not effective in improving immobility after sleep deprivation or immobilization stress.

Suppressive effect of nantenine, isolated from Nandina domestica Thunberg, on the 5-hydroxy-L-tryptophan plus clorgyline-induced head-twitch response in mice.

We investigated the effects of nantenine (9,10-Methylenedioxy-1,2 dimethoxyaporphine), a major alkaloid isolated from the fruit of Nandina domestica Thunb (Berberidaceae), on the 5-HT2A receptor-mediated head-twitch response (HTR) in mice. Intraperitoneal (i.p.) injection of nantenine (13.3, 20 and 30 mg/kg) as well as the 5-HT2A receptor antagonist ketanserin (0.0625, 0.25 and 1 mg/kg) inhibited the 5-hydroxy-L-tryptophan (l-5-HTP; 75 mg/kg, i.p.) plus monoamine oxidase inhibitor, clorgyline (1 mg/kg, i.p.)-induced HTR in a dose-dependent manner. In contrast, neither l-5-HTP plus clorgyline nor 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 5 microg/mouse, i.c.v.)-induced head weaving was affected by nantenine or ketanserin. Furthermore, neither nantenine (up to 30 mg/kg) nor ketanserin (up to 1 mg/kg) affect on the locomotor activity. In the receptor binding studies, nantenine showed affinity to the 5-HT2A receptors (Ki = 0.4 microM), while it had less affinity toward alpha1-adrenergic (Ki = 2.1 microM) and D2-dopaminergic (Ki = 1.7 microM) receptors of the mouse brain. These results suggest that nantenine inhibits l-5-HTP plus clorgyline-induced head- twitch response by blocking 5-HT2A receptors in the central nervous system.