Involvement of catecholaminergic and GABAAergic mediations in the anxiety-related behavior in long-term powdered diet-fed mice.

Dietary habits are important factors which affect metabolic homeostasis and the development of emotion. We have previously shown that long-term powdered diet feeding in mice increases spontaneous locomotor activity and social interaction (SI) time. Moreover, that diet causes changes in the dopaminergic system, especially increased dopamine turnover and decreased dopamine D4 receptor signals in the frontal cortex. Although the increased SI time indicates low anxiety, the elevated plus maze (EPM) test shows anxiety-related behavior and impulsive behavior. In this study, we investigated whether the powdered diet feeding causes changes in anxiety-related behavior. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control). The percentage (%) of open arm time and total number of arm entries were increased in powdered diet-fed mice in the EPM test. We also examined the effects of diazepam, benzodiazepine anti-anxiety drug, bicuculline, GABA-A receptor antagonist, methylphenidate, dopamine transporter (DAT) and noradrenaline transporter (NAT) inhibitor, atomoxetine, selective NAT inhibitor, GBR12909, selective DAT inhibitor, and PD168077, selective dopamine D4 receptor agonist, on the changes of the EPM in powdered diet-fed mice. Methylphenidate and atomoxetine are clinically used to treat attention deficit/hyperactivity disorder (ADHD) symptoms. The % of open arm time in powdered diet-fed mice was decreased by treatments of atomoxetine, methylphenidate and PD168077. Diazepam increased the % of open arm time in control diet-fed mice, but not in powdered diet-fed mice. The powdered diet feeding induced a decrease in GABA transaminase, GABA metabolic enzymes, in the frontal cortex. Moreover, the powdered diet feeding induced an increase in NAT expression, but not DAT expression, in the frontal cortex. These results suggest that the long-term powdered diet feeding may cause low anxiety or impulsivity, possibly via noradrenergic and/or dopaminergic, and GABAAergic mediations and increase the risk for onset of ADHD-like behaviors.

Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice.

Our previous study suggested that the non-competitive N-methyl-d-aspartate receptor antagonist memantine (MEM) inhibits dopamine (DA) reuptake and turnover by inhibiting brain monoamine oxidase. Clinical studies have reported that MEM may improve depressive symptoms; however, specific mechanisms underlying this effect are unclear. We performed emotional behavior, tail suspension, and forced swimming tests to examine whether MEM has antidepressant effects in olfactory bulbectomized (OBX) mice, an animal model of depression. Subsequently, we investigated the effects of MEM on the distribution of tyrosine hydroxylase (TH), altered microglia morphometry, and astrocyte and cell proliferation in the hippocampus with immunohistochemistry. We also investigated MEM effects on the levels of norepinephrine (NE), DA, and their metabolites with high performance liquid chromatography, and of neurotrophic, proinflammatory, and apoptotic molecules in the hippocampus with western blotting. Forty-two days after surgery, OBX mice showed depressive-like behaviors, as well as decreased levels of monoamines, reduced cell proliferation, and lower levels of TH, phospho(p)-TH (ser31 and ser40), p-protein kinase A (PKA), p-DARPP-32, p-ERK1/2, p-CREB, brain-derived neurotrophic factor (BDNF), doublecortin, NeuN, and Bcl-2 levels. In contrast, the number of activated microglia and astrocytes and the levels of Iba1, GFAP, p-IκB-α, p-NF-κB p65, TNF-α, IL-6, Bax, and cleaved caspase-3 were increased in the hippocampus. These changes (except for those in NE and Bax) were reversed with chronic administration of MEM. These results suggest that MEM-induced antidepressant effects are associated with enhanced hippocampal cell proliferation and neuroprotection via the PKA-ERK-CREB-BDNF/Bcl-2-caspase-3 pathway and increased DA levels.

Time-dependent role of prefrontal cortex and hippocampus on cognitive improvement by aripiprazole in olfactory bulbectomized mice.

Dopamine (DA) modulates cognitive functions in the prefrontal cortex (PFC) and hippocampus. Olfactory bulbectomy (OBX) in mice induces cognitive dysfunctions. Recently, we reported that aripiprazole (ARI) normalizes the behavioral hyper-responsivity to DA agonists in OBX mice. However, it remains unclear whether ARI affects OBX-induced cognitive dysfunctions. To address this question we evaluated ARI-treated and untreated OBX mice in a passive avoidance test. Then, we investigated the effects of ARI on cell proliferation in the hippocampal dentate gyrus by immunohistochemistry, and on c-fos levels in the PFC and hippocampus, as well as nerve growth factor (NGF) levels in the hippocampus by western blotting. On the 14th day after surgery OBX mice showed an alteration in passive avoidance and decreases in both cell proliferation and levels of p-ERK, p-CREB and NGF in the hippocampus. The cognitive dysfunctions in OBX mice improved 30min to 24h after the administration of ARI (0.01mg/kg). C-fos levels in the PFC but not in the hippocampus was increased 30min after the administration (early response). This early response was inhibited by the selective D1 receptor antagonist SCH23390. Cell proliferation and NGF levels in the hippocampus increased 24h after ARI administration (late response), and these effects were also inhibited by SCH23390. The MEK1/2 inhibitor U0126 prevented ARI from improving the behavioral impairment as well as enhancing NGF levels in OBX mice. These findings revealed the potential of ARI to improve cognitive dysfunctions via D1 receptors with the PFC and hippocampus being affected sequentially.

Effects of methylphenidate on the impairment of spontaneous alternation behavior in mice intermittently deprived of REM sleep.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. We have previously shown that abnormal behaviors elicited by intermittent rapid eye movement (REM) sleep deprivation stress may fulfill the profile of a model of ADHD. It is well known that the impairment of spontaneous alternation behavior (SAB) in the Y-maze indicates inattentive features of ADHD model animals. On the other hand, it has been reported that nitric oxide (NO) in the hippocampus is required for SAB. In this study, using mice, we investigated whether intermittent REM sleep deprivation stress causes changes in SAB and the expression of NO synthase (NOS) mRNA and in the levels of NO metabolites in the hippocampus. Mice were deprived of REM sleep intermittently by the small-platform method (20 h/day) for 3 days. The SAB, the level of nitrite and expression of endothelial NOS (eNOS) and inducible NOS (iNOS) mRNA in the hippocampus, but not neuronal NOS (nNOS), were significantly decreased by intermittent REM sleep deprivation stress. The decreased levels of SAB, nitrite and iNOS mRNA were significantly increased by methylphenidate treatment, which is used clinically to treat ADHD symptoms. Moreover, these improvement effects of methylphenidate on SAB and the nitrite level were decreased by the administration of selective iNOS and eNOS inhibitors. However, the eNOS inhibitor decreased both nitrate and total NOx levels of the hippocampus in saline treated intermittent REM sleep-deprived mice. These results suggest that the impairment of SAB induced by intermittent REM sleep deprivation stress may serve as a model of the inattention symptom in ADHD. Further, the ameliorating effects of methylphenidate on the impairment of SAB may be mediated through NO production mainly by iNOS in the hippocampus of mice.

Alterations in behavioral responses to dopamine agonists in olfactory bulbectomized mice: relationship to changes in the striatal dopaminergic system.

BACKGROUND: Olfactory bulbectomy (OBX) in rodents is considered a putative animal model of depression. It has been reported that some abnormal behaviors observed in this animal model of depression involve dopaminergic neurons of the mesolimbic pathway. Therefore, we examined changes in the dopaminergic system in the caudate putamen (CPu), nucleus accumbens core (NAcC), and shell (NAcSh) of OBX mice and whether or not these alterations were reversed by chronic administration of imipramine. METHODS: We observed climbing behavior, which is a dopamine (DA) receptor-associated behavior, to demonstrate changes in the dopaminergic system of the mesolimbic pathway, when mice were administrated either the nonselective DA agonist apomorphine only or were pre-treated with the selective D1 antagonist SCH23390, with the selective D2 antagonist sulpiride, or with the D2/D3 partial agonist aripiprazole (ARI). Moreover, we examined tyrosine hydroxylase (TH) and D1- and D2-like receptor levels in the CPu, NAcC, and NAcSh using immunohistochemistry and autoradiography. RESULTS: The OBX group exhibited significantly enhanced apomorphine-induced climbing behavior, and this enhanced behavior was reversed by administration of sulpiride, ARI, and imipramine but not SCH23390. Moreover, we found a reduction in TH levels in the CPu, NAcC, and NAcSh of OBX mice and an increase in D2 receptor densities in the NAcC of OBX mice. The increased D2 receptor density observed in OBX mice was reversed by imipramine administration. CONCLUSIONS: These findings reveal that OBX mice display enhanced DA receptor responsiveness, which may relate to some of the behavioral abnormalities reported in this animal model.

Influence of a long-term powdered diet on the social interaction test and dopaminergic systems in mice.

It is well known that the characteristics of mastication are important for the maintenance of our physical well-being. In this study, to assess the importance of the effects of food hardness during mastication, we investigated whether a long-term powdered diet might cause changes in emotional behavior tests, including spontaneous locomotor activity and social interaction (SI) tests, and the dopaminergic system of the frontal cortex and hippocampus in mice. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control). The dopamine turnover and expression of dopamine receptors mRNA in the frontal cortex were also evaluated. Spontaneous locomotor activity, SI time and dopamine turnover of the frontal cortex were increased in powdered diet-fed mice. On the other hand, the expression of dopamine-4 (D4) receptors mRNA in the frontal cortex was decreased in powdered diet-fed mice. Moreover, we examined the effect of PD168077, a selective D4 agonist, on the increased SI time in powdered diet-fed mice. Treatment with PD168077 decreased the SI time. These results suggest that the masticatory dysfunction induced by long-term powdered diet feeding may cause the increased SI time and the changes in the dopaminergic system, especially dopamine D4 receptor subtype in the frontal cortex.

Chronic fluvoxamine treatment changes 5-HT(2A/2C) receptor-mediated behavior in olfactory bulbectomized mice.

AIMS: Olfactory bulbectomy (OBX) in rodents represents a valuable experimental model of depression. This study was designed to shed further light on the impact of putative serotonergic neuronal degeneration in OBX mice and to assess the effect of a widely used antidepressant on serotonergic related behavioral changes induced by OBX. MAIN METHODS: Adult male ddY mice were subject to bilateral OBX or sham surgery. The serotonin (5-HT)(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) enhanced a head-twitch response (HTR) in OBX mice. Effects of 5-HT(2A), 5-HT(2C) antagonists and fluvoxamine were observed in OBX mice following DOI administration. KEY FINDINGS: The HTR elicited by the administration of DOI (0.5 mg/kg and 1 mg/kg, i.p.) was increased about twofold in OBX mice when compared with controls on the 14th day after the surgery. The injection of ketanserin (0.025 mg/kg, i.p.), a 5-HT(2A) receptor antagonist, inhibited the enhancement of the DOI-induced HTR after OBX. Likewise, the administration of SB 242084 (1 mg/kg, s.c.), a 5-HT(2C) receptor antagonist, also inhibited the DOI-induced HTR in OBX mice. Chronic but not acute treatment with the antidepressant fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), suppressed the enhancement of DOI-induced HTR after OBX. SIGNIFICANCE: These findings indicate that OBX, and the subsequent degeneration of neurons projecting from the olfactory bulb, caused a supersensitivity of 5-HT(2A/2C) receptors which may be involved in symptoms of depression.

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.

p-Hydroxyamphetamine causes prepulse inhibition disruptions in mice: contribution of dopamine neurotransmission.

It is well known that amphetamine induces disrupted prepulse inhibition (PPI) in humans and rodents. We have previously reported that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine (p-OHA) induces multiple behavioral responses, such as increased locomotor activity and head-twitch response in rodents. To reveal the characteristics of p-OHA on sensorimotor function in rodents, herein we tested the effects of p-OHA on PPI in mice. i.c.v. administration of p-OHA dose-dependently induced PPI disruptions for all prepulse intervals tested. This effect of p-OHA on PPI was attenuated by pretreatment with haloperidol or clozapine. p-OHA-induced PPI disruptions were also attenuated by pretreatment with L-741,626 (a selective D(2) receptor antagonist), L-745,870 (a selective D(4) receptor antagonist) or 6-hydroxydopamine (a neurotoxin which targets DA-containing neurons), but not by SCH 23390 (a selective D(1) receptor antagonist), eticlopride (a D(2)/D(3) receptor antagonist) or GBR 12909 (a DA-reuptake inhibitor). These results indicate that selective blockade of either the D(2) or D(4) receptor subtype may prevent disruption of PPI induced by p-OHA via presynaptic DA release.

Effects of atomoxetine on levels of monoamines and related substances in discrete brain regions in mice intermittently deprived of rapid eye movement sleep.

An imbalance between noradrenergic and dopaminergic systems is implicated in hyperactivity disorders, such as attention deficit/hyperactivity disorder (ADHD). We previously showed that the explosive jumping behavior elicited by intermittent rapid eye movement sleep deprivation (REMSD) may serve as a useful model of ADHD (see [Biogenic Amines, 20, 99-111]). Here, we investigated whether intermittent REMSD might cause changes in monoamine turnover in the mouse forebrain. Our main findings were as follows. Intermittent REMSD led to a significant decrease in dopamine turnover and a significant increase in noradrenaline turnover in the frontal cortex. The latter effect, but not the former, was attenuated by atomoxetine, which is used clinically to treat ADHD symptoms. These results suggest (a) that intermittent REMSD induces hypernoradrenergic and hypodopaminergic states within the frontal cortex, and (b) that the therapeutic effects of atomoxetine may include an inhibition of this hypernoradrenergic state.

Central administration of p-hydroxyamphetamine produces a behavioral stimulant effect in rodents: evidence for the involvement of dopaminergic systems.

RATIONALE AND OBJECTIVES: It is well-known that amphetamine induces increased locomotor activity in rodents. We previously found that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine (p-OHA), an amphetamine metabolite, increases synaptic dopamine (DA) levels in the striatum. In the present study, we investigated the effect of p-OHA on locomotor activity in rodents. RESULTS: In mice, i.c.v. administration of p-OHA significantly increased locomotor activity in a dose-dependent manner. p-Hydroxynorephedrine, another amphetamine metabolite, did not increase locomotor activity. This effect of p-OHA was inhibited by pretreatment with nomifensine, a dopamine-uptake inhibitor, but not by fluoxetine, a serotonin-uptake inhibitor, or diethyldithiocarbamate, a dopamine-beta-hydroxylase inhibitor. Furthermore, we tested the effects of microinjections of p-OHA into the rat nucleus accumbens (NAc) on locomotor activity. Local infusion of p-OHA into the NAc significantly increased locomotor activity. As in mice, the increased locomotor activity induced by p-OHA microinjection into the NAc in rats was inhibited by nomifensine. CONCLUSIONS: These data suggest that dopaminergic systems in the NAc may play important roles in p-OHA-induced locomotor activity in rodents.

Influence of memantine on brain monoaminergic neurotransmission parameters in mice: neurochemical and behavioral study.

Memantine, a non-competitive antagonist of NMDA receptors, has recently been used in Alzheimer's disease. The influences of memantine on behavioral changes, monoamine oxidase (MAO) activity and reuptake of both serotonin (5-HT) and dopamine in mice were examined in the present study. Memantine dose-dependently increased locomotor activity. This effect was inhibited by intraperitoneal (i.p.) administration of haloperidol. Furthermore, administration [intracerebroventricular (i.c.v.)] of memantine did not induce the head-twitch response (HTR). However, the 5-HT-induced HTR was potentiated by the combined administration of memantine. The enhanced HTR was inhibited by i.p. administration of haloperidol or 5-HT(2A) antagonist ketanserin. Memantine at 1 mM inhibited both MAO-A and MAO-B activities in mouse forebrain homogenates to 37% and 64% of controls, respectively. Lineweaver-Burk plots analysis revealed competitive inhibition with both MAO-A and MAO-B. The inhibitions were also reversible. Memantine inhibited the reuptake of both 5-HT and dopamine into mouse forebrain synaptosomes. 5-HT and dopamine reuptakes were inhibited to 2% and 16% of controls, respectively, with 1 mM memantine. These findings suggest that the increased locomotor activity and enhanced 5-HT-induced HTR by memantine may result from the reuptake and turnover inhibitions of 5-HT and dopamine.

Subchronic stress-induced depressive behavior in ovariectomized mice.

AIMS: Mood disorders including depression are more common in women than men, particularly in times of lower estradiol levels. In this study, we investigated the effect of estrogen on emotional behavior in mice in a stress environment. MAIN METHODS: Female mice were divided into four groups: two groups were ovariectomized (OVX) and two were sham-operated. One group each of OVX and sham mice was kept in a normal environment and the other groups were assigned to a daily stress (1 h/day) for 7 days from 5 days after operation. On the 14th day after operation, subjects were measured to assess behavioral specificity, locomotor activity, elevated plus-maze (EPM) behavior, passive avoidance (PA) behavior and forced swimming behavior. KEY FINDINGS: The OVX plus stress (OVX+S) group showed a significant prolongation of immobility compared with the other groups. In all the groups there were no changes in locomotor activity, EPM behavior or PA behavior. We further examined the effect of estrogen against depressive behavior in the OVX+S group. The vehicle or 17beta-estradiol (E2) was administered s.c. to OVX+S mice for 4 days beginning on post-operative day 11. Subchronic E2 treatment decreased the stress response and improved depressive behavior relative to the vehicle group. SIGNIFICANCE: These data have important implications regarding the prevention of depression in postmenopausal women undergoing estrogen therapy.

Cysteine protease inhibitors suppress the development of tolerance to morphine antinociception.

The effects of various protease inhibitors on the development of antinociceptive tolerance to morphine were examined in mice. Intrathecal (i.t.) administration of morphine (0.01-1 nmol) produced a dose-dependent and significant antinociceptive effect in the 0.5% formalin test. When the doses of morphine (mg/kg, s.c. per injection) were given as pretreatment twice daily for two days [first day (30) and second day (60)], i.t. administration of morphine (0.1 nmol) was inactive due to antinociceptive tolerance on the third day. Tolerance to i.t. morphine was significantly suppressed by the i.t. injection of N-ethylmaleimide or Boc-Tyr-Gly-NHO-Bz, inhibitors of cysteine proteases involved in dynorphin degradation, as well as by dynorphin A, dynorphin B and (-) U-50,488, a selective kappa-opioid receptor agonist. On the other hand, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, lisinopril, an angiotensin-converting enzyme inhibitor, and phenylmethanesulfonyl fluoride, a serine protease inhibitor, were inactive. These results suggest that cysteine protease inhibitors suppress the development of morphine tolerance presumably through the inhibition of dynorphin degradation.

Alterations in cognitive function in prepubertal mice with protein malnutrition: relationship to changes in choline acetyltransferase.

We have found that protein malnutrition (PM) causes a significant impairment of memory-related behavior on the 15th and 20th day after the start of PM (5% casein) feeding in prepubertal mice but not in postpubertal mice, as measured by a passive-avoidance task. This impairment was almost completely reversed by merely switching to a standard protein (20% casein) diet on the 10th day after the start of PM. However, the reversal was not observed when the switching to a standard protein regimen was done on the 15th day of the PM diet. Interestingly, the impairment of memory-related behavior on the 20th day was improved by the chronic administration of physostigmine (0.1 mg/kg/day x last 10 days, i.p.), a cholinesterase inhibitor. To correlate brain cholinergic neuron function with the memory-related behavior impairment induced by PM, microphotometry was used to determine the histological distribution of the imunofluorescence intensity for choline acetyltransferase (ChAT), a functional marker of presynapse in cholinergic neurons. The change in the intensity of fluorescence indicated that ChAT protein was decreased in the hippocampus (CA1, CA3 and dentate gyrus) on the 20th day after PM feeding in comparison with controls. These results suggest the possibility that the memory-related behavior deficits observed in prepubertal mice with PM are caused by a dysfunction of the cholinergic neurons in the hippocampus.

[Dysfunction of serotonergic systems in thiamine-deficient diet fed mice: effects of SSRI on abnormality induced by thiamine deficiency].

Mice fed a thiamine deficient (TD) diet, showed some abnormal behaviors such as amnesia and mood abnormality. It is known that several neurons, especially marked in serotonergic neuron, are damaged in humans and rodents in the earlier phase of TD. The symptoms derived from dysfunction of serotonergic neurons are observed in Wernicke-Korsakoff patients (WKS)-derived TD, and it is known that fluvoxamine is effective for WKS. However, the mechanism of this dysfunction is still unclear. For that reason, we studied the relative mechanism between abnormal behaviors and selective dysfunction of serotonergic neurons in TD animals. As a result, this dysfunction by TD is much affected by the brainstem region. But the effect of fluvoxamine on depressive symptoms in WKS patients is not reported; therefore we also studied the effects of fluvoxamine on the depressive behaviors in TD mice as a model of WKS. The increase of immobility time in a forced swimming test as depressive behavior in TD mice was significantly inhibited by fluvoxamine, suggesting an improvable effect on depressive symptoms. With those results of ours, the possible mechanisms between the abnormal behaviors derived from the dysfunction of serotonergic neurons and the role of serotonin in TD and WKS are reviewed here.

Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives.

It is well known that head-twitch response (HTR) in mice represents hallucinations, since administration of lysergic acid diethylamide (LSD) produces hallucinations in humans, and the HTR in mice is induced by administration of LSD as a hallucinogen. The HTR is produced by excitation of 5-hydroxytryptamine (5-HT)2A receptors. In this paper, we review the mechanisms of HTR induced by various drugs such as 5-HT precursor, 5-HT receptor agonist, 5-HT releaser, hallucinogenic compounds, benzodiazepins and cannabinoid. The response induced by HTR-inducers is significantly enhanced by combined treatment with a non-selective form of monoamine oxidase (MAO) inhibitor. Thus, the relationship between MAO activity and HTR caused by these drugs (especially, alpha-methylated analogous compounds which 5-fluoro-alpha-methyltryptamine, 6-fluoro-alpha-methyltryptamine and p-hydroxyamphetamine) is presented in detail.

Immunohistochemical fluorescence intensity reduction of brain somatostatin in the impairment of learning and memory-related behaviour induced by olfactory bulbectomy.

The role of brain somatostatin (SST) on memory function after olfactory bulbectomy (OBX) was investigated by using the passive-avoidance task and immunohistochemical analyses in mice. The present study indicated that the learning and memory-related behaviour was impaired on the 7th and 14th day, but not on the 1st day after OBX. The impairment of learning and memory-related behaviour on the 14th day after OBX was dose-dependently reversed by intracerebroventricularly administered SST (1 microg per mouse). To ascertain the correlation between SST in mouse brain and the impairment of learning and memory-related behaviour induced by OBX, the immunohistochemical distribution of brain SST was determined by fluorescence intensity using two-dimensional microphotometry. The intensity of SST fluorescence was low in the hippocampus on the 14th day after OBX in comparison with Sham controls. These results suggest that SST in the hippocampus is related to the impairment of learning and memory-related behaviour induced by OBX.

Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy.

Memory function after olfactory bulbectomy (OBX) was examined in two tasks, namely, step-through passive avoidance task and elevated plus-maze task. OBX mice showed a significant impairment of learning and memory-related behavior on the 7th and 14th day, as measured by passive avoidance task but not elevated plus maze task. The impairment of learning and memory-related behavior on the 14th day was improved by administration of the cholinesterase inhibitor physostigmine (0.1 mg/kg, i.p.), the non-selective muscarinic agonist oxotremorine (0.1 mg/kg, i.p.) or the selective muscarinic M(1) agonist McN-A-343 (10 microg/mouse, i.c.v.). In contrast, administration of the nicotinic agonist lobeline (5-9.8 mg/kg, i.p.) or the selective muscarinic M(2) antagonist methoctramine (2.25-18 microg/mouse, i.c.v.) has no effect on the impairment of learning and memory-related behavior induced by OBX. In addition, we have demonstrated that the intensity of choline acetyltransferase (ChAT) fluorescence is significantly decreased in the cortex, hippocampus and amygdala on the 14th day after OBX. These results suggest that the impairment of learning and memory-related behavior induced by OBX may be caused by degeneration of cholinergic neurons and muscarinic M(1) receptors play an important role in the improvement process.