Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic ...benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer's disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-beta pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.
An opiate antagonist was found to induce motivational withdrawal signs 24 h or even up to 48 h after a single dose of morphine in rats.
The present study was undertaken to determine whether such a ...withdrawal state would modify the neuronal activity in the brain.
A conditioned place aversion was established following a one-trial paradigm in rats undergoing a single exposure to morphine (10 mg/kg) 24 h prior to naloxone administration (0.5 mg/kg). Subsequently, the expression of the protein product of c-fos gene (c-Fos) following naloxone administration was measured within the extended amygdala.
A significant increase in c-Fos immunoreactivity was seen in the centromedial amygdala (CMA), but not in the bed nucleus of the stria terminalis (BST) and the shell (AcbSh) of the nucleus accumbens (Acb) in rats treated with both morphine and naloxone. Further examination of the distribution of c-Fos-positive neurons along the rostrocaudal axis within CMA showed that the positive neurons distributed throughout this brain area and the caudal level of its central division (the central nucleus of the amygdala, CeA) exhibited the most robust labeling.
Neuronal activity can be increased by naloxone at a dose that produces conditioned place aversion 24 h after a single morphine exposure. CMA, particularly the caudal level of its central division, was of high sensitivity. The current data also suggest a possible involvement of CMA in negative motivational component of precipitated withdrawal from acute morphine dependence.
Aripiprazole is a recently introduced antipsychotic with a unique pharmacological profile, a dopamine partial agonist. Dopaminergic neural transmission has two different components, tonic and phasic, ...which have different physiological functions, but the effects of aripiprazole on tonic and phasic components are not reported.
Studies on antipsychotics including aripiprazole and tonic/phasic dopamine transmission are summarized.
Antipsychotics exert efficacy without extrapyramidal side effects (EPS's) when their occupation of dopamine D2 receptors reaches 65-80%. When a "tightly binding" antipsychotic binds 70% of D2 receptors, the remaining 30% are available for endogenous dopamine to bind. These tight antipsychotics suppress dopamine transmission in both tonic/phasic components equally so that similar proportions are kept. Aripiprazole is effective when >90% of D2 receptors are occupied. In this condition, less than 10% of D2 receptors are available for endogenous dopamine to bind; however, EPS's do not occur because aripiprazole exerts partial dopaminergic agonistic activity. Because the concentration of aripiprazole in the brain is relatively constant and it binds to D2 receptors tightly, the added dopaminergic agonism may show a tonic nature. Thus, aripiprazole suppresses the phasic component relatively more than the tonic component. In contrast, under treatment with "loosely binding" antipsychotics, phasic dopaminergic transmission is relatively preserved.
Tight antipsychotics suppress both tonic and phasic components equally. Aripiprazole suppresses the phasic component relatively more than the tonic; that is, aripiprazole is a phasic corrected component buster. By contrast, suppression of the phasic component by loosely binding antipsychotics may be relatively weak.
Acute administration of typical and atypical antipsychotics has been reported to induce regionally distinct patterns of c-Fos expression in the rat forebrain. Furthermore, atypical index, the ...difference in the extent of increased Fos-like immunoreactivity (Fos-LI) in the nucleus accumbens (NAc) shell versus the dorsolateral striatum (DLSt), has been proposed to classify antipsychotics into typical or atypical antipsychotics. The present study was conducted to investigate the atypical properties of 24 antipsychotics that are used in Japan and blonanserin, a novel 5-HT
2A and D
2 receptor antagonist. We systematically examined the effects of the drugs on Fos-LI in the NAc and DLSt in the rat brain using immunohistochemistry and calculated the atypical index, comparing with those of haloperidol and clozapine. Floropipamide, oxypertine, nemonapride, pimozide and mosapramine, as well as clozapine, olanzapine, quetiapine and risperidone, showed high positive atypical index. Zotepine, perospirone, sulpiride, moperone, sultopride, thioridazine, carpipramine, clocapramine and blonanserin showed moderate ones. In contrast, fluphenazine, bromperidol, timiperone, spiperone, propericiazine, perphenazine, chlorpromazine and levomepromazine had negative atypical index like haloperidol. These results suggest that not only so-called atypical antipsychotics, but also several conventional drugs, possess atypical properties.
Case 1 A 57-yr-old male had his first depressive episode with insomnia, loss of concentration, and suicidal ideas at age 22 yr. He was diagnosed with bipolar I disorder when a manic episode occurred ...at age 38 yr. Because antidepressants induced rapid mood changes, he was hospitalized 14 times and lost his job at the age of 50. Since his last hospitalization when he was aged 51 yr, his symptoms were relatively stable under a medication regimen of 1000 mg/d lithium carbonate and 600 mg/d carbamazepine.
Acute morphine exposure has been hypothesized to produce long-lasting central changes that contribute to the withdrawal aversion. We have most recently demonstrated that those changes may involve the ...glutamatergic system, including multiple classes of receptors. The present study was undertaken to further determine the involvement of the glutamatergic system by examining the effect of riluzole, a glutamate release inhibitor, on the motivational component of withdrawal from acute morphine dependence. The role of the amygdala in the action of riluzole was also assessed. We investigated the effects of riluzole on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h before, and on c-Fos expression within the amygdala during the withdrawal period in rats. Riluzole (2, 4, 8 mg/kg) dose-dependently attenuated the CPA without producing place conditioning itself. This result provided further evidence that glutamatergic mechanisms may be recruited in adaptational changes following acute morphine exposure and play a role in withdrawal aversion. In addition, riluzole appeared to produce nonspecific effects on c-Fos expression by itself, without specifically modifying c-Fos expression following naloxone-precipitated withdrawal in any region of the amygdala examined, suggesting that the amygdala may not serve as a specific site of action for riluzole.
This study examined the extent to which chronic d-amphetamine administration sensitizes animals to some behavioral and neurochemical effects of foot shock stress. Rats received daily injections of ...saline for 14 days or d-amphetamine (2 mg/kg 7 days and 4 mg/kg 7 days). After a 7 day drug abstinent period, extracellular dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations were measured in the medial prefrontal cortex using in vivo microdialysis in freely moving rats. The behavioral responses to mild foot shock stress were enhanced in the d-amphetamine-pretreated subjects. Concomitant with this behavioral sensitization, d-amphetamine-pretreated subjects showed greater stress-induced increases in extracellular dopamine in the medial prefrontal cortex than in controls. d-Amphetamine (2 mg/kg)-induced stereotyped behavior was also enhanced in the amphetamine-pretreated animals compared to controls; however, d-amphetamine-induced increases in extracellular dopamine in the medial prefrontal cortex were not enhanced in the amphetamine-pretreated group. These results suggest that the mesocortical dopaminergic system is involved in cross-sensitization between d-amphetamine and stress, but not in d-amphetamine-induced behavioral sensitization.
Repeated administration of cocaine in animals results in behavioral sensitization. In order to investigate the neurochemical mechanism underlying such behavioral sensitization, we designed the ...following two experiments. In both experiments, rats were pretreated with cocaine (20 mg/kg i.p.) or saline, once daily for 14 consecutive days. Exp. 1: 7 days after withdrawal from the drug, the stereotyped behavioral response to a challenge of cocaine (20 mg/kg i.p.) was measured. Exp. 2: 7 days after withdrawal from the drug, we measured extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) after the challenge administration of cocaine using an in vivo intracerebral dialysis technique. The rats pretreated with cocaine (20 mg/kg i.p.) exhibited behavioral augmentation in response to a challenge of cocaine. The challenge administration of cocaine caused an increase in DA and a decrease in DOPAC. The DA level in the striatal perfusates of the cocaine-pretreated rats was significantly greater than that in the saline-pretreated rats. These results suggest that the increased extracellular DA concentration in the striatum plays an important role in the cocaine-induced behavioral sensitization.
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