Escitalopram attenuates fear stress-induced increase in amygdalar dopamine following methamphetamine-induced sensitisation: Implications of fine-tuning action of selective serotonin reuptake inhibitors on emotional processing.

Serotonin reuptake inhibitors modulate the serotonergic pathways of the nervous system and are widely used for treating psychiatric conditions such as anxiety and depression. The dopaminergic system is related to the development of these conditions. Previous studies on methamphetamine-sensitised rats (behavioural models of stress vulnerability) have shown increased release of dopamine in response to conditioned stress in the amygdala. This biochemical abnormality was proposed to underlie the pathophysiology of stress vulnerability. However, the effect of serotonin reuptake inhibitors on dopamine levels and its consequent impact on emotional processing is unclear. Here we examined the acute effect of escitalopram, a highly selective serotonin reuptake inhibitor, on fear-related behaviour, baseline dopamine release and dopamine release in response to conditioned fear stress in the amygdala of model rats. Male Sprague-Dawley rats received 2 mg/kg/day, s.c. of methamphetamine for 10 days to sensitise them to the drug, and a fear conditioning paradigm was instituted to model psychological stress. Dopamine changes in the amygdala in response to systemic administration of escitalopram followed by conditioned fear stress were measured using microdialysis and high-performance liquid chromatography. Baseline dopamine release in the amygdala was increased by escitalopram in non-sensitised rats but not in methamphetamine-sensitised rats. Escitalopram attenuated dopamine release in response to the fear-conditioned stimulus in both sensitised and non-sensitised rats. The extent of suppression in methamphetamine-sensitised rats (- 90%) was greater than that in non-sensitised rats (- 48%). These findings suggest that serotonin reuptake inhibitors indirectly stabilise the dopaminergic pathway and modulate emotional processing in the amygdala.

Diazepam suppresses the stress-induced dopaminergic release in the amygdala of methamphetamine-sensitized rat.

Although the benzodiazepine class of drugs has proven useful in treating anxiety symptoms, recent studies yield no consistent empirical support for their use in treating psychiatric disorders. However, animal studies using a fear conditioning paradigm have suggested that benzodiazepines facilitate fear memory extinction, dependent on treatment timing and subject conditions. However, we have no data on the effect of subject conditions. The purpose of this study was to investigate whether the effect of benzodiazepines depends on hypersensitivity to fear-memory processing. We examined the effect of diazepam, a benzodiazepine, on the extracellular dopamine level in the left amygdala of methamphetamine-sensitized, fear-conditioned model rats, using microdialysis and high-performance liquid chromatography. In this model, the dopamine level in the amygdala excessively increases in response to a fear-conditioned stimulus; the phenomenon has been proposed as a biological marker for hypersensitivity to fear-memory processing. Diazepam inhibited this excessive increase. The extent of the inhibitory effect was greater in the sensitized condition. Diazepam alone increased amygdalar dopamine levels under physiological conditions but not under sensitized conditions. Diazepam did not shorten freezing time in any group. These results suggest that diazepam modulates amygdala dopamine with state dependence and that amygdalar dopamine fine-tuning accounts for part of the therapeutic effect of benzodiazepines on fear memory processing. Further investigation is required to identify patients suitable for treatment with benzodiazepines. This is the first report on the pharmacodynamic effects of benzodiazepine on the amygdalar dopamine basal level and on fear memory processing.

Dopamine dynamics during emotional cognitive processing: Implications of the specific actions of clozapine compared with haloperidol.

Clozapine has improved efficacy relative to typical antipsychotics in schizophrenia treatment, particularly regarding emotional symptoms. However, the mechanisms underlying its therapeutic benefits remain unclear. Using a methamphetamine-sensitised rat model, we measured changes in dopamine levels in the amygdalae in response to a fear-conditioned cue, serving as a biochemical marker of emotional cognitive processing disruption in psychosis, for analysing the biochemical mechanisms associated with the clinical benefits of clozapine. We also compared how clozapine and haloperidol affected basal dopamine levels and phasic dopamine release in response to the fear-conditioned cue. Extracellular dopamine was collected from the amygdalae of freely moving rats via microdialysis and was analysed by high-performance liquid chromatography. Clozapine or haloperidol was injected during microdialysis, followed by exposure to the fear-conditioned cue. We analysed the ratio of change in dopamine levels from baseline. Haloperidol treatment increased the baseline dopamine levels in both non-sensitised and sensitised rats. Conversely, clozapine only increased the basal dopamine levels in the non-sensitised rats, but not in the sensitised rats. Although both antipsychotics attenuated phasic dopamine release in both the non-sensitised and sensitised rats, the attenuation extent was greater for clozapine than for haloperidol under both dopaminergic conditions. Our findings indicate that stabilized dopamine release in the amygdalae is a common therapeutic mechanism of antipsychotic action during emotional processing. However, the specific dopaminergic state-dependent action of clozapine on both basal dopamine levels and stress-induced dopamine release may be the underlying mechanism for its superior clinical effect on emotional cognitive processing in patients with schizophrenia.

[The benzodiazepines use disorder].

Benzodiazepines are widely used as anti-anxiety drugs and sleeping drugs. On the other hand, it is also true that use disorders such as abuse or dependence is often a problem. Including the distinctive usual dose depends on the BZ drugs use disorders, I outlined the actual situation, diagnostic criteria, and the treatment.

Risk factors for the transmission of foot-and-mouth disease during the 2010 outbreak in Japan: a case-control study.

BACKGROUND: In 2010, foot-and-mouth disease (FMD) occurred for the first time in a decade in Japan. Movement or shipment of people and animals around infected farms was restricted; however these contingency measures proved insufficient to prevent FMD spread. Consequently, a total of 292 farms were confirmed as infected during this outbreak. We conducted a case-control study to identify the risk factors associated with FMD transmission between farms during these restrictions. As there was discordance in the control measures taken, risk factors were examined separately for two areas. Analyses were also performed separately for cattle and pig farms given their different infectivity and susceptibility. RESULTS: For cattle farms in the movement restriction area, the odds of having the factor 'farm equipment was shared with other farms' was significantly higher for case farms than for control farms. For cattle farms in the shipment restriction area, the odds of having the factors 'feed transport vehicles visited the farm' and 'staff of livestock-related companies visited the farm' were significantly higher on case farms than control farms. In pig farms in the movement restriction area, the odds of having factor 'farm staff commuted from outside' was 20 times higher for case farms than control farms. In addition, case farms were less likely to have the factors 'fattening farm' and 'barn has physical barriers' compared with control farms. CONCLUSIONS: In the movement restriction area, the disease was likely to spread regardless of the movement of people and vehicles, and physical barriers were found to be a protective factor. Therefore, physical barriers from the surrounding environments seemed to prevent farms from being infected. Conversely, in the shipment restriction area, movement of people and vehicles was strongly associated with disease spread. These results allow a better understanding of the risk factors associated with FMD transmission and are useful to enhance future preventive measures against transmission during FMD outbreaks.