[In vivo analysis for mechanism of drug action by juxtacellular recording].

Electrophysiological methods are commonly used in neuroscience and pharmacology to reveal the mechanisms of drug action. In vivo analysis of the mechanisms of drug action is a particularly important method in neuropharmacology. Here, we show the juxtacellular recording method to characterize the electrophysiological and neurochemical properties of neurons. Using juxtacellular recording, researchers can record the membrane potential from single neurons, and examine action potential parameters, such as the width and coefficient variance of inter-spike intervals. Additionally, recorded neurons can be labeled using neurobiotin, and neurochemical properties can be revealed by a combination of immunohistochemical staining and in situ hybridization. We introduce an experiment testing the effects of a phosphodiesterase 4 (PDE4) inhibitor on the fronto-striatal circuit using juxtacellular recording. The cerebral cortex-nucleus accumbens (NAcc)-external segment of globus pallidus (GPe)-subthalamic nucleus (STN)-substantia nigra pars reticulata (SNr) pathway is the neurobiological basis of many neuropsychiatric disorders. Several components of this pathway are particularly important for the regulation of motor action and cognitive function: 1) STN-SNr pathway (hyperdirect pathway), 2) NAcc-SNr pathway (direct pathway), and 3) GPe-STN-SNr pathway (indirect pathway). Researchers can record tri-phasic responses reflecting these pathways using electro-stimulation in cerebral cortex. A PDE4 inhibitor, roflumilast, affected the 2) direct pathway as well as the 3) indirect pathway, but not the 1) hyperdirect pathway. The current findings suggest that PDE4 inhibition could be considered as a possible treatment for cognitive deficits related to fronto-striatal disorders such as attention deficit/hyperactivity disorder, and Parkinson's disease.

Anxiolytic effects of yokukansan, a traditional Japanese medicine, via serotonin 5-HT1A receptors on anxiety-related behaviors in rats experienced aversive stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan, a traditional Japanese medicine (Kampo), has been reported in the treatment of behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety and depression in patients with Alzheimer's disease and other forms of senile dementia. AIMS OF THE STUDY: In the present study, we investigated the anxiolytic effects of yokukansan on anxiety-related behaviors in rats that have experienced aversive stress. MATERIALS AND METHODS: We used male Wistar/ST rats which received an electrical footshock as aversive stress. Yokukansan at a dose of 1.0 g/kg was administered orally once a day for 14 or 16 day before behavioral tests. To evaluate the anxiolytic effects, we used the contextual fear conditioning (CFC) test and elevated plus-maze (EPM) test. And we also investigated effects of yokukansan on locomotor activity in the Open-field (OF) test and on the change in plasma corticosterone after CFC stress, in rats that had experienced footshock stress. RESULTS: In the CFC test, rats that had experienced footshock showed significant freezing behavior on re-exposure to the box 14 day after footshock stress. Yokukansan significantly suppressed freezing behavior in the CFC test. In the EPM test on the 16th day after the CFC test, yokukansan significantly increased the time spent in open arms after footshock stress compared to control rats. However, repeated administration of yokukansan on the 14th day did not affect the decrease in locomotor activity and the increase in plasma corticosterone by re-exposure to the box 14 day after footshock stress in the OF test and determination of serum corticosterone, respectively. These anxiolytic effects by yokukansan were antagonized by WAY-100635, a selective 5-HT(1A) receptor antagonist, in the CFC test, but not the EPM test. Furthermore, 5-HT(1A) receptor agonist buspirone significantly suppressed freezing behavior in the CFC test; however, buspirone induced no change in the time spent in open arms in the EPM test. CONCLUSION: These findings suggested that yokukansan has anxiolytic effects on anxiety-like behaviors induced by both innate fear and memory-dependent fear. In particular, yokukansan produced anxiolytic effects via 5-HT(1A) receptors in memory-dependent fear induced by aversive stress. Furthermore, yokukansan could be useful as one of the therapeutic drugs for the treatment of anxiety disorders and various mental disorders that have comorbid anxiety.

Lithium, but not valproic acid or carbamazepine, suppresses impulsive-like action in rats.

RATIONALE: Higher impulsivity is a pathological symptom in several psychiatric disorders, including bipolar disorder, and is a risk factor for suicide. OBJECTIVES: Our goal was to determine whether major mood-stabilizing drugs used for the treatment of bipolar disorder could suppress impulsive-like action in the three-choice serial reaction time task (3-CSRTT). METHODS: Following training for the 3-CSRTT, rats were acutely administered lithium chloride (LiCl; 0, 3.2, 10, and 32 mg/kg, i.p.), valproic acid (0, 10, 32, and 100 mg/kg, i.p.), or carbamazepine (0, 10, 20, and 30 mg/kg, i.p.). To assess the anorexic effects of lithium, a simple food consumption test was conducted. RESULTS: LiCl dose-dependently decreased the number of premature responses, an index of impulsive-like action. A high dose of LiCl (32 mg/kg) decreased food consumption, but its anorexic effects were not correlated with the effects of LiCl on premature responses. A moderate dose of LiCl (20 mg/kg) significantly reduced the number of premature responses without affecting motivation-related measures in the 3-CSRTT or the amount of food consumption. Although carbamazepine prolonged reward latency, an index of motivation for food, neither valproic acid nor carbamazepine significantly affected premature responses. CONCLUSION: It is likely that lithium has a suppressive effect on impulsive action independent of the anorexic effect. Lithium may suppress impulsive behavior and thereby decrease the risk of suicide. The present results could provide an explanation for the antisuicidal effects of lithium and suggest that lithium could be a beneficial treatment for impulsivity-related disorders.

[Validity of forced swimming as an animal model of depression].

Forced swimming is a brief and excellent assessment method for antidepressant drugs. However, a complete animal model of depression does not exist, because (1) we can not make sure the existence of psychiatric symptoms by interview, (2) individual clinical symptoms of depression were not disease-specific, and (3) there are few reliable biological markers of depression. We tried to summarize these issues by evaluating the validity of forced swimming as an animal model of depression.