Repeated fluvoxamine treatment recovers early postnatal stress-induced hypersociability-like behavior in adult rats.

Childhood maltreatment is associated with impaired adult brain function, particularly in the hippocampus, and is not only a major risk factor for some psychiatric diseases but also affects early social development and social adaptation in later life. The aims of this study were to determine whether early postnatal stress affects social behavior and whether repeated fluvoxamine treatment reverses these changes. Rat pups were exposed to footshock stress during postnatal days 21-25 (at 3 weeks old: 3wFS). During the post-adolescent period (10-14 weeks postnatal), the social interaction test and Golgi-cox staining of dorsal hippocampal pyramidal neurons were performed. Following exposure to footshock stress, 3wFS rats showed an increase in social interaction time, which might be practically synonymous with hypersociability, and a decrease in spine density in the CA3 hippocampal subregion, but not in CA1. These behavioral and morphological changes were both recovered by repeated oral administration of fluvoxamine at a dose of 10 mg/kg/day for 14 days. These findings suggest that the vulnerability of the hippocampal CA3 region is closely related to social impairments induced by physical stress during the juvenile period and shed some light on therapeutic alternatives for early postnatal stress-induced emotional dysfunction.

Tandospirone suppresses impulsive action by possible blockade of the 5-HT1A receptor.

Higher impulsivity is observed in several psychiatric disorders and could be a risk factor for drug addiction, criminal involvement, and suicide. Although the involvement of the 5-HT1A receptor in impulsive behavior has been indicated, the effects of clinically relevant drugs have been rarely tested. In the present study, we examined whether (3aR,4S,7R,7aS)-rel-hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dione hydrochloride (tandospirone), an anxiolytic and a partial agonist of the 5-HT1A receptor, could affect impulsive action in the 3-choice serial reaction time task. Rats were acutely administered tandospirone (0, 0.1, and 1 mg/kg, i.p.). Tandospirone decreased the number of premature responses, an index of impulsive action, in a dose-dependent manner. N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635; 0.3 mg/kg, s.c.), a 5-HT1A receptor antagonist, did not reverse the suppressing effects of tandospirone on impulsive action. Moreover, a higher dose of WAY100635 (1 mg/kg, s.c.) suppressed impulsive action without tandospirone. Thus the effects of tandospirone on impulsivity might be due to the antagonistic action. Tandospirone could be a therapeutic candidate for impulsivity-related disorders.

Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex.

RATIONALE: Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action. OBJECTIVES: Our goal was to identify whether D(1)- and/or D(2)-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task. METHODS: The rats were bilaterally injected with SCH23390, a selective D(1)-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D(2)-like receptor antagonist (0.3 or 1 µg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg). RESULTS: Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action. CONCLUSIONS: This is the first report that demonstrates a critical role for D(1)-like receptors of the IL in milnacipran-enhanced control of impulsive action.

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.