Neonatal phencyclidine treatment in mice induces behavioral, histological and neurochemical abnormalities in adulthood.

We investigated the involvement of glutamic acid in neural development by injecting phencyclidine (PCP) into neonatal ICR mice. Neonatal mice were injected with PCP at 10 mg/kg or saline on postnatal days 7, 9 and 11, and their behavioral, anatomical and neurochemical changes were analyzed in adulthood. PCP-treated mice exhibited an increase in PCP-induced hyperactivity and impairments of spatial working memory and social interaction behavior. The impairment of social interaction behavior was significantly reversed by administration of clozapine, D-cycloserine, flumazenil, or SHC50911, a gamma-aminobutyrate B (GABA(B)) receptor antagonist. A decrease in the number of parvalbumin-positive cells and spine density in the frontal cortex, nucleus accumbens and hippocampus were evident in the brains of PCP-treated mice. Measurement of brain monoamine and their metabolite contents in adulthood indicated brain area-dependent and neurotransmitter-specific changes in monoamine metabolism. These findings suggest that neonatal treatment with PCP in mice leads to enhanced sensitivity to PCP and impairment of spatial working memory and social interaction behaviors in adulthood, which may be associated with reduced spine density and GABAergic interneurons and changes in monoamine metabolism. Furthermore, pharmacologic experiments suggest the potential applicability of neonatally PCP-treated mice as a useful animal model for new antipsychotic drug screening.

Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model.

The responses of olfactory bulbectomized (OBX) rats to antidepressant treatment are similar to those of depressed patients since chronic administration of an antidepressant reverses OBX-induced behavioral and physiological changes. Previously, using several animal models, it was demonstrated that single treatment with delta-opioid receptor agonists produced an antidepressant-like effect. This study examined the antidepressant effects resulting from subchronic exposure for 8 days to the delta-opioid receptor agonist SNC80 in an OBX rat model of depression. The olfactory bulbs were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed a significant increase in emotionality score and a decrease in the time spent and entries in the open arm of a plus-maze. In the case of OBX rats, these changes were dose- and time-dependently reversed by chronic SNC80 treatment (1-10 mg/kg, s.c.) for 7 days, as same as desipramine (10 mg/kg, i.p.). Moreover, the concentration of 5-HT and its metabolite 5-HIAA in the frontal cortex, hippocampus, and amygdala were decreased in OBX rats, and these changes were also normalized by SNC80 treatment, rather than desipramine treatment. In addition, SNC80 also significantly reversed the loss of TH-positive cells produced by OBX in the dorsal raphe. In conclusion, we demonstrated that subchronic SNC80 treatment could completely reverse OBX-induced behavioral abnormalities and defects in serotonergic function.

Effects of milnacipran and fluvoxamine on hyperemotional behaviors and the loss of tryptophan hydroxylase-positive cells in olfactory bulbectomized rats.

RATIONALE: It has been reported that many of the behavioral and serotonergic neuronal changes observed in olfactory bulbectomy (OBX) were improved by subchronic administration of a variety of antidepressants. OBJECTIVE: We examined the effects of subchronic treatment with milnacipran, a dual serotonin and noradrenaline reuptake inhibitors (SNRIs) and fluvoxamine, selective serotonin reuptake inhibitors (SSRI) in the OBX-induced hyperemotional behaviors and tryptophan hydroxylase (TPH), rate-limiting enzyme of 5-HT. MATERIALS AND METHODS: The olfactory bulbs were removed by suction. Drugs were administered p.o. once daily for 8 days beginning 14 days post-surgery. The hyperemotionality behaviors of OBX rats were measured by rating scale and in the elevated plus-maze test. RESULTS: OBX rats, after milnacipran or fluvoxamine treatment, showed significant decrease in the score of hyperemotional responses on 7th day as compared with vehicle-treated OBX rats. In addition, milnacipran and fluvoxamine in OBX rats respectively produced a significant increase in the percentage of time spent in and number of entries into open arms in the elevated plus maze test. Furthermore, when 5-HTnergic neuronal function was examined using antibodies against tryptophan hydroxylase (TPH) following the behavioral tests, fluvoxamine significantly reversed the loss of TPH-positive cells produced by OBX in the dorsal raphe. CONCLUSION: We demonstrated that chronic treatment with milnacipran or fluvoxamine was effective to improve both the hyperemotional behavior and the loss of TPH-positive cells seen in OBX rats.