PPAR alpha as a therapeutic target of psychiatric diseases

Currently available psychopharmacological therapies have limited efficacies; consequently, developing novel pharmacological targets beyond the existing ones for treating mood disorders has become increasingly critical. Increasing preclinical evidences that peroxisome proliferator-activated receptor alpha PPAR-α agonists can impact mood regulation have opened a new line of research in psychopharmacological discovery. However, the effects of clofibrate; a fibric acid derivative acting as a synthetic PPAR-α agonist; on psychiatric behavior are poorly understood. The present thesis was designed to evaluate the prospective anxiolytic and antipsychotic effect of the synthetic PPAR-α agonist clofibrate in pharmacological animal models of anxiety and schizophrenia in Sprague-Dawley rats. Open field test, social interaction test, and elevated plus maze test were used to evaluate anxiety-like behaviors after clofibrate treatments. Anxiogenic effects were produced upon injecting clofibrate (25 mg/kg) acutely, by increasing the number of entries and time spent in the corners of the open field test, and decreasing the duration of time spent in social interaction in the social interaction test. These effects were normalized in the open field test after giving clofibrate once daily for 3 consecutive days only, and reversed into anxiolytic effects upon chronic treatment. In contrast, no significant effects were detected in the elevated plus maze test by acute clofibrate treatment. Moreover, it has been showed that an acute administration of the non-competitive N-methyl-D-aspartate receptor antagonist phencyclidine (PCP 5 mg/kg intraperitoneally), or amphetamine (Amph 3 mg/kg intraperitoneally), was able to induce positive-like symptoms of schizophrenia such as hyperactivity, stereotypies and impaired sensorimotor gating in the prepulse inhibition (PPI) test of the acoustic startle reflex. Using these glutamatergic and dopaminergic models, we found that an acute injection of clofibrate, at dose that by itself does not affect spontaneous locomotor activity (25 mg/kg), was unable to revert hyperlocomotion, stereotypies and impaired PPI induced by the acute injections of phencyclidine or amphetamine. However, when we used the sub-chronic treatment of PCP (5 mg/kg i.p. twice day for 7 consecutive days) that induced cognitive deficits in the novel object recognition (NOR) test, acute clofibrate (25 mg/kg i.p.) that by itself does not affect recognition memory in NOR paradigm, was able to significantly attenuate the cognitive deficits. In preclinical research, catalepsy is an animal behavior widely used to evaluate the antipsychotic-induced extrapyramidal symptoms in humans. Compared to haloperidol, clofibrate did not induce catalepsy in the bar test at any dose tested (100, 250 and 500 mg/kg i.p.). Finally, the activity of clofibrate (25 mg/kg) was also obtained by determining the levels of dopamine, serotonin and and their metabolites in the prefrontal cortex, nucleas accumbens, striatum, amygdala, hippocampus and hypothalamus of rats, following the acute and chronic administration regimes. No significant alteration in the selected neurotransmitters and their metabolites was revealed in any brain site upon acute administration of clofibrate (25 mg/kg). In contrast, the chronic administration of clofibrate at the same dose showed some significant alterations in the selected neurotransmitters and their metabolites, manifested as a reduction the levels of dopamine and its metabolites; DOPAC and HVA, in the amygdala, the levels of DOPAC and HVA in the prefrontal cortex, and the level of the serotonin metabolite 5-HIAA in both the hippocampus.