Possibile ruolo dei recettori PPARα in modelli animali di ansia e depressione

Alpha-type peroxisome proliferator-activated nuclear receptors (PPARα), which regulate many important physiological responses such as lipid metabolism, energy balance and inflammation, are the endogenous target of the fatty acid amides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Like the endogenous cannabinoid anandamide (AEA), OEA and PEA are synthetized on demand and are primarily degraded by fatty acid amide hydrolase (FAAH), but do not show affinity for cannabinoid receptors. On the other hand, AEA and other endocannabinoids such as noladin ether and virodhamine, show binding affinity for PPARα receptors and increase their transcriptional activity. Endocannabinoids and PPAR agonists share targets and functions in both the brain and the periphery. Since the endocannabinoid system (ECBs) is involved in several psychiatric disorders like schizophrenia, bipolar disorder and depression, this thesis investigated the role of involvement of OEA and PEA in depression and other disorders. In particular this work characterized the behavioral profiles of OEA and PEA in the tail flick test, elevated plus maze and forced swimming test (FST) in adult male Sprague Dawley rats. For all drugs used in this study, motor activity test was conducted to select doses avoid of any aspecific effect on animal behaviour. Both compounds did not affect the antinociception response of rats in the tail flick test and show neither anxiolytic nor anxiogenic-like effects in the elevated plus maze test. More intriguingly the sub-chronic treatment with OEA (2.5 mg/kg and 5 mg/kg) and PEA (1 mg/kg and 2 mg/kg) significantly decreased the duration of immobility and increased swimming with respect to control rats. The PPARα antagonist MK886, at a dose (1 mg/kg, i.p) that by itself did not show any effect in the FST, fully reversed the effects of OEA and PEA thus confirming the direct involvement of PPARα in the observed antidepressant-like effects. Moreover, the CB1r antagonist/inverse agonist rimonabant, likewise MK886, antagonized the antidepressant-like effect of OEA and PEA, suggesting a possible involvement of the endocannabinoid system. Immunohistochemical staining was conducted on brains of animals treated with OEA and PEA before performing the FST, to evaluate molecular and morphological changes in the hippocampus by studying the expression of glutamic acid decarboxylase (GAD67) and microtubule-associated protein-2 (MAP-2), which are known to be involved in several psychiatric and neurodegenerative diseases. These two markers are modified by drug treatments, in line with behavioral data supporting antidepressant-like effects of OEA and PEA. PPAR also mediate the deactivation (phosphorylation) of nicotinic acetylcholine receptors (nAChRs) which are widely expressed (particularly the α4β2 and 7 nAChR) in brain areas involved in analgesia, anxiety, depression, reward and cognitive functions. Thus the possibility of a link between the cholinergic system, known to be modulated by ECBs, and PPAR was investigated in the FST by using the specific 7 nAChRs agonist PNU282987 (PNU, 3 mg/kg, i.p), alone and in combination with MK886. In support to this, PNU elicits antidepressant-like effect that are reversed by MK886. Although the mechanisms through which OEA and PEA exert antidepressant –like effects are still to be clarified, the present study suggests that these compounds could have a role in the neurobiology of psychiatric diseases and particularly in depression.