GAMBARANA CARLA

Research Topics

Neurobiological basis of symptoms of mood disorders in animal models

Neurobiology of motivational anhedonia in animal models of psychiatric disorders

Animal models are of fundamental importance to study the neurobiological underpinnings of mental disorders and develop possible new therapeutic strategies. The research activity has contributed to the development and validation of experimental models of psychiatric symptoms, in particular mood disorder symptoms. We developed a model of long-lasting stress-induced depressive-like phenotype in rats that has relevance to the field as the behavioral modifications are consistent, long-lasting, and are not accompanied by a general impairment in animal welfare. The model has been characterized demonstrating that it allows the study of behavioral phenotype and neurochemical responses to relevant environmental stimuli. We focused on the mesolimbic dopaminergic system and showed that extraneuronal dopamine levels are persistently decreased in the brain of rats showing depressive-like symptoms.  The model has also been used to study the effects of novel compounds or to further characterize the effects of drugs already used in the clinical practice, with psychiatric or non-psychiatric indications.

A second related topic of interest is the study of blunted responses to natural rewarding stimuli in rodents, since this condition models motivational anhedonia, a core symptom of major depression and other psychiatric disorders, autism included.  We demonstrated that exposure to the chronic stress model has a disruptive effect of on appetitive behavior: rats exposed to the stress protocol fail to acquire the appetitive behavior and to show dopaminergic responses to natural rewards.  Of relevance, pro-motivational activity does not completely overlap with “antidepressant-like” effects, in line with evidence from clinical studies.  While, typical antidepressant drugs lack promotivational/anti-anhedonic effects, or relieve motivational anhedonia only in a subpopulation of animals, treatment with the mood-stabilizer lithium is endowed with a remarkable pro-motivational effect, both on behavioral and neurochemical end-points.  Moreover, pro-motivational activity is observed after repeated administration of atypical antipsycotic drugs or of a PPARα agonist, clinically used with metabolic indications. The results on motivational anhedonia support the validity of the model and its usefulness to investigate mechanisms underpinning anhedonia and responses to treatments.