Supervisors info:
Λεωνίδας Στεφανής, Καθηγητής, Ιατρική, ΕΚΠΑ
Κωνσταντίνος Βεκρέλλης, Ερευνητής Β', Ιδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Αντώνιος Σταματάκης, Αναπληρωτής Καθηγητής, Νοσηλευτική, ΕΚΠΑ
Summary:
Parkinson’s Disease (PD), in spite of being known as a motor-impairing neurodegenerative disease, has numerous non motor symptoms. Parkinson’s disease Psychosis (PDP) is the most challenging non-motor symptom with an estimated 50% incidence, affecting both the prognosis and the progression of the disease and dramatically reducing patients’ quality of life. PDP is commonly perceived as a complication of dopamine therapy used to treat motor symptoms. However, some evidence indicates that PDP may precede motor symptoms and manifest in the absence of PD medications. In addition, there are no safe therapeutic options and no specific animal models available to study this condition.
Herein, we used in-house bred humanized alpha-synuclein BAC (AS BAC) transgenic rats created by Nuber et al (2013). We initially evaluated locomotor activity in an open field, prepulse inhibition, striatal, cortical and olfactory dopamine levels with HPLC and electrochemical detection and markers of dopaminergic activity with Western immunoblotting. Locomotor activity was assessed following pharmacological manipulations with haloperidol, a typical antipsychotic, clozapine, an atypical antipsychotic, pimavanserin, an atypical antipsychotic approved specifically for PDP, D-amphetamine, a psychostimulant or SCH 23390, a D1 receptor antagonist, and ropinirole, a D2 receptor agonist.
We show that compared to their wild type littermates, AS BAC rats exhibit increased striatal dopamine levels and locomotor hyperactivity from the early age of 3 mo and a prepulse inhibition deficit at 12 mo. Their hyperactive phenotype is reversed following the administration of haloperidol, clozapine, SCH-23390. In addition, this phenotype is exacerbated following the administration of ropinirole and d-amphetamine. The animals had a broad response spectrum regarding pimavanserin administration and no conclusive results could be drawn. Western blot data demonstrated similar levels between WT and AS ΒΑC rats in two proteins regulating dopamine levels in the synapse, Dopamine Transporter (DAT) and Vescicular Monoamine Transporter (VMAT). Immunohistochemical analysis did not reveal differences in the levels of D1 receptors in the striatum between the two groups.
These data support a connection between aberrant human alpha-synuclein expression and a psychosis-like phenotype in AS BAC rats. Fascinatingly, this in vivo data may have analogies to clinical PD, where recent findings suggest that a premotor hyperdopaminergic state may occur.
Keywords:
Parkinson's Disease, Synuclein, Dopamine, Behavior
