CB(1), A(2A) and D(2) receptors balance as a target against psychotic-like symptoms associated to Alzheimer’s disease and cannabis abuse

[eng] Psychosis is a mental health problem characterized by a loss of contact with reality, which is considered the defining feature of schizophrenia spectrum disorders. However, psychotic symptoms may occur in other medical conditions such as neurodegenerative diseases and substance abuse or intoxication. Here, we have focused on the psychotic symptoms associated with AD and chronic use of cannabis because of two main reasons: (i) their neurobiological bases are poorly understood, what limits the development of specific and effective treatments, and (ii) epidemiology data suggest that the prevalence of both disorders will increase worldwide in the next years due to the increase in life expectancy and in cannabis consumption among the population. Thus, the overall aim of this thesis project is to provide novel insights about the neurobiological bases underlying such psychotic symptoms with the ultimate goal to identify new therapeutic targets to reduce the negative consequences of these mental problems in the quality of life of patients. The hypothesis of this study is that alterations in the interplay between DAergic, adenosinergic and endocannabinoid systems are a common neurobiological substrate for different psychotic disorders and, consequently, that reversing such unbalance between these neurotransmitter systems could lead to therapeutic consequences. To evaluate this hypothesis, the specific aims (SA) of this thesis project are: - SA1: To evaluate the age-dependent psychotic symptoms in an AD model (i.e. APP/PS1 mice). - SA2: To correlate these psychotic symptoms in APP/PS1 mice with alterations in the balance between relevant components of the DAergic, adenosinergic and endocannabinoid systems. - SA3: To test the potential therapeutic properties of targeting adenosinergic and endocannabinoid systems against the psychotic symptoms in APP/PS1 mice. 84 - SA4: To evaluate the long-lasting behavioral consequences of chronic exposure to high doses of THC during the adolescence and the adulthood. - SA5: To correlate these behavioral consequences of THC exposure in the balance between relevant components of the DAergic, adenosinergic and endocannabinoid systems. - SA6: To explore the anatomical substrates underlying these behavioral consequences of THC exposure by analyzing the functional connectivity alterations between specific brain areas in treated mice. - SA7: To investigate the differential effects of THC on the activity of DAergic neurons in the VTA depending on the age of the individuals and the role played by A2AR in such effects as a potential substrate underlying the higher vulnerability to the psychotic symptoms induced by cannabis reported in the adolescence.