Rescuing neuronal network from amphetamine sensitization

Amphetamine is a sympathomimetic drug that elicits psychostimulant effects in the brain, such as wakefulness, euphoria, and enhanced cognitive performance. Thus, the amine is used illegally as recreational drug and by athletes as performance enhancer; in pharmacotherapy, amphetamine is employed to treat attention deficit hyperactivity disorders, narcolepsy, and obesity. Cycles of drug administration and withdrawal lead to amphetamine sensitization (AS), a condition in which continuous re-exposure to the amine induces progressive amplification of the system response to the stimulus. This state is characterized by neuroplastic adaptations in brain structures and by cognitive and behavioural alterations that resemble those of psychosis. AS and psychosis are thought to originate from unbalanced neurotransmission and altered cortical activity. The underlying mechanisms involve changes in several neurotransmitter systems with a key role of glutamatergic and dopaminergic pathways. Unveiling these mechanisms and how amphetamine hijacks brain circuits might aid in discovering novel targets to reverse cognitive dysfunctions and psychotic-like traits associated with AS. In this set of studies, we will employ a system-oriented, multidisciplinary approach and a murine model of AS to investigate how recurrent amphetamine exposure disrupts operations in specific brain circuits that support both, cognitive and motivational processing, namely the mesolimbic system. We will test the hypothesis that rescuing mesolimbic neuronal activity from deterioration by the amine may reverse sensitization and alleviate psychotic symptoms. Brain circuits will be tuned by chemogenetic and pharmacological manipulations selectively impinging on both, glutamatergic and dopaminergic systems We will determine the impact of these procedures on brain network activity as well as behaviour. The data to be obtained will pave the way towards novel biological targets and more effective therapeutic strategies for the treatment of both, amphetamine addiction and psychosis. Moreover, this research will illuminate mechanisms that lead to cognitive dysfunctions associated with alterations within the mesolimbic system.