Septal Glucagon-like Peptide 1 Receptor Signalling in Neuroplasticity and Drug-induced Behaviour

Abstract

The transition from controlled to compulsive drug use involves changes at both a neuronal and circuit level in the brain-reward system. The mesocorticolimbic system mediates the effects for natural rewards and is also involved in the addiction to illicit drugs, which can overreach these core circuits. Recent pharmacological studies established the Glucagon-like Peptide 1 Receptor (GLP-1R) signalling system as a target for the treatment of addiction. To date, central sites of action remain unclear and underlying molecular mechanisms are undetermined. The aim of this thesis is to unravel the function of GLP-1R signalling in drug-induced neuroplasticity and emotional behaviour. Anatomical analysis in the mouse brain revealed that glp-1r mRNA is abundantly expressed in the dorsal lateral septum (LS). The LS has a key function in reward perception and is also involved in stress-induced relapse to drugs of abuse. In a novel genetic approach GLP-1R KO mice were employed in specialized paradigms informing on cocaine-induced behaviour. GLP-1R KO mice revealed enhanced drug-induced responses that were restored by viral vector-mediated glp-1r gene delivery to the dLS. Whole-cell patch-clamp electrophysiological characterization revealed that genetic GLP- 1R ablation leads to an increased excitability of septal neurons. Further co-expression studies suggest a functional interplay of GLP-1R signalling with GABA transmission. This hyperexcitability of GABAergic neurons after loss of GLP-1R signalling potentially alters dopamine levels in septal target brain areas, which are involved in reward-mediated behaviour and drug-induced neuronal adaptations. Three independant gene therapy strategies, centred on the septal GLP-1R system, were investigated for the treatment of drug abuse. Insufficiency of receptor overexpression or chronic activation suggests the focus of research should concentrate on GLP-1R downstream signalling pathways to define novel targets for the treatment of addiction. Novel molecular tools, including a viral vector construct for gene silencing developed in this study, will enable future investigations to examine receptor transduction pathways under spatio-temporal control. In summary, these data are clinically relevant since they provide functional evidence that the central GLP-1R signalling system is a target for the treatment of mood disorders and unequivocally shows that septal GLP-1R play an essential physiological role in drug-induced behaviour.