Gut-brain axis: Central impact of gut peptides and metabolic drug on monoamine neurotransmission
Gastrointestinal peptides like insulin and glucagon-like peptide are not only essential metabolic hormones but can also modulate important brain function, unrelated to feeding behaviour and glucose homeostasis. Different evidence suggests that these peptides, as well as synthetic insulin secretagogue such as tolbutamide, can affect cognition, motivation, addiction as well as neuronal survival. In this thesis, we have investigated in rats whether insulin, or the insulin-releasing agent tolbutamide, and the stable glucagon-like-peptide-1 (GLP-1) receptor agonist exendin-4 as well as putative GLP-1 congener geniposide, can affect the electrical activity of dopamine neurons in the ventral tegmental area (VTA) and of pyramidal neurons in the prefrontal cortex (PFC), using single-unit activity recording techniques. We have also investigated, whether these peptides can alter some dopamine-dependent behaviours such as, D-Amphetamine (a dopamine-releasing agent) -induced motor activity, quinpirole (a dopamine D2/D3 receptor agonist) and pramipexole (a dopamine D3 preferred receptor agonist) -induced yawning, pica eating and pelvic grooming activities, as well as phencyclidine ( an N-Methyl-D-aspartate receptor antagonist)-induced cognitive deficit. We also examined the pharmacological mechanism of these drugs on radiometric in vitro [DA] release and uptake assays and investigated whether GLP-1 can modulate the effect of diet modification in form of chronic sucrose intake on behavioural and electrophysiological parameters. Interestingly, in uptake assay, exendin-4 and insulin weakened dopamine D2/D3 agonist (pramipexole and quinpirole)-induced [DA] uptake which suggests a potential interaction with D2/D3 receptor signalling. In addition, insulin and tolbutamide similarly reduced basal [DA] in striatal synaptosomes. Our electrophysiological data shows that GLP-1 receptor activation can change the excitability of prefrontal cortex neurons, an effect that can be associated with the putative pro-cognitive action of some GLP-1 analogues. Interestingly, on VTA dopamine neurons, GLP-1 receptor activation potentiated a moderate inhibitory action of insulin on firing activity. However, a slight progressive decrease in the firing activity of ventral tegmental area dopamine neurons was observed, when insulin was administered through an electrode to allow for local diffusion into the brain region. The insulin secretagogue agent tolbutamide exerts biphasic or excitatory effects on VTA dopamine and PFC neurons, probably via K+ATP channels blockage through sulphonylurea receptors activation, indicating that most dopamine neurons and PFC neurons can be metabolic-sensitive. On sucrose treated rats, we noticed that sucrose treatment induced a partial but significant decrease in the sensitivity of dopamine autoreceptors which was surprisingly exacerbated by exendin-4 co-administration, indicating that exendin-4 may interact negatively with both pre- and post-synaptic dopamine receptors. Our behavioural data shows that exendin-4 and insulin alter dopamine-dependent behaviour with a remarkable inhibitory effect on D-amphetamine-induced motor activity and pramipexole and quinpirole-induced yawning, pica eating, and pelvic grooming activities. As this behaviour is mainly mediated by dopamine D3 receptors our data suggest the existence of an interaction between GLP-1 and dopamine D3 receptors. This may implicate GLP-1 mediated neuronal processes as a particularly interesting therapeutic target for disorders involving dopamine D2/D3 receptors and dopamine transporter malfunction. GLP-1 also exhibited a pro-cognitive effect on PCP-induced cognitive impairment, through the enhanced glutamatergic transmission. Finally, data on sucrose revealed that prolonged ad libitum access to sucrose by adolescent rats may alter brain circuits related to dopamine neurotransmission. It increases the behavioural responses of dopamine agonists and is possibly associated with hypersensitivity of some postsynaptic dopamine receptors. These effects were partially prevented by exendin-4, which may elicit some protective effects on dopamine receptor function. In succinct, gut peptides impact on neurotransmission as well as behavioural activities and potentially modulate psychostimulant effects.
- PhD