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Gut-brain Peptides in Corticostriatal-Limbic Circuitry and Alcohol Use Disorders

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Review

Gut-brain Peptides in Corticostriatal-Limbic Circuitry and Alcohol Use Disorders

Chelsea A Vadnie et al. Front Neurosci.

Abstract

Peptides synthesized in endocrine cells in the gastrointestinal tract and neurons are traditionally considered regulators of metabolism, energy intake, and appetite. However, recent work has demonstrated that many of these peptides act on corticostriatal-limbic circuitry and, in turn, regulate addictive behaviors. Given that alcohol is a source of energy and an addictive substance, it is not surprising that increasing evidence supports a role for gut-brain peptides specifically in alcohol use disorders (AUD). In this review, we discuss the effects of several gut-brain peptides on alcohol-related behaviors and the potential mechanisms by which these gut-brain peptides may interfere with alcohol-induced changes in corticostriatal-limbic circuitry. This review provides a summary of current knowledge on gut-brain peptides focusing on five peptides: neurotensin, glucagon-like peptide 1, ghrelin, substance P, and neuropeptide Y. Our review will be helpful to develop novel therapeutic targets for AUD.

Keywords: GLP-1; NPY; alcohol; ghrelin; neurotensin; peptide; substance P.

Figures

Figure 1
Figure 1
Simplified schematic of corticostriatal-limbic circuitry. (A) Key corticostriatal-limbic connections where gut-brain peptides may act to influence addictive behaviors. AMG, amygdala; DS, dorsal striatum; GP, globus pallidus; HIPP, hippocampus; LDTg, laterodorsal tegmental area; SN, substantia nigra; STN, subthalamic nucleus; VP, ventral pallidum; VS, ventral striatum; VTA, ventral tegmental area. (B) A hypothetical schematic of the direct and indirect pathways in the VS. Glutamatergic projections from the cortex synapse onto MSNs expressing predominantly dopamine D1 receptors (D1R) or dopamine D2 receptors (D2R). MSNs expressing D1R may project directly to the VP or the substantia nigra (SN) pars reticulata forming the direct pathway. Inhibition of GABAergic neurons in the VP or SN can then disinhibit downstream thalamocortical targets. MSNs expressing dopamine D2 receptors project to the VP which synapses onto glutamatergic neurons in the STN. Therefore, activation of the indirect pathway results in reduced glutamatergic projections to the SN pars reticulata. Another possible indirect pathway involves projections from the VP to dopaminergic neurons in the VTA. The VTA may inhibit downstream thalamocortical targets. Green, glutamatergic fibers; red, dopaminergic fibers; blue, GABAergic fibers; purple, cholinergic fibers.
Figure 2
Figure 2
Regulation of alcohol consumption by neurotensin. (A) Neurotensin (NT) has opposing presynaptic and postsynaptic effects on dopaminergic signaling in the nucleus accumbens (NAc). Presynaptically, NT may increase dopamine (DA) release through neurotensin receptor type 1 (NTS1)-, or possibly even neurotensin receptor type 2 (NTS2)-mediated inhibition of dopamine D2 receptors (D2R) on ventral tegmental area (VTA) dopaminergic (DAergic) terminals. Postsynaptically, NTS1 or even NTS2 dimerizes with D2R and attenuates D2R signaling. Functional studies suggest that the effect of NT on inhibiting postsynaptic D2R signaling may predominate in the nucleus accumbens (NAc). (B) Alcohol increases dopamine release in the NAc. Alcohol may excite VTA dopaminergic neurons by inhibiting GABAergic interneurons in the VTA, which results in reduced activation of GABA receptors (GABAR) on VTA dopaminergic neurons. Increased VTA-mediated dopamine in the NAc may promote alcohol consumption and mediate alcohol reward. NT receptor agonists may reduce alcohol consumption by acting on postsynaptic NT receptors which may inhibit alcohol-mediated dopamine signaling in the NAc.
Figure 3
Figure 3
Possible mechanisms by which GLP-1 may reduce alcohol consumption. (A) Glucagon-like peptide 1 (GLP-1), by acting on the GLP-1 receptor (GLP-1R) on presynaptic glutamatergic (GLUergic) terminals in the ventral tegmental area (VTA), may increase glutamate (GLU) release. Increased glutamate release in the VTA may enhance the activity of VTA dopaminergic (DAergic) neurons through glutamatergic AMPA receptors (AMPARs) or kainate receptors (KARs). Increased activity of VTA dopaminergic neurons may then promote dopamine release in postsynaptic targets such as the amygdala (AMG). Increased dopamine D2 receptor (D2R) signaling in the amygdala has been linked with decreased food intake and therefore may mechanistically explain how GLP-1 decreases alcohol consumption. (B) GLP-1 through GLP-1R on presynaptic glutamatergic terminals may increase glutamate release in the nucleus accumbens (NAc). Increased NAc glutamate may activate AMPARs or KARs which may reduce alcohol consumption by enhancing the activity of striatopallidal medium spiny neurons (MSNs).
Figure 4
Figure 4
Ghrelin signaling and alcohol consumption. (A) One mechanism by which ghrelin may increase ventral tegmental area (VTA) dopaminergic neuron activity and nucleus accumbens (NAc) dopamine (DA) levels involves ghrelin-mediated activation of laterodorsal tegmental area (LDTg) cholinergic neurons. Ghrelin through growth hormone secretagogue receptor 1a (GHS-R1a) may activate LDTg cholinergic neurons and subsequently increase acetylcholine (ACh) levels in the VTA. Activation of nicotinic acetylcholine receptors (nAChR) on VTA dopaminergic neurons can increase neuronal activity and promote dopamine release in postsynaptic regions. Increased dopamine signaling may explain how ghrelin can promote alcohol consumption. (B) There is also evidence that ghrelin may activate VTA dopaminergic neurons by promoting presynaptic glutamate (GLU) release in the VTA. Ghrelin through GHS-R1a on glutamatergic terminals in the VTA may enhance glutamate release. Subsequent activation of NMDA receptors (NMDAR) could then increase VTA dopaminergic activity. (C) Finally, ghrelin through GHS-R1a may activate glutamatergic ventral hippocampal (vHIPP) neurons, which may result in increased glutamate release in the NAc. Increased glutamate in the NAc may increase dopamine release by activating glutamate receptors on presynaptic dopaminergic terminals. Increased activation of dopamine D1 or D2 receptors (D1R/D2R) on medium spiny neurons (MSNs) in the NAc may then promote alcohol consumption.
Figure 5
Figure 5
Regulation of alcohol consumption by substance P. (A) Increased levels of substance P (SP) released from neurons or by microinjection of SP into the ventral tegmental area (VTA) interacts with neurokinin receptor 1 (NKR1) on VTA dopaminergic (DAergic) neurons resulting in increased release of dopamine (DA) to areas like the nucleus accumbens (NAc). Increased dopamine release in the NAc, as a result of increased SP in the VTA, would be expected to increase alcohol consumption since alcohol is known to disinhibit VTA dopaminergic neurons. Alcohol is thought to inhibit GABAergic interneurons in the VTA, which results in reduced activation of GABA receptors (GABAR) on VTA dopaminergic neurons. (B) NK1R is also found in the ventral pallidum (VP) and the amygdala (AMG). SP may increase administration of rewarding substances like alcohol by increasing the excitability of neurons in the VP and AMG.
Figure 6
Figure 6
NPY signaling in the amygdala and alcohol consumption. Neuropeptide Y (NPY) receptor type 1 (Y1R) agonists and NPY receptor type 2 (Y2R) antagonists in the central amygdala (CeA) may reduce alcohol consumption through mimicking the effects of acute alcohol on GABAergic signaling. Both receptors are thought to be inhibitory, but differ in their location. Y2R may be predominantly on presynaptic GABAergic interneurons, where Y1R may be expressed postsynaptically on GABAergic output neurons. Therefore, inhibiting Y2R function would increase GABA release from GABAergic interneurons in the CeA, similar to alcohol which is known to facilitate GABAergic signaling in the amygdala. Increased activation of GABA receptors (GABAR) in the CeA would reduce CeA output. Activating Y1R would also inhibit postsynaptic CeA neurons similar to increasing GABAergic signaling. Furthermore, Y2R antagonists would be expected to increase NPY which would facilitate the effect at Y1R. Decreased CeA output has been linked with reduced anxiety which is hypothesized to suppress stress-induced alcohol relapse.

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