Jeff K. – Update GLP-1
Mechanisms and function in substance use disorders
Anecdotal reports, observational studies, and early clinical trials point to the potential use of GLP-1 agonist medications in treatment of alcohol use disorders and possibly other substance disorders.
As the effects in decreasing consumption of alcohol and other addictive substances was unexpected there was little known about the mechanisms of action in the central nervous system. There is now widespread use for treatment of obesity and type 2 diabetes.
There has been little known about the biological mechanisms involved for this indication. These studies are important in securing FDA approval and reimbursement. This post is a brief review of some of these newer studies.
Earlier clinical trials and metabolic mechanisms have been reviewed in earlier posts linked to in the reference section below.
GLP-1 is a peptide hormone produced by intestinal cells. It enters the bloodstream and causes release of insulin and other metabolic effects. GLP receptors are present in multiple organs including the heart muscle and GI system. While the native hormone degrades quickly commercial longer acting modified peptides have been developed.
The receptor depicted above bridges the cell membrane with an extracellular ligand, transmembranous and intracellular subunits.
This diagram shows clusters of GLP-1R receptors in the brain stem and midbrain. The solitary tract nucleus in the brainstem is at or near neurons forming the vagus and other cranial nerves. From here fibers intersect the dopamine reward pathway at the VTA and nucleus accumbens.
GLP-1Rs in the subforniceal organ and arcuate nucleus are associated with satiety signaling and autonomic function.
Receptors binding GLP1s and afferent fibers from the midbrain synapse in the frontal and parietal cortex. There areas are associated with executive function and movement.
The hormone, both native and in oral or injected form must enter the systemic circulation and pass through the blood brain barrier or through capillaries to peripheral nerves. This may be a problem for larger protein like molecules such as the GLP-1 agonists.
The blood brain barrier (BBB) is highly selective in allowing and restricting specific molecules into the brain. It is formed by lining endothelial cells bound together by tight junctions. Astrocytes surround the blood vessels playing important roles in both restriction and active transport.
When activated the GLP receptor can initiate one of two reactions. In most cases it will cause the opening of ion channels. This results in depolarization and release of neurotransmitter. In some instances a different pathway hyperpolarizes the cell membrane and transmitter release is prevented.
GLP-1r is not restricted to a particular cell type. They may be present on excitatory Glutamate or inhibitory GABA or other types of neurons. The end action is highly dependent on anatomical location and other individual factors.
Table listing the principal actions of GLP-1s in the presence of differing substances. In the case of alcohol and psycho stimulants there is decrease of dopamine release. In alcohol the primary mechanism dampens reward memory and drinking relapse.
In psycho stimulants increased D1 receptor the “no go” dopamine signal plays a role in reduced cue induced reactivity.
Opiates appear to activate the Orexin pathway with decrease of withdrawal signs in animal models.
This was an animal study investigating behavioral effects with alcohol administration. Agents used were native GLP-1 hormone and the analogue blocking agent Extendin-9.
On the left a conditioned place preference experiment was employed. In this setup the animal is first conditioned to obtain the alcohol reward in one of two chambers. The other chamber has a bottle containing only water.
Then in the experimental condition, injection of GLP-1, the animal is placed in the center and time spent or number of attempts is measured with only the water bottle present in both chambers.
The result was less time spent acquiring alcohol and fewer chamber entries with GLP-1 present. This indicates decreased motivational drive.
On the right the blocking agent Ex-9 was given preventing native GLP activity at 24 hours abstinence following alcohol conditioning. To the left are one hour and to the right 24 hours post administration if the blocking agent.
In both the blockaded animals voluntarily sought more alcohol. This indicates a regulatory role for native GLP.
The researchers went further to explore the specific site of action by microinjecting GLP directly into the ventral tegmental area (VTA) both native GLP-1 and EX-4 agonist were injected.
Results above indicate decreased voluntary alcohol intake versus placebo. The VTA is central in the reward pathway and is thought to be a main site of action by GLP-1 analogues.
This study explored the functional neuroanatomy by microinjection in the above regions.
A) Ventral Tegmental area (VTA)
B) Nucleus Accumbens core (NAc c)
C) Nucleus Accumbens shell (NAc s)
D) Basolateral Amygdala (BLA)
E) Dorsomedial Hippocampus (DMHipp)
F) Paraventricular Nucleus (PVN)
G) Lateral Habenula (LH)
In this part control injection is far left followed by increasing doses of GLP analog. Decreased voluntary alcohol consumption was observed in the primary reward pathway (VTA, NAc) as well as the lateral habenula which has been shown to have direct connections with the VTA. This is in keeping with the hypothesis that GLP-1 modulates reward value and processing.
Opiates
This experiment tested the effects on opiate consumption in rats with increasing administration of GLP-1 agonist. In the first part voluntary consumption was measured demonstrating decreased consumption.
On the right a behavioral reinstatement model was used. The animals were first conditioned to press a lever to obtain oxycodone. Following an extinction paradigm EX-4 was given and the lever was again introduced. The rats demonstrated supression of the behavior following the GLP-1 agent. This persisted up to 30 days indicating a potential relapse supression effect
This is from a large retrospective chart review study from a major health facility. The study looked at patients receiving a GLP-1 agent for treatment of obesity or type 2 diabetes. The patients were followed for 12 months for new onset diagnosis of cannabis use disorder. A control population was included.
The results are expressed as a hazard ratio. 1 = no effect. Less than one equals decreased incidence of cannabis use disorder. Results are listed as total risk followed by breakdown into demographic variables. The combined HR was 0.4 meaning a 60% less risk of developing cannabis use disorder in patients taking the GLP-1 agonist compared with controls.
There is now a large body of evidence from observational studies and early clinical trials supporting the use of GLP-1 agents in treatment of alcohol and potentially other substance use disorders. Larger clinical trials are underway.
This post reviews newer information concerning the biological properties involved in human and animal studies. The GLP-1 receptor has clusters with neural centers involving reward value, incentive, and cue related reinstatement.
Examples of studies in use of GLP-1 agents in opioid and cannabis use disorders show promise in use in other addictive substances.
Basic science investigations such as these are important in clinical indications, development of new agents, and in the FDA approval process. As larger phase 3 clinical trials become available specific patient selection and indications in substance use disorders can be established.
For information and educational purposes only. This post should not me considered medical advice. No commercial or institutional interests. Images and data obtained from sources freely avilble in the World Wide web. Comments are suggestions are always welcome.
Jeffk072261@gmail.com
…https://sobersynthesis.com/2024/04/03/glp-1-agonists-role-in-addiction/
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References
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Opioids and GLP
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A rapid review of the effects of GLP-1 receptor agonists on opioid and
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Jeff Kleinman 10/2016
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