Kari Johnson: mGlu2, Addiction, and the Brain Circuits Alcohol Rewires

The brain circuits governing reward, motivation, and decision making are not fixed - they are continuously reshaped by experience. In alcohol use disorder and other substance addictions, one of the most consequential changes is the shift from goal-directed to habitual behavior: a state in which drug seeking persists not because of pleasure, but because the underlying circuit no longer responds to consequences.

mGlu2, a presynaptic metabotropic glutamate receptor coupled to Gi/o proteins, sits at a critical junction in this process. By suppressing glutamate release across circuits in the basal ganglia, mGlu2 is positioned to modulate drug seeking, habit formation, and reward processing - and has been pursued as a potential therapeutic target in addiction, depression, schizophrenia, and Parkinson's disease.

Kari Johnson's research follows this receptor from the bench to the behaving animal, using optogenetics and circuit-selective mouse models to ask which specific corticostriatal pathways are driving behavioral change after alcohol exposure - and whether pharmacological rescue is possible after those circuits have already been disrupted. The question has been central to Johnson's career since long before the tools to answer it properly existed.

ABOUT THE GUEST

Kari Johnson is an assistant professor of neuropharmacology at the Uniformed Services University of Health Sciences in Bethesda. Her lab investigates how GPCRs modulate synaptic transmission in brain circuits involved in reinforcement learning, with a particular focus on how chronic alcohol exposure disrupts those mechanisms across levels ranging from gene expression to neural circuit function to behavior.

She trained in high-throughput drug discovery at Vanderbilt - contributing to early functional assay development for metabotropic glutamate and muscarinic receptors - before completing postdoctoral training at the National Institute on Alcohol Abuse and Alcoholism with Dave Lovinger. Her current work combines whole-cell patch clamp electrophysiology, optogenetics, and operant behavioral pharmacology to study mGlu2 function in specific corticostriatal circuits and its role in the transition from controlled to compulsive drug use.

SCIENTIFIC THEMES OF THE CONVERSATION

1. mGlu2 as a convergence target across addiction, psychiatric disease, and movement disorders
   

2. Circuit-specific GPCR modulation and the "modulomics" framework
   

3. Goal-directed versus habitual behavior as a mechanistic framework for understanding addiction
   

4. Pharmacological rescue of alcohol-disrupted receptor function using positive allosteric modulators
   

5. The translational gap: why a decade of preclinical mGlu2 evidence has not yet reached clinical success
   

6. The limits of brain slice electrophysiology - and why optogenetics redefines the questions the field can ask

KEY INSIGHTS FROM THE CONVERSATION

mGlu2 Sits at the Center of Multiple CNS Disorders

Because mGlu2 regulates glutamate release in brain regions linked to reward, executive function, motivation, and stress responses, it has become a target of interest across an unusually broad disease landscape - alcohol use disorder, schizophrenia, depression, Parkinson's disease, and multiple other substance addictions. That breadth is a signal of the receptor's centrality in CNS function. It is also a complication: a receptor that modulates so many circuits will inevitably produce wanted and unwanted effects that are difficult to predict from any single experimental system.

Alcohol Disrupts mGlu2 - But a PAM Can Restore It

Johnson's lab demonstrated that adolescent alcohol exposure disrupts mGlu2 function in the striatum in a way that might seem to close off therapeutic targeting - if the receptor is impaired, can it still be activated pharmacologically? Their answer was yes: a positive allosteric modulator restored mGlu2 signaling even after alcohol-induced disruption. This finding shifts the question from whether mGlu2 is a viable target in addiction to how to reach it once its function has already been compromised.

The Years Before the Tools Existed

For most of the history of GPCR electrophysiology, researchers used electrical stimulation in brain slices and could observe that a receptor modulated synaptic transmission - but not which specific set of synaptic inputs was responsible. For Johnson, this was a formative constraint she navigated across her entire training: drawn to circuit-level questions that her early tools could not fully answer, she made the shift to optogenetics and genetically defined neuronal populations specifically because the biology demanded it. The tools arrived late relative to the questions. That gap, in Johnson's framing, is both a limitation of the past and an argument for the field's current momentum.

Modulomics: Naming the Question Changes What You Can Ask

Johnson's postdoc mentor Dave Lovinger coined the term "modulomics" to describe the systematic study of circuit-specific neuromodulation by GPCRs - using light-activated ion channels expressed in anatomically or genetically defined neurons to isolate receptor effects at individual synaptic inputs rather than across an entire stimulated pathway. Giving the approach a name formalizes it as a research program, not just a technique. Johnson's lab has extended this using conditional knockout mice that allow selective deletion of mGlu2 from specific cell types, enabling circuit-level pharmacology with direct behavioral readouts.

The Habit Framework Changes What Addiction Means Pharmacologically

The shift from goal-directed to habitual behavior is not just a behavioral description of addiction - it implies a specific circuit mechanism. Goal-directed behavior is sensitive to changes in outcome value; habitual behavior is not. When alcohol exposure biases the brain toward habit formation, the circuit underlying that inflexibility becomes the pharmacological target. Johnson's lab uses this framework to ask whether activating mGlu2 in specific corticostriatal circuits can reverse the habit bias that chronic alcohol produces - not just dampen the pleasure of drinking, but restore the flexibility of the decision that precedes it.

Clinical Trial Results for mGlu2 Ligands Have Not Been Made Public

Johnson noted that multiple clinical trials testing mGlu2 ligands in substance use disorders - including for smoking cessation and cocaine use disorder - have been conducted and completed. The results have not been released to the research community. Without access to those data, researchers cannot determine why promising preclinical findings did not translate, cannot adjust future trial designs, and cannot evaluate whether the receptor was genuinely ineffective or whether confounds such as prior antipsychotic exposure were responsible - a hypothesis already supported by subsequent preclinical work following the disappointing schizophrenia trials. The gap is consequential, and Johnson named it directly.

Translating GPCR Research May Require Releasing Attachment to Specific Receptors

One of Johnson's more quietly contrarian observations is that attachment to a "favorite receptor" may be limiting translational success. If mGlu2 activation produces the desired circuit effect in rodents but not in humans, the value of that work is not lost - it defines the functional target. A different receptor capable of achieving the same circuit-level effect in a human brain might carry the therapy further. The question, in Johnson's framing, is not which receptor you prefer, but which receptor is correctly positioned in the human circuit you need to modify.

EPISODE TIMELINE

Note: Timestamps are AI-generated from the transcript and may require manual verification after video editing.

00:00 Introduction

01:27 Johnson's career path - from Vanderbilt drug discovery to NIH postdoc to independent lab

07:31 Alcohol disrupts mGlu2 in adolescent mice - and a positive allosteric modulator rescues it

09:45 Why mGlu2 is Johnson's receptor of focus: synaptic plasticity and long-term depression

11:26 mGlu2 and drug seeking: preclinical evidence across alcohol, cocaine, methamphetamine, and heroin

13:28 How mGlu2 modulates dopamine release and the neurobiology of habit formation

16:28 Optogenetics and modulomics - studying circuit-specific GPCR function in the basal ganglia

20:45 Operant behavioral models: how habit formation is measured in mice

25:25 Clinical trials for mGlu2 ligands - what advanced, what disappointed, and what remains unpublished

28:41 Are GPCRs still good drug targets? A circuit-level argument

33:12 Advice for junior scientists: let the biology lead the method

35:28 Diversity in STEM and who carries the labor of change

SELECTED QUOTES

About this episode

Dr. Kari Johnson is currently an assistant professor at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. She is a neuropharmacologist with an interest in the long-term effects of alcohol abuse on neural circuits. Kari completed her Ph.D. in Pharmacology at Vanderbilt University before continuing her training as a postdoctoral fellow at the Vanderbilt Center for Neuroscience Drug Discovery, the National Institute of General Medical Sciences, and the National Institute on Alcohol Abuse and Alcoholism. All through her career, the recurring theme in Kari’s work has been GPCRs and more specifically Metabotropic Glutamate Receptors. Join me and learn more about how Kari studies GPCRs in basal ganglia circuits following chronic alcohol exposure in mice.

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