Connexin-36-expressing Gap Junctions in VTA GABA Neurons Sustain Opiate Dependence
Bibliographic record
Abstract
Abstract Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance becomes negatively reinforcing. Ventral tegmental area (VTA) GABA neurons form a point of divergence between two double dissociable pathways responsible for these respective motivational states. Here we show that this switch from drug-naïve to opiate-dependent and withdrawn (ODW) motivation is contingent upon the gap junction-forming protein, connexin-36 (Cx36), in VTA GABA neurons. Intra-VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug-naïve motivational state and a loss of opiate withdrawal aversions. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons ( GAD65-Cre;Cx36 fl(CFP)/fl(CFP) ) were perpetually drug-naïve and never experienced opiate withdrawal aversions. Further, viral-mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to ODW motivation. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction. Significance The motivation to seek drugs can vary depending on prior exposure. For instance, recreational and habitual drug use can stem from a desire to experience the pleasurable or relieving properties of the substance, respectively. Here we identify a subpopulation of midbrain neurons that dictate opiate-seeking motivation via expression of the gap junction protein, connexin-36. We show that connexin-36 expression increases upon opiate dependence and withdrawal. We then demonstrate that this is not merely a correlation, as pharmacological or genetic manipulations that interfere with connexin-36 function prevent the development of opiate dependence in rats and mice. Our results identify gap junctions as a critical node in the pathogenesis of opiate addiction, and a potential new target for substance use disorder pharmacotherapies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".