Clonidine blocks stress‐induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons
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Bibliographic record
Abstract
Using a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug-taking behaviour in rats. Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that decreases NE cell firing and release, on stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg per infusion, IV, three 3-h sessions per day) for 9-10 days. Extinction sessions were given for up to 11 days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testing, clonidine was injected systemically (10-40 microgram/kg, i.p.) or directly into the lateral or fourth ventricles (1-3 microram). Clonidine (1-2 microgram per site) or its charged analogue, 2-[2, 6-diethylphenylamino]-2-imidazole (ST-91, 0.5-1 microgram per site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress-induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST-91 consistently altered stress-induced reinstatement when injected into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress-induced reinstatement. 6-Hydroxydopamine (6-OHDA) lesions performed after training for heroin self-administration had no effect on extinction of heroin-taking behaviour, but significantly attenuated reinstatement induced by intermittent footshock. These data suggest that: (i) clonidine prevents stress-induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to stress-induced reinstatement of heroin seeking.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.002 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it