Functional Adaptation in the Brain Habenulo–Mesencephalic Pathway During Cannabinoid Withdrawal
Sonia Aroni, Claudia Sagheddu, Marco Pistis, Anna Lisa Muntoni
Cells November 1, 2024 DOI: 10.3390/cells13211809 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Adult male Sprague–Dawley rats |
| Interventions | Δ9-tetrahydrocannabinol (THC) rimonabant |
| Dose | THC 15 mg/kg i.p. twice daily; rimonabant 5 mg/kg i.p. |
| Duration | 6.5–7 days of THC treatment, with withdrawal precipitated by rimonabant or abrupt suspension |
| Keywords | Adaptation eye Kindling Endocannabinoid system Stimulation Receptor |
| Citations | 6 |
| Key findings | THC withdrawal reduces VTA dopamine neuron firing and burst activity, prolongs RMTg-evoked inhibition, and depresses spontaneous activity in RMTg and LHb neurons. |
Abstract
The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb–RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ9-tetrahydrocannabinol (THC) dependence, adult male Sprague–Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5–7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo–mesencephalic circuit are implicated in the mechanisms underlying substance use disorders.