CB1 Cannabinoid Receptors Drive the Memory Problems That Occur During Nicotine Withdrawal | Research

The takeaway

In mice, cognitive deficits during nicotine withdrawal were caused by increased 2-AG signaling through CB1 receptors on GABAergic neurons, and blocking CB1 receptors prevented both the memory impairment and associated brain structural changes.

Readers interested in the connection between the endocannabinoid system and tobacco addiction.

Blocking CB1 receptors prevented both cognitive deficits and structural brain changes during nicotine withdrawal

What the researchers found

Researchers discovered that the cognitive deficits occurring during nicotine withdrawal are mediated by the endocannabinoid system, specifically through CB1 receptors on inhibitory (GABAergic) neurons.

During nicotine withdrawal in mice, 2-AG levels (but not anandamide) increased. This 2-AG surge, acting through CB1 receptors on GABA neurons, caused memory impairment. Blocking CB1 receptors with rimonabant or genetically deleting CB1 receptors specifically from GABA neurons prevented the cognitive deficits.

The withdrawal also caused structural brain changes: mature dendritic spines on hippocampal CA1 neurons decreased at day 4 of withdrawal, and this decrease correlated with memory performance. These structural changes were normalized in mice lacking CB1 receptors on GABA neurons and by rimonabant treatment.

Why it matters

Cognitive difficulties during nicotine withdrawal are a major predictor of relapse in people trying to quit smoking. Identifying the endocannabinoid system as the mechanism driving these cognitive deficits opens a potential therapeutic target. If CB1 modulation could prevent withdrawal-related cognitive impairment, it might help smokers quit more successfully.

The numbers in context

2-AG levels increased during nicotine withdrawal (anandamide unchanged). 2-AG synthesis inhibitor O7460 abolished cognitive deficits. CB1 antagonist rimonabant prevented memory impairment. Mature dendritic spines decreased at day 4 of withdrawal. Spine density correlated with memory performance.

How the study worked

Nicotine withdrawal was precipitated by the nicotinic antagonist mecamylamine in mice. Multiple pharmacological (rimonabant, 2-AG synthesis inhibitor O7460, 2-AG degradation inhibitor JZL184) and genetic (conditional CB1 receptor knockout on GABA neurons) approaches were used. Memory was assessed behaviorally. Dendritic spine density was quantified on hippocampal neurons.

What this study cannot tell us

Mouse model of precipitated withdrawal may not fully replicate the gradual withdrawal humans experience when quitting smoking. Rimonabant was withdrawn from the human market due to psychiatric side effects, limiting direct clinical translation. The study examined a specific type of memory; other cognitive domains were not assessed.

How to read the evidence

Preliminary evidence from an animal study using multiple complementary approaches (pharmacological and genetic).

When this study was published

Published in 2017. Important preclinical finding linking endocannabinoid and nicotinic systems.

The bigger picture

This study reveals a surprising connection between the endocannabinoid and nicotinic systems. The finding that endocannabinoid signaling drives cognitive problems during nicotine withdrawal has implications beyond smoking cessation. It suggests that cannabis use during nicotine withdrawal attempts could potentially worsen cognitive symptoms by further activating the same CB1 receptor pathway.

Questions still open

Would cannabis use during nicotine withdrawal worsen the cognitive deficits by activating the same CB1 pathway? Could safer CB1 modulators be developed for smoking cessation support? Do the structural brain changes reverse completely with extended abstinence?

Common questions

Does using cannabis make it harder to quit smoking?

This study suggests it could. The memory problems during nicotine withdrawal are driven by increased endocannabinoid signaling through CB1 receptors. THC in cannabis also activates CB1 receptors, which could theoretically amplify the same pathway causing cognitive difficulties. However, this was an animal study and the question has not been definitively answered in humans.

Why do people have trouble thinking clearly when quitting nicotine?

This study identified a specific mechanism: during nicotine withdrawal, the brain produces more of the endocannabinoid 2-AG, which acts on CB1 receptors on inhibitory neurons. This disrupts normal hippocampal function and even causes physical changes (loss of dendritic spines) on memory-related neurons.

Read the original research

CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.

Biological psychiatry, 81(7), 625-634

View on PubMed ↗Publisher’s paper ↗

Citation

Saravia, Rocio; Flores, África; Plaza-Zabala, Ainhoa; Busquets-Garcia, Arnau; Pastor, Antoni; de la Torre, Rafael; Di Marzo, Vincenzo; Marsicano, Giovanni; Ozaita, Andrés; Maldonado, Rafael; Berrendero, Fernando. (2017). CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.. Biological psychiatry, 81(7), 625-634. https://doi.org/10.1016/j.biopsych.2016.07.007