Cellular mechanisms underlying the anxiolytic effect of low doses of peripheral Delta9-tetrahydrocannabinol in rats.
Tiziana Rubino, Mariaelvina Sala, Daniela Viganò, Daniela Braida, Chiara Castiglioni, Valeria Limonta, Cinzia Guidali, Natalia Realini, Daniela Parolaro
Neuropsychopharmacology September 2007 DOI: 10.1038/sj.npp.1301330 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Delta(9)-tetrahydrocannabinol (THC) AM251 |
| Dose | 0.075 to 1.5 mg/kg THC; 0.75 mg/kg most effective |
| Measures | elevated plus maze (EPM), cFos expression, phosphorylated CREB, ERK activation, CAMKII activity |
| Topics | Cannabis |
| Key points | Low doses of THC (0.075-1.5 mg/kg, most effective at 0.75 mg/kg) produced anxiolytic effects in rats on the elevated plus maze, reversed by the CB1 antagonist AM251. THC reduced cFos in prefrontal cortex and amygdala and increased CREB activation in prefrontal cortex and hippocampus, with the prefrontal cortex effect linked to ERK activation and the hippocampal effect to reduced CAMKII activity. The authors suggest CB1 receptor stimulation in these regions and subsequent signaling pathway activation is the first event underlying cannabinoid effects on anxiety. |
Abstract
We investigated the effect of low doses of intraperitoneal Delta(9)-tetrahydrocannabinol (THC) on anxiety behavior in rats using the elevated plus maze (EPM). An anxiolytic effect was obtained in a range of doses between 0.075 and 1.5 mg/kg, the 0.75 dose being the most effective. Pretreatment with the CB1 receptor antagonist AM251 fully reversed THC's effect, suggesting CB1 receptors were involved. In order to elucidate the neuroanatomical substrates underlying the effect of the maximal effective dose of THC, we investigated cFos expression in anxiety-related brain regions (prefrontal cortex, nucleus accumbens, amygdala, and hippocampus) of rats exposed to the EPM. THC significantly lowered the amount of cFos in prefrontal cortex and amygdala without affecting the other cerebral areas. As there is increasing evidence that CREB function regulates anxiety-like behavior in rats, the second biochemical parameter we measured was phosphorylated CREB in the same brain areas. Rats treated with THC showed a significant increase in CREB activation in the prefrontal cortex and hippocampus. In the prefrontal cortex this increased activation was linked to an increase in ERK activation, whereas in the hippocampus there was a drop in the activity of CAMKII, a kinase with inhibitory effect on CREB activation. All these effects were reversed by AM251 pretreatment, suggesting that stimulation of CB1 receptors is fundamental for triggering the biochemical events. Our results suggest that the stimulation of these receptors in the prefrontal cortex, amygdala, and hippocampus with the subsequent activation of different signaling pathways is the first event underlying the effects of cannabinoids on anxious states.
Comparable studies
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Citations in the library
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- Cannabis, a cause for anxiety? A critical appraisal of the anxiogenic and anxiolytic properties Journal of Translational Medicine October 2, 2020
- Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity. Neuropsychopharmacology 2023
- Cannabinoid Modulation of Amygdala Subregion Functional Connectivity to Social Signals of Threat The International Journal of Neuropsychopharmacology December 28, 2014
- Inhibition of Fatty Acid Amide Hydrolase Alters Cortical CREB Signaling and Social Behavior in a Rat Model of Schizophrenia European Journal of Neuroscience February 1, 2026
- Reward-related neural activity after low doses of LSD in participants with depressed mood. Journal of Psychopharmacology January 13, 2026
and 16 more in the library
Cites 2
- Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. Journal of Pharmacology and Experimental Therapeutics July 2006
- Modulation of extracellular signal-regulated kinases cascade by chronic delta 9-tetrahydrocannabinol treatment. Molecular and cellular neurosciences March 2004