Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway

Abstract

Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ9-tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.

Temperament and Character Profile and Its Clinical Correlates in Male Patients with Dual Schizophrenia

“…All of these characteristics have been previously related to a worse clinical state, a greater number of relapses, and more suicide attempts [ 9 , 10 , 15 ]. In line with previous works [ 15 , 27 ], we observed a higher consumption of cannabis in the SZ+ group, which is of special interest since the evidence points to the consumption of this substance as a risk factor for the development of a SZ [ 66 , 67 ]. Moreover, it becomes even more relevant when we consider that, in our study, the onset of SUD happened earlier than that of SZ in the SZ+ group, in line with that found in previous studies [ 15 , 30 ].…”

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

“…Notably, THC reduced % PPI in female WT mice, suggesting that a history of drug exposure leads to psychotic-like behaviors. Conflicting results have been reported concerning the effects of adolescent chronic exposure to THC on psychotic-like behaviors in rodents (Rodriguez et al, 2017;Todd et al, 2017;Ibarra-Lecue et al, 2018). Differences in THC doses, mice genetic background and specific experimental conditions among different research groups may explain some of these conflicts.…”

The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids

“…As mentioned beforehand, the cannabinoids may indeed exert their effects differently between species. Another example of non-cannabinoid interaction is THC and CBD’s agonistic actions on the serotonin (5-hydroxytryptamine) receptors (5-HTR), which are highly involved in many of the processes related to cannabis’s actions (e.g., relief of anxiety and pain) and neuronal electrochemical activity [110,111,112]. CBD has been shown to inhibit the equilibrative nucleoside transporter (ENT1) that is involved in the synaptic uptake of adenosine, thereby increasing extracellular adenosine.…”