Association of Cannabis Use during Adolescence, Prefrontal CB1 Receptor Signaling, and Schizophrenia

Abstract

The cannabinoid receptor 1 (CB1R) is the G-protein coupled receptor responsible for the majority of the endocannabinoid signaling in the human brain. It is widely distributed in the limbic system, basal ganglia, and cerebellum, which are areas responsible for cognition, memory, and motor control. Because of this widespread distribution, it is not surprising that drugs that activate CB1R have expected behavioral outcomes consistent with dysregulated signaling from these areas (e.g., memory loss, cognitive deficits, etc). In the context of this review, we present evidence for the role of CB1R signaling in the prefrontal cortex (PFC), an area involved in executive functions, with emphasis on the developmental regulation of CB1R signaling in the acquisition of mature PFC function. We further hypothesize how alterations in CB1R signaling specifically during adolescent maturation might confer liability to psychiatric disorders.

Keywords: adolescence; cannabinoids; prefrontal cortex; schizophrenia.

Figure 1

Working model of prefrontal dysfunction induced by cannabinoid exposure during adolescence. (A) During normal development, the adolescent facilitation of glutamatergic transmission onto prefrontal PV-positive interneurons is thought to determine the maturation local GABAergic transmission in the PFC (Tseng et al., 2009). (B) Based on the expression and function of CB1R in the cortex, the acute effect of cannabinoids on prefrontal dysfunction could occur by suppression of synaptic transmission at any of the following synapses (black triangles): (i) CCK-positive interneuron → pyramidal neurons, (ii) glutamatergic afferents → pyramidal neurons, and (iii) glutamatergic afferents → PV-positive interneurons. Regarding the long-lasting effects of adolescent exposure to cannabinoids, we hypothesize that cannabinoid-induced (e.g., Δ9-THC) suppression of glutamatergic drive onto PV-positive cells will prevent the normal maturation of these interneurons. If such interneuronal activity does not become enhanced during this transitional period, the control of PFC inhibition will be profoundly reduced, resulting in a lack of synchrony in the PFC and consequent impairment of cognitive functions.