The effects of CB1R activation in the prefrontal cortex (PFC) may provide a mechanism for the cognitive deficits and negative symptoms induced by cannabinoids. Systemically administered cannabinoids have been shown to modulate the activity of dopaminergic pathways in the PFC either directly or indirectly, by influencing the activity of dopaminergic neurons through either post- or presynaptic mechanisms [56, 124, 177]. By suppressing GABAergic and dopaminergic inhibitory neurotransmission, CB1R activation might lead to non-specific activation of the PFC which in turn may disrupt normal signal processing and result in poor integration of transcortical inputs [178, 237]. The stimulation of mesoprefrontal DA transmission by CB1R activation [34, 50, 108, 178] may contribute to working memory deficits associated with cannabis exposure. Given that either too high or low DAergic activity in the PFC can lead to impairments in PFC-related cognitive functions [73, 165, 238], this may explain some of the cognitive effects of cannabinoids. The effects of cannabinoids on dopaminergic activity in the PFC may also exacerbate the effects of decreased mesocortical dopaminergic transmission and reduced D1 receptor density reported in schizophrenia [2, 168, 169] which would result in the worsening of working memory deficits and negative symptoms of schizophrenia.
