According to the literature reviewed above, sustained cannabis exposure during adolescence induces long-lasting cognitive impairments and neuropsychiatric-like phenotypes, associated with robust dysfunction of the mesocorticolimbic system. Functionally, the profound dysregulation in sub-cortical DAergic signaling has been associated with disturbances in GABAergic vs. glutamatergic balance in the PFC, leading to dysregulated control of VTA DA transmission via PFC > VTA pathways [81,84]. That considered, novel pharmacotherapeutic interventions targeting the cortical inhibitory/excitatory signaling have now been examined aimed to either minimize, revert, or prevent such cannabis-induced detrimental effects. Renard and colleagues [59] demonstrated that THC-induced neuronal and behavioral abnormalities could be reversed in adulthood by pharmacologically restoring physiological GABA tone directly in the PFC. Specifically, pharmacological agonist activation of GABA_A receptors in the PFC at adulthood reversed short-term and social memory impairments as well as reduced anxiety and alterations in exploratory behavior induced by THC exposure during adolescence. Notably, these manipulations of PFC GABAergic neurotransmission also normalized the long-lasting sub-cortical DAergic hyperactivity (Table 1). These findings corroborate the crucial role of cortical GABAergic hypofunction in adolescent THC-induced pathological outcomes and underscore the potential therapeutic benefits of targeting cortical GABAergic tone to mitigate cannabis-related neuropsychiatric side-effects [81]. Importantly, these promising benefits of GABAergic compounds have been already observed in schizophrenic patients, in which the administration of a benzodiazepine-like agent selective for GABA_A receptors was shown to improve cognitive performance and attenuated schizophrenia-related abnormalities in frontal gamma oscillatory activity [91]. Future studies are required to see if similar interventions into the GABAergic system may be therapeutic for the reversal of cannabis-induced neuropsychiatric side-effects following long-term adolescent exposure.

Concomitant to the loss of GABAergic inhibition, chronic THC exposure during adolescence was found to induce a remarkable potentiation in firing and bursting activity of PFC pyramidal neurons [54,59], consistent with the dysregulation of GABA/Glutamate balance within this region. Thus, modulation of glutamatergic dysfunction has been proposed as a potential pharmacological intervention to prevent or reverse THC-induced psychopathology. Specifically, L-theanine, an amino acid analogue of L-glutamate and L-glutamine derived from green tea leaves, has been investigated due to its established therapeutic properties in anxiety, schizophrenia and depressive phenotypes [92,93,94,95]. Research in our laboratory has recently demonstrated that co-administration of L-theanine with THC in a neurodevelopmental rodent model of adolescent THC exposure, was able to powerfully block a wide range of THC-induced behavioral abnormalities into adulthood, including anhedonia, anxiety and impairments in memory and sensorimotor gating [96]. These preventative effects of L-theanine might result from its ability to normalize DAergic hyperactivity in the VTA, which in turn could ameliorate the cortical hyper-bursting state, restoring the inhibitory/excitatory balance and the oscillation patterns within PFC. In support of this, we found that L-theanine was able to fully prevent the overactivation of both sub-cortical VTA DAergic neuronal activity and cortical PFC activity states and gamma-oscillatory dysregulation induced by adolescent THC exposure. Furthermore, we found that down-regulation of cortical GSK-3α/β and Akt-Thr308, two critical molecular biomarkers for THC-related neuropsychiatric side effects, was similarly reversed by L-theanine [96] (Table 1). Such decreases in GSK-3α/β and Akt-Thr308 expression levels have been previously associated with hyper-DAergic states, as demonstrated following sustained activation of DA D₂ receptors [97]. In addition, an in vitro study has demonstrated that L-theanine protects against excess DA-related neurotoxicity through modulation of glutathione levels in astrocytes [98]. This suggests a potential role of astrocytic-glutathione mechanisms underlying mesocorticolimbic PFC/VTA dysregulation induced by hyperactive DAergic drive following adolescent THC exposure.

Beyond the role of DA, adolescent THC exposure has been found to induce long-term dysregulation in serotonin transmission [60,68], highlighting this system as a potential target for novel therapeutic approaches. In particular, Berthoux and colleagues [99] have shown that co-administration during adolescence of THC and the 5HT₆ receptor antagonist SB258585, was able to prevent long-lasting cognitive impairments and aberrations in cortical networks, such as sustained activation of mTOR, excitatory/inhibitory transmission imbalances as well as changes in the intrinsic properties of cortical pyramidal neurons and LTD (Table 1). These THC-induced abnormalities were abolished also following concomitant treatment with the mTOR inhibitor rapamycin and were not detected in 5HT₆ receptor deficiency mice, supporting the crucial role of these receptors in THC-related pathology. Consistently, antagonism of 5HT₆ receptor has been previously observed to be effective in developmental models of schizophrenia [100]. In addition, these findings underscore the important role of mTOR dysregulation as a molecular mechanism underlying THC-induced neurodevelopmental pathophysiology [54,81].

Many studies have also investigated the potential protective properties of CBD, due to its antipsychotic profile and apparent lack of deleterious side-effects. Indeed, CBD has been found to induce opposite effects on various neurophysiological measures when compared with THC [101], resulting in a promising therapeutic treatment for various neuropsychiatric disorders. For example, previous evidence has demonstrated that intra-NASh CBD administration ameliorated amphetamine-induced deficits in PPI, hyperlocomotion, and increased VTA DA activity [102]. A potential mechanism underlying these CBD effects has been suggested by Norris and colleagues [103], which have reported that CBD decreases spontaneous DAergic firing and bursting rates via functional interaction with the 5HT_1A receptor system. In addition, adolescent CBD in spontaneous hypertensive rats prevented the emergence of hyper-motility as well as impairments in sensorimotor gating and contextual fear memory, through modulation of the serotonin system [104]. Notably, therapeutic properties of CBD have been reported in chronic cannabis users, in which prolonged treatment significantly improved memory and cognition as well as decreased depressive-like symptoms, without inducing any side effects [105]. Moreover, CBD was found to normalize the anatomical and neurochemical hippocampal aberrations associated with chronic cannabis consumption [106,107]. Similar preventive effects of CBD on long-term schizophrenia-like symptoms have been also reported in pre-clinical investigations. For example, Murphy and colleagues found that CBD and THC co-administration in adolescent mice prevented deficits in working memory, anxiety, and compulsive-like behaviors [108] (Table 1). Although the mechanisms are not yet fully elucidated, CBD may either antagonize THC effects via negatively modulating an allosteric site of CBRs [109] or interacting with other molecular substrates [101,110,111,112]. For instance, CBD has been found to exert its therapeutic properties by increasing serum levels of endogenous AEA, potentially through inhibition of the enzyme fatty acid amide hydrolase (FAAH) [113]. In support of this finding, administration of the FAAH inhibitor URB597 in adult female rats was able to rescue cognitive and depressive-like symptoms induced by adolescent THC exposure. Such effects, mediated by CB1R signaling, were associated with a higher density of cortical CB1Rs and restoration of THC-related functional aberrations occurring in PFC and DG [70,87] (Table 1). Moreover, increased levels of AEA may activate nuclear peroxisome proliferator-activated receptors alpha (PPARα), an isoform of the nuclear ligand-activated transcription factors family, which has been previously demonstrated to provide neuroprotective effects when measured in several neurodevelopmental models [114,115].

As previously mentioned, several genetic polymorphisms may be associated with increased susceptibility for cannabis-related neurodevelopmental pathology. For example, transgenic mice with dominant-negative disrupted in schizophrenia 1 (DN-DISC1) mutations exposed to THC during late adolescence, exhibited anxiolytic behaviors and memory impairments at adulthood, correlated with reduced synaptic plasticity in HC. Notably, wild-type (WT) but not DN-DISC1 THC-treated mice, showed a robust increase of BDNF levels, suggesting that the BDNF response may be a protective mechanism against environmental insults, which fail when other vulnerability factors co-exist. Indeed, BDNF over-expression selectively in DN-DISC1-THC mice was found to prevent the cognitive deficits [116] (Table 1). In addition, a more recent study suggested that such THC-induced memory impairments are mediated by astrocytic mechanisms. For example, adolescent THC treatment in mice expressing DN-DISC1 selectively in astrocytes, activates the proinflammatory pathway NF-kB-COX-2, leading to increased glutamate levels and decreased parvalbumin-positive boutons in HC. Remarkably, selective inhibition of COX-2 signaling, aimed to counteract this neuroinflammatory state, prevented the emergence of these cognitive and glutamatergic abnormalities following adolescent THC exposure [117] (Table 1).

Further investigations have suggested potential protective properties though the modulation of Neuregulin 1 (Nrg1), another gene related to schizophrenia and cannabis-induced neuropsychiatric effects. For example, Long and colleagues [118] reported that a transgenic model of mice heterozygous in the Nrg1 transmembrane domain (Nrg1 HET) exhibited less susceptibility to anxiety following adolescent acute THC exposure, while chronic THC did not reduce exploratory sniffing behavior during social interaction, as observed in WT control groups. Extending these behavioral effects, THC induced different consequences in the binding density of CB1 and 5-HT_2A receptors between Nrg1 HET and WT groups in brain areas related to schizophrenia. In addition, Nrg1 HET THC-exposed mice showed differential expression of hippocampal proteins associated with NMDA receptor trafficking, excessive glutamatergic transmission, excitotoxity and apoptosis when compared with WT mice [119] (Table 1). These observations suggested that the Nrg1 mutation may exert some protective effects toward THC-induced neurodevelopmental pathology.

Lastly, interventions targeting the epigenetic mechanisms involved in THC-related neurodevelopmental abnormalities have been proposed as a potential therapeutic target. In particular, THC exposure in adolescent female rats was found to significantly enhance a marker of the cortical repressive histone H3, through upregulation of the histone-modifying enzyme Suv39H. Co-administration during adolescence of a selective blocker of this enzyme was able to prevent the THC-induced cognitive impairments by normalization of these selective histone modifications [69] (Table 1). Notably, H3 methylation plays a crucial role in normal brain development and GABAergic neurotransmission [120], which raise the possibility that modulation of the histone H3 may restore the cortical inhibitory/excitatory imbalance induced by adolescent THC exposure. Future studies are required to further clarify these possibilities.