Adolescent Cannabinoid Exposure Induces a Persistent Sub-Cortical Hyper-Dopaminergic State and Associated Molecular Adaptations in the Prefrontal Cortex

Abstract

Considerable evidence suggests that adolescent exposure to delta-9-tetrahydrocanabinol (THC), the psychoactive component in marijuana, increases the risk of developing schizophrenia-related symptoms in early adulthood. In the present study, we used a combination of behavioral and molecular analyses with in vivo neuronal electrophysiology to compare the long-term effects of adolescent versus adulthood THC exposure in rats. We report that adolescent, but not adult, THC exposure induces long-term neuropsychiatric-like phenotypes similar to those observed in clinical populations. Thus, adolescent THC exposure induced behavioral abnormalities resembling positive and negative schizophrenia-related endophenotypes and a state of neuronal hyperactivity in the mesocorticolimbic dopamine (DA) pathway. Furthermore, we observed profound alterations in several prefrontal cortical molecular pathways consistent with sub-cortical DAergic dysregulation. Our findings demonstrate a profound dissociation in relative risk profiles for adolescent versus adulthood exposure to THC in terms of neuronal, behavioral, and molecular markers resembling neuropsychiatric pathology.

Consequences of adolescent use of alcohol and other drugs: Studies using rodent models

“…This type of cognitive filtering is often indexed in rodent studies via assessing the reduction in startle response to a loud tone when that stimulus is immediately preceded by a weaker, non-startle-inducing tone – a phenomenon known as pre-pulse inhibition (PPI). Long-term deficits in PPI have been frequently observed in rodent studies after CB exposure during adolescence, but not when animals received equivalent exposure in adulthood (e.g., Renaud et al, 2016), supporting the association of CB action on the adolescent brain with the later induction of schizophrenia-like alterations.…”

“…Several studies have observed reductions in social behavior (O’Shea et al, 2004, 2006; Schneider, 2008; Schneider et al, 2008; Realini et al, 2011), perhaps associated in part with decreases in social motivation (Renaud et al, 2016) and increases in social anxiety (O’Shea et al, 2004, 2006). Social anxiety has occasionally (O’Shea et al, 2006; Quinn et al, 2008) but not typically (O’Shea et al, 2004; Schneider, 2008; Schneider et al, 2008) been reported after equivalent CB exposure in adulthood.…”

“…Studies using non-social measures of anxiety have reported mixed results. Some studies, for instance, have reported increased anxiety after adolescent CB exposure in the light-dark box (indexed via fewer entries and longer latencies to enter the light side - Renaud et al, 2016) and in the EPM (Stopponi et al, 2014). Others, in contrast, have reported no notable alterations in anxiety (e.g., Higuera-Matas et al, 2009; O’Tuathaigh et al, 2010; Keeley et al, 2015) or in some cases even decreases in anxiety (e.g., Biscaia et al, 2003; also, see O’Tuathaigh et al, 2010; Keeley et al, 2015) in EPM tests – a diversity that, as discussed earlier, could potentially reflect the same tests reflecting anxiety versus “disinhibitory” profiles, depending on the specific pre-test or test conditions.…”

Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System

“…Importantly, the ability of CBD to inhibit mesolimbic DAergic activity and blunt fearrelated memory formation is particularly intriguing given the large body of evidence demonstrating that the primary psychoactive phytochemical in cannabis, THC, produces propsychotic effects (Kuepper et al, 2011). Furthermore, in direct contrast to the effects of CBD, THC has been shown to induce a state of hyperactive mesolimbic DAergic activity following adolescent neurodevelopmental exposure (Renard et al, 2016a). In addition, we have recently reported that intra-NASh CBD blocks hyper-DAergic activity and psychomotor sensitization induced by amphetamine exposure (Renard et al, 2016b).…”

“…In terms of psychotropic profiles, THC is associated with transient and long-term psychotomimetic effects Murray et al, 2007), whereas clinical and preclinical research has shown that CBD can produce antipsychotic and anxiolytic effects (Crippa et al, 2011;Campos et al, 2012;Fogaca et al, 2014;Zuardi et al, 2006Zuardi et al, , 2012Mechoulam et al, 2007;Leweke et al, 2012;Renard et al, 2016a;Schubart et al, 2014;Gomes et al, 2015). In addition, CBD may modulate emotional memory processing and decrease symptoms associated with emotional memory disorders such as post-traumatic stress disorder (PTSD; Blessing et al, 2015,Betthauser et al, 2015.…”