Δ9-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation.

Salvatore Lecca,Maria Scherma,Marco Pistis,Anna Lisa Muntoni,Antonio Luchicchi,Paola Fadda

doi:10.3389/fnbeh.2019.00202

Abstract

The combination of prenatal, such as maternal infections, and postnatal environmental insults (e.g., adolescent drug abuse) increases risks for psychosis, as predicted by the two-hit hypothesis of schizophrenia. Cannabis abuse during adolescence is widespread and is associated with increased risk of psychoses later in life. Here, we hypothesized that adolescent Δ9-tetrahydrocannabinol (THC) worsens the impact of prenatal maternal immune activation (MIA) on ventral tegmental area (VTA) dopamine cells in rat offspring. Additionally, since substance abuse disorder is particularly prevalent among schizophrenia patients, we also tested how VTA dopamine neurons in MIA offspring respond to acute nicotine and cocaine administration. We used a model of neurodevelopmental disruption based on prenatal administration of the polyriboinosinic-polyribocytidilic acid [poly (I:C)] in rats, which activates the maternal immune system by mimicking a viral infection and induces behavioral abnormalities and disruption of dopamine transmission relevant to psychiatric disorders in the offspring. Male offspring were administered THC (or vehicle) during adolescence (PND 45–55). Once adult (PND 70–90), we recorded the spontaneous activity of dopamine neurons in the VTA and their responses to nicotine and cocaine. MIA male offspring displayed reduced number, firing rate and altered activity pattern of VTA dopamine cells. Adolescent THC attenuated several MIA-induced effects. Both prenatal [poly (I:C)] and postnatal (THC) treatments affected the response to nicotine but not to cocaine. Contrary to our expectations, adolescent THC did not worsen MIA-induced deficits. Results indicate that the impact of cannabinoids in psychosis models is complex.

Highlights

Environmental factors, such as prenatal exposure to a variety of infectious agents and consequent maternal immune activation (MIA), can lead to aberrant brain development, emerging in pathological phenotypes, such as autism and schizophrenia (Hornig et al, 2018)
Considering that in humans early marijuana intake is associated with increased risk of psychoses later in life (Arseneault et al, 2004; Fergusson, 2004; Degenhardt and Hall, 2006), our hypothesis is that cannabinoid administration during adolescence in male rats exposed to MIA would worsen the outcome, as the two-hits hypothesis of schizophrenia predicts
Since substance abuse disorder, heavy tobacco smoking (Winterer, 2010) and stimulant use disorder (Hunt et al, 2018), is prevalent among schizophrenia patients we tested how ventral tegmental area (VTA) dopamine neurons in MIA offspring treated with THC and their controls respond to acute nicotine and cocaine administration

Summary

INTRODUCTION

Environmental factors, such as prenatal exposure to a variety of infectious agents and consequent maternal immune activation (MIA), can lead to aberrant brain development, emerging in pathological phenotypes, such as autism and schizophrenia (Hornig et al, 2018). In our previous studies we observed a marked alteration of VTA dopamine neuron activity (reduced firing rate, reduced number of spontaneously active cells and altered firing pattern) in male but not female offspring coupled with disruption of sensorimotor gating and of cognitive and social behavior, and increase in dopamine levels in the nucleus accumbens (Luchicchi et al, 2016; De Felice et al, 2019). Considering that in humans early marijuana intake is associated with increased risk of psychoses later in life (Arseneault et al, 2004; Fergusson, 2004; Degenhardt and Hall, 2006), our hypothesis is that cannabinoid administration during adolescence in male rats exposed to MIA would worsen the outcome, as the two-hits hypothesis of schizophrenia (genetic/prenatal plus postnatal environment factors) predicts. Since substance abuse disorder, heavy tobacco smoking (Winterer, 2010) and stimulant use disorder (Hunt et al, 2018), is prevalent among schizophrenia patients we tested how VTA dopamine neurons in MIA offspring treated with THC and their controls respond to acute nicotine and cocaine administration

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT