Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure

Highlights

• Prenatal THC induces an aberrant dopaminergic function in vivo.

• PCE male offspring manifest a DAD2 receptor sensitivity.

• PCE male progeny display maladptive responses to an acute unescapable stress.

Abstract

Cannabis is the illicit drug most widely used by pregnant women worldwide. Its growing acceptance and legalization have markedly increased the risks of child psychopathology, including psychotic-like experiences, which lowers the age of onset for a first psychotic episode. As the majority of patients with schizophrenia go through a premorbid condition long before this occurs, understanding neurobiological underpinnings of the prodromal stage of the disease is critical to improving illness trajectories and therapeutic outcomes. We have previously shown that male rat offspring prenatally exposed to Δ⁹-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area (VTA), converging on a hyperdopaminergic state. This leads to a silent psychotic-like endophenotype that is unmasked by a single exposure to THC. Here, we further characterized the VTA dopamine neuron and sensorimotor gating functions of PCE rats exposed to acute stress or a challenge of the D2 receptor agonist apomorphine, by using in vivo single-unit extracellular recordings and Prepulse Inhibition (PPI) analyses. At pre-puberty, PCE male rat offspring display a reduced population activity of VTA dopamine neurons in vivo, the majority of which are tonically active. PCE male progeny also exhibit enhanced sensitivity to dopamine D2 (DAD2) receptor activation and a vulnerability to acute stress, which is associated with compromised sensorimotor gating functions. This data extends our knowledge of the multifaceted sequelae imposed by PCE in the mesolimbic dopamine system of male pre-adolescent rats, which renders a neural substrate highly susceptible to subsequent challenges that may trigger psychotic-like outcomes.

Introduction

Psychosis and schizophrenia affect 20 million people worldwide GBD, 2018(WHO, 2019)(2018). Although it is typically diagnosed in late adolescence, it emerges earlier on in life, especially in males (Hollis and Rapoport, 2008). Clinical evidence indicates that prenatal cannabis exposure increases the risk for child psychopathology, including psychotic-like experiences (Bolhuis et al., 2018; Fine et al., 2019; Singh et al., 2020). Of note, these studies also suggest that PCE contributes to a significantly lower age of typical onset of first psychotic episode. However, the research on the mechanisms of prenatal cannabis-induced psychotic-like experiences and the underlying loss of sensorimotor gating functions before puberty remains understudied (Frau et al., 2019).

Although an association between prenatal cannabis exposure and diverse psychiatric disorders has been established, in high-income countries cannabis use among pregnant women has been on an alarming sharp rise, with the greatest use in the first trimester (Brown et al., 2017, Singh et al., 2020, Volkow et al., 2019). Indeed, this increasing cannabis legal availability has led to a common misconception that it is a safe natural remedy even during vulnerable periods such as pregnancy (Dickson et al., 2018; Jarlenski et al., 2017; O'Connor, 2018). Consequently, offspring neurodevelopment is at risk due to the interference of cannabis' ingredients with the important functions played by the endocannabinoid system during this period of vulnerability to insults (Alpar et al., 2016; Richardson et al., 2016; Scheyer et al., 2019). In particular, in utero exposure to cannabinoids such as cannabis' main psychoactive ingredient Δ9-tetrahydrocannabinol (THC), is an animal model of PCE (Hurd et al., 2019, Scheyer et al., 2019, Tirado Munoz et al., 2020).

According to the “two-hit” hypothesis of psychiatric disorders, PCE acts as a “first hit” by deranging offspring neurodevelopment towards the manifestation of psychiatric symptoms upon a “second hit” (e.g., early life adversity, drug abuse) (Richardson et al., 2016). Evidence shows that PCE affects the development of many brain regions involved in processing the salience of stimuli to support adaptive behaviors (Calvigioni et al., 2014; Hurd et al., 2019; Richardson et al., 2016; Scheyer et al., 2019; Szutorisz and Hurd, 2018; Tirado Munoz et al., 2020) where dopamine is key (Bromberg-Martin et al., 2010). The mesolimbic dopamine pathway, projecting from the ventral tegmental area (VTA) to subcortical regions, including the nucleus accumbens (NAc), signals motivational and incentive salience (Berridge, 2012; Kapur, 2003) and is closely related to psychosis and positive symptoms in schizophrenia (Ziauddeen and Murray, 2010). This signaling system, in males, is sensitized by PCE, which endows it with ‘silent’ functional aberrations, such as impaired sensorimotor gating, which manifest when acutely exposed to THC before puberty (Frau et al., 2019). In particular, PCE increases the probability of dopamine release upon an acute THC challenge exemplified by ex vivo firing activity of VTA dopamine neurons, in vivo extracellular dopamine levels in the NAc shell (NAcS), deficits of gating functions measured by pre-pulse inhibition (PPI) of startle reflex and psychomotor agitation. Notably, malnutrition or altered maternal care do not account for any of the abovementioned behavioral, cellular and molecular effects observed in male offspring (Frau et al., 2019).

Ergo, we further tested the hypothesis that PCE, in male pre-adolescent rats, induces a multifaceted dysregulation of the mesolimbic dopamine system conferring the offspring with a psychotic-like endophenotype vulnerable to acute challenges, including stress. By using in vivo electrophysiological and behavioral analyses, we find that PCE reduced the population activity of VTA dopamine neurons while increasing the percentage of those neurons tonically active in male offspring before puberty. Enhanced sensitivity of these cells to dopamine D2 (DAD2) receptor activation by apomorphine and to its PPI-disruptive effects accompany this PCE-endophenotype at prepuberty in male offspring. Furthermore, acute inescapable and restraint stress deteriorate gating functions only in PCE male pre-adolescent rats. This data extends our understanding of the multifaceted developmental deviations of the male rat mesolimbic dopamine system imposed by PCE and beginning early in life. We propose that this animal model potentially recapitulates a vulnerable phenotype to psychosis that might prove useful for elucidating the mechanisms underlying the vulnerability displayed by PCE children towards psychotic-like experiences.