Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure
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.
Section snippets
Subjects
All procedures were performed in accordance with the European legislation EU Directive 2010/63 and were approved by the Animal Ethics Committees of the University of Cagliari and by Italian Ministry of Health (auth. n. 659/2015-PR). We made all efforts to minimize pain and suffering and to reduce the number of animals used. Primiparous female Sprague Dawley (Envigo) rats were used as mothers and single housed during pregnancy. Offspring were weaned at ~PND21 and maintained without any further
Impact of PCE on VTA putative dopamine neurons in vivo
Aberrant reward learning is common in symptomatic schizophrenic patients and in individuals at risk of developing psychosis (Roiser et al., 2013; Roiser et al., 2009). To further investigate whether PCE impacts electrophysiological properties of dopamine neurons, we recorded the extracellular spontaneous activity of 133 putative dopamine neurons located in the lateral posterior VTA (Fig. 1a) of in vivo anesthetized male preadolescent rats. In fact, we previously found that PCE effect on
Discussion
The major finding of the present study is that maternal THC exposure induces a multifaceted dysregulation of dopamine cell activity in vivo in male rat offspring at prepuberty. This not only promotes a psychotic-like endophenotype susceptible to an otherwise ineffective dose of THC (present data and (Frau et al., 2019), but also to acute stress. As acute stress deteriorates gating functions, one of the best established translational endophenotypes of schizophrenia, only in PCE male
Funding and disclosure
This work was supported by University of Cagliari (RICCAR 2018 and 2019 to MM), Fondazione Zardi Gori (to CS), National Institute of Health (DA044925 to MM and JFC). The authors declare no conflict of interest.
Declaration of Competing Interest
None.
Acknowledgements
We thank M. Tuveri, S. Aramo, and B. Tuveri for their skillful assistance.
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These authors contributed equally to this work.