Developmental consequences of perinatal cannabis exposure : behavioral and neuroendocrine effects in adult rodents

Patrizia Campolongo, Viviana Trezza, Patrizia Ratano, Maura Palmery & Vincenzo Cuomo

Psychopharmacology, 2011, 214, 5–15

Doi : 10.1007/s00213-010-1892-x

 

Abstract

Rationale : Cannabis is the most commonly used illicit drug among pregnant women. Since the endocannabinoid system plays a crucial role in brain development, maternal exposure to cannabis derivatives might result in longlasting neurobehavioral abnormalities in the exposed offspring. It is difficult to detect these effects, and their underlying neurobiological mechanisms, in clinical cohorts, because of their intrinsic methodological and interpretative issues.

Objectives : The present paper reviews relevant rodent studies examining the long-term behavioral consequences of exposure to cannabinoid compounds during pregnancy and/or lactation.

Results : Maternal exposure to even low doses of cannabinoid compounds results in atypical locomotor activity, cognitive impairments, altered emotional behavior, and enhanced sensitivity to drugs of abuse in the adult rodent offspring. Some of the observed behavioral abnormalities might be related to alterations in stress hormone levels induced by maternal cannabis exposure.

Conclusions : There is increasing evidence from animal studies showing that cannabinoid drugs are neuroteratogens which induce enduring neurobehavioral abnormalities in the exposed offspring. Several preclinical findings reviewed in this paper are in line with clinical studies reporting hyperactivity, cognitive impairments and altered emotionality in humans exposed in utero to cannabis. Conversely, genetic, environmental and social factors could also influence the neurobiological effects of early cannabis exposure in humans.

Keywords : Cannabis . THC . Pregnancy . Lactation . Development . Neurobehavioral teratology . Learning and memory . Anxiety . Stress hormones

 

Introduction

Since the identification of the fetal alcohol syndrome (FAS) in the 1970s (Jones and Smith 1973), there has been a dramatic increase in the number of clinical and preclinical reports examining the short- and long-term effects of maternal exposure to drugs of abuse. While maternal exposure to high doses of alcohol, cocaine, opiates, cannabis, and tobacco results in impaired growth and morphological abnormalities in the offspring (El Marroun et al. 2009; Kosofsky and Hyman 2001; Thompson et al. 2009), low to moderate drug abuse during pregnancy and lactation has also been related to subtle, albeit lasting, postnatal alterations in brain function and behavior. Research into these mostly subtle associations between maternal drug use and offspring neurobehavioral alterations utilizes the concepts and methods of neurobehavioral teratology (Coyle et al. 1976; Vorhees 1989).

Over the years, general teratological principles have been modified and extended to research in behavioral teratology, resulting in two major postulates (Vorhees 1989): (1) vulnerability of the central nervous system (CNS) to injury extends throughout the fetal and neonatal periods and beyond the infancy stage, including all aspects of nervous system development (e.g., neurogenesis, neuronal differentiation, arborization, synaptogenesis, functional synaptic organization, myelination, gliogenesis, glial migration, and differentiation), and (2) the most frequent manifestation of injury to the developing CNS does not result in nervous system malformations, but rather in functional abnormalities that may not be detectable at birth.

In recent years, both clinical and preclinical studies have shown that exposure to cannabis preparations during pregnancy and lactation can induce behavioral teratogenic consequences (Campolongo et al. 2009b; Fried 2002; Fried and Smith 2001; Huizink and Mulder 2006; Navarro et al. 1995; Schneider 2009; Trezza et al. 2008b); indeed, the main psychoactive component of cannabis, Δ9 tetrahydro-cannabinol (THC), can cross the placenta during gestation, and be secreted in the maternal milk during lactation (Hutchings et al. 1989; Jakubovic et al. 1977). Studies on the long-term behavioral ab-normalities induced by maternal cannabis exposure are of special relevance, for two main reasons. First, nowadays cannabis preparations are among the illicit drugs most widely used by pregnant women in Western countries (Fried and Smith 2001); for instance, the self-reported use of cannabis during
pregnancy is approximately 2.9% in the United States (Huizink and Mulder 2006), and reaches 5% in the United Kingdom (Fergusson et al. 2002). Second, since the endocannabinoid system is present and already functional in early pregnancy (Fernandez-Ruiz et al. 2000; Fride 2008; Harkany et al. 2007), the active ingredients of cannabis and their metabolites could directly affect the brain by altering endocannabinoid signaling and related neurotransmitter and neuroendocrine systems.

A common problem in neurobehavioral teratology is that the identification of subtle neurodevelopmental phenotypes after exposure to drugs of abuse during pregnancy and lactation is often elusive (Kosofsky and Hyman 2001; Thompson et al. 2009). The effects of drugs that alter brain development without a physical phenotype or an easily identified neurodevelopmental behavioral phenotype such as seizures or retardation may go undetected and underreported, despite significant impact on brain development and behavior (Kosofsky and Hyman 2001). Furthermore, clinical studies face the extreme complexities of interacting genetic, intrauterine, and postnatal environmental factors that contribute to the drug-induced phenotype. Thus, in order to provide a deeper understanding of the impact of maternal exposure to drugs of abuse on infant and child on later development, and to adopt effective public health strategies, it is critical to stimulate a dialogue between clinical and preclinical investigators. While clinical studies allow to detect basic behavior and some aspects of functional neural activity in humans exposed to drugs of abuse during development, they do not provide information about the specific neuroanatomical, molecular, and cellular consequences that underlie the observed behavioral changes
(Thompson et al. 2009). Furthermore, animal studies are essential in controlling for prenatal and postnatal confounding factors and for examining the independent contribution of a certain drug to adverse neurodevelopmental consequences (Fried 2002).

Here, we will summarize and discuss rodent studies examining the long-term behavioral consequences induced by exposure to cannabinoid compounds during pregnancy and/or lactation. First, we will focus on the impact of maternal exposure to cannabinoids on motor behavior, cognitive performance and emotionality in the rat adult offspring. Then, we will examine the role played by maternal cannabinoid
exposure in the susceptibility to discriminative and reinforcing effects of drugs of abuse later in life. Last, we will provide experimental evidence showing that maternal cannabis exposure induces long-lasting changes in stress hormones which, in turn, might underlie some of the behavioral changes observed in the exposed offspring. We will consider only studies that used doses of cannabinoid compounds devoid of overt signs of toxicity and/or grossmalformations, and that are equivalent to moderate cannabis consumption in humans. For a review of morphological abnormalities and overt signs of toxicity induced by maternal exposure to high doses of cannabinoid compounds, see Abel (1980), El Marroun et al. (2009), Fergusson et al. (2002), Linn et al. (1983).

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