Miriam Schneider

Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure

During puberty, neuronal maturation of the brain, which began during perinatal development, is completed such that the behavioral potential of the adult organism can be fully achieved. These maturational events and processes of reorganization are needed for the occurrence of adult behavioral performance but simultaneously render the organism highly susceptible to perturbations, such as exposure to psychoactive drugs, during this critical developmental time span. Considering the variety of maturational processes occurring in the endocannabinoid system during this critical period, it is not surprising that the still‐developing brain might by highly susceptible to cannabis exposure. Emerging evidence from human studies and animal research demonstrates that an early onset of cannabis consumption might have lasting consequences on cognition, might increase the risk for neuropsychiatric disorders, promote further illegal drug intake and increase the likelihood of cannabis dependence. These findings suggest that young people represent a highly vulnerable cannabis consumer group and that they run a higher risk than adult consumers of suffering from adverse consequences from cannabinoid exposure. The aim of the present review is to provide an overview over the possible deleterious residual cannabinoid effects during critical periods of postnatal maturation and to offer a more precise delineation of the vulnerable time window for cannabinoid exposure.

Acute and chronic cannabinoid treatment differentially affects recognition memory and social behavior in pubertal and adult rats.

Although cannabis belongs to the most widely used drugs among adolescents, little is known about its acute and lasting neurobehavioral effects during critical developmental periods. In the present study we investigated acute and long‐term behavioral effects of the cannabinoid agonist WIN 55,212‐2 (WIN) in pubertal and adult rats. Chronic WIN (1.2 mg/kg)/vehicle treatment was extended over 25 days throughout puberty, from postnatal day (pd) 40 to pd 65, or for a similar time period in adult rats (> pd 80). All animals were tested at three time points for object/social recognition memory, social interaction and spontaneous social behavior. First, acute cannabinoid effects were investigated directly after the first injection. Additionally, behavioral performance was retested 24 hours and 15 days after cessation of WIN treatment. Chronic pubertal WIN treatment induced persistent object/social recognition deficits, indicating a general impairment in short‐term information processing. Lasting disturbances in social behavior, social play and self‐grooming were also found. Furthermore, behavioral deficits seen after acute WIN administration were more pronounced in pubertal than in adult rats. These results confirm our recent findings that chronic pubertal cannabinoid treatment leads to lasting behavioral alterations in adulthood, and they show that acute cannabinoid administration induces more severe behavioral deficits in pubertal rats than in mature animals. We therefore conclude that an immature brain is more susceptible to the acute and chronic effects of exogenous cannabinoids than an adult organism, which might be explained by an overactive endocannabinoid system and concomittant maturational disturbances in further neurotransmitter systems during pubertal development.

Deficient social and play behavior in juvenile and adult rats after neonatal cortical lesion: effects of chronic pubertal cannabinoid treatment.

The aim of the present study was to investigate the effects of neonatal excitotoxic lesions of the medial prefrontal cortex (mPFC) on social play, social behavior unrelated to play, and self-grooming in juvenile and adult rats. We additionally examined the behavioral effects of chronic pubertal treatment with the cannabinoid agonist WIN 55,212-2 (WIN) in order to test the hypothesis that early lesions render the brain vulnerable to cannabinoid intake in later life. Neonatal mPFC lesions and pubertal WIN treatment disrupted social play, social behavior, and self-grooming in juvenile and adult rats. Additionally, we observed more social play behaviors during light cycle in WIN-treated than in vehicle-treated rats. Notably, the combination of surgery and WIN treatment disrupted social behavior in lesioned and sham-lesioned rats. The present data indicate that the mPFC is important for adequate juvenile response selection in the context of social play and might be involved in the development of adult social and nonsocial behavior. Moreover, our data add further evidence for an involvement of the cannabinoid system in anxiety and social behavior. Additive effects of neonatal surgery-induced stress or cortical lesions in combination with pubertal cannabinoid administration are also shown. The disturbances of social and nonsocial behavior in rats are comparable to symptoms of early frontal cortex damage, as well as neurodevelopmental disorders in humans, such as schizophrenia and autism. Therefore, we propose the combination of neonatal cortical lesions with chronic cannabinoid administration during puberty as an animal model for studying neuronal mechanisms of impaired social functioning in neuropsychiatric disorders.

The cannabinoid agonist WIN 55,212-2 reduces sensorimotor gating and recognition memory in rats.

Cannabinoids can disrupt short-term memory in humans and animals and induce learning deficits and other cognitive impairments. In the present study we examined the role of a full cannabinoid agonist in short-term memory, sensorimotor gating, and the acquisition and expression of an operant learning paradigm in rats. We tested the effects of the synthetic cannabinoid WIN 55,212-2 (0.6 and 1.2 mg/kg) on short-term memory in social and object recognition tests, on prepulse inhibition (PPI) of startle, as well as on lever pressing for palatable food. Injections of 0.6 and 1.2 mg/kg WIN 55,212-2 impaired recognition memory and PPI in a dose-dependent manner, but had no effect on lever-pressing acquisition or expression, or on food preference. The PPI deficit was reversed by the administration of 0.1 mg/kg haloperidol. These data suggest that the synthetic cannabinoid WIN 55,212-2 does not lead to a general impairment of learning in an appetitive instrumental task, but significantly affects short-term memory and sensorimotor integration. The impairment in recognition and PPI might be due to deficits in attention-based short-term information processing.

Behavioral and morphological alterations following neonatal excitotoxic lesions of the medial prefrontal cortex in rats

The prefrontal cortex (PFC) is essential for executive functions in mammals. Damage of the developing PFC may partly be compensated over time, but may also lead to structural and functional deficits due to neurodevelopmental disturbances. The present study investigated the effects of excitotoxic lesions of the medial PFC (mPFC) in neonatal rats on brain morphology, myelination and behavior. Neonatal lesions were induced with ibotenate on postnatal day (pd) 7 and all animals were tested pre- and postpubertally for prepulse inhibition (PPI) of the acoustic startle reflex (ASR), locomotor activity and food preference. Furthermore, adult rats were tested for apomorphine sensitivity of PPI and for their performance in a progressive ratio operant response task. Neonatally lesioned animals showed a reduced volume of the mPFC, enlarged ventricles and a deficient myelination in some projection areas of the mPFC, including the thalamus, hippocampus, nucleus accumbens (NAC) and amygdala. PPI was enhanced in lesioned rats when tested as juveniles, but PPI-deficits induced by the dopamine receptor agonist apomorphine were exacerbated in adult rats after neonatal mPFC lesion. Furthermore, the break point in a progressive ratio task was lower in lesioned animals, whereas the total number of lever presses was initially increased, indicating an impulsive response of rats for food reward under a progressive ratio schedule after neonatal mPFC lesion. No effects were found on food preference and open field performance. These data support the hypothesis that neonatal mPFC lesions lead to disruptions of neurodevelopmental processes in a cortico-limbic-striatal network, which are manifested in adult animals as morphological and behavioral disturbances.

Effects of the cannabinoid receptor agonist win 55,212-2 on operant behavior and locomotor activity in rats

Cannabinoids influence the motivational state of a subject and affect motor behavior. In the present study, we examined the acute effects of the cannabinoid (CB) receptor agonist WIN 55,212-2 (WIN) in three different doses (0.6, 1.2 and 1.8 mg/kg) on the performance of rats in a progressive ratio operant behavior task and on locomotor activity. WIN dose-dependently reduced the break point and the total number of lever-presses under a progressive ratio schedule. A food preference test revealed a preference for freely available casein pellets over lab chow in all treatment groups, indicating no WIN-effects on primary motivation. There was a significant reduction in the amount of casein pellets consumed by animals treated with 1.8 mg/kg WIN. Locomotor activity in the open field was increased by 0.6 mg/kg, but not by higher doses of WIN. These data show that administration of the synthetic cannabinoid receptor agonist WIN leads to dose-dependent alterations of the performance in an operant behavior task and of motor behavior. We confirm previous findings of dose-dependent motor stimulating and inhibiting effects of cannabinoids, and show an impairment of a complex operant behavior at higher doses of WIN.

Reward Sensitivity for a Palatable Food Reward Peaks During Pubertal Developmental in Rats

Puberty is a critical period for the initiation of drug use and abuse. Because early drug use onset often accounts for a more severe progression of addiction, it is of importance to understand the underlying mechanisms and neurodevelopmental changes during puberty that are contributing to enhanced reward processing in teenagers. The present study investigated the progression of reward sensitivity toward a natural food reward over the whole course of adolescence in male rats (postnatal days 30–90) by monitoring consummatory, motivational behavior and neurobiological correlates of reward. Using a limited-free intake paradigm, consumption of sweetened condensed milk (SCM) was measured repeatedly in adolescent and adult rats. Additionally, early- and mid-pubertal animals were tested in Progressive Ratio responding for SCM and c-fos protein expression in reward-associated brain structures was examined after odor conditioning for SCM. We found a transient increase in SCM consumption and motivational incentive for SCM during puberty. This increased reward sensitivity was most pronounced around mid-puberty. The behavioral findings are paralleled by enhanced c-fos staining in reward-related structures revealing an intensified neuronal response after reward-cue presentation, distinctive for pubertal animals. Taken together, these data indicate an increase in reward sensitivity during adolescence accompanied by enhanced responsiveness of reward-associated brain structures to incentive stimuli, and it seems that both is strongly pronounced around mid-puberty. Therefore, higher reward sensitivity during pubertal maturation might contribute to the enhanced vulnerability of teenagers for the initiation of experimental drug use.

Mechanisms of disturbed emotion processing and social interaction in borderline personality disorder: state of knowledge and research agenda of the German Clinical Research Unit

The last two decades have seen a strong rise in empirical research in the mechanisms of emotion dysregulation in borderline personality disorder. Major findings comprise structural as well as functional alterations of brain regions involved in emotion processing, such as amygdala, insula, and prefrontal regions. In addition, more specific mechanisms of disturbed emotion regulation, e.g. related to pain and dissociation, have been identified. Most recently, social interaction problems and their underlying neurobiological mechanisms, e.g. disturbed trust or hypersensitivity to social rejection, have become a major focus of BPD research. This article covers the current state of knowledge and related relevant research goals. The first part presents a review of the literature. The second part delineates important open questions to be addressed in future studies. The third part describes the research agenda for a large German center grant focusing on mechanisms of emotion dysregulation in BPD.

Cannabis use in pregnancy and early life and its consequences: animal models

Cannabinoid receptors and their endogenous ligands have been detected from the earliest stages of embryonic development. The endocannabinoid system appears to play essential roles in these early stages for neuronal development and cell survival, although its detailed involvement in fundamental developmental processes such as proliferation, migration and differentiation has not yet been completely understood. Therefore, it is not surprising that manipulations of the endocannabinoid system by cannabinoid exposure during early developmental stages can result in long-lasting neurobehavioural consequences. The present review will summarize the possible residual behavioural effects of cannabinoid administration during pre- and perinatal as well as early postnatal development, derived from animal studies.

Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour

Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-CreFoxp1−/−mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-CreFoxp1−/− mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.