Development of Cannabinoid 1 Receptor Protein and Messenger RNA in Monkey Dorsolateral Prefrontal Cortex

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Cerebral Cortex (Impact Factor: 8.67). 09/2009; 20(5):1164-74. DOI: 10.1093/cercor/bhp179
Source: PubMed


Adolescent cannabis use is associated with an increased risk of schizophrenia and with impairments in cognitive processes reliant on the circuitry of the dorsolateral prefrontal cortex (DLPFC). Additionally, maternal cannabis use is associated with cognitive dysfunction in offspring. The effects of cannabis are mediated by the cannabinoid 1 receptor (CB1R), which is present in high density in the primate DLPFC. In order to determine how developmental changes in CB1Rs might render DLPFC circuitry vulnerable to cannabis exposure, we examined the density and innervation patterns of CB1R-immunoreactive (IR) axons and the expression of CB1R mRNA in the DLPFC from 81 macaque monkeys, ranging in age from embryonic 82 days to 18 years. Overall CB1R immunoreactivity in the gray matter robustly increased during the perinatal period and achieved adult levels by 1 week postnatal. However, laminar analyses revealed that CB1R-IR axon density significantly decreased with age in layers 1-2 but significantly increased in layer 4, especially during adolescence. In contrast, CB1R mRNA levels were highest 1 week postnatal, declined over the next 2 months, and then remained unchanged into adulthood. These findings provide a potential substrate for discrete, age-dependent effects of cannabis exposure on the maturation of primate DLPFC circuitry.

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Available from: Stephen Eggan, Mar 29, 2014
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    • "GABAergic neurons in the prefrontal cortex are rich in CB1 receptors which, when activated, result in a decrease in extracellular GABA release (28). It has been hypothesized that repeated exposure to cannabis during adolescence may alter the balance of GABAergic inhibitory inputs to pyramidal neurons in the prefrontal cortex that could lead to impaired cognitive function (29). Furthermore, CU leads to increased extracellular dopamine; probably through the activation of CB1 receptors on GABAergic interneurons, which in turn disinhibit dopaminergic neurons (30). "
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    ABSTRACT: The nature of the relationship between cannabis use (CU) and psychosis is complex and remains unclear. Researchers and clinicians remain divided regarding key issues such as whether or not cannabis is an independent cause of psychosis and schizophrenia. This paper reviews the field in detail, examining questions of causality, the neurobiological basis for such causality and for differential inter-individual risk, the clinical and cognitive features of psychosis in cannabis users, and patterns of course and outcome of psychosis in the context of CU. The author proposes two major pathways from cannabis to psychosis based on a differentiation between early-initiated lifelong CU and a scenario where vulnerable individuals without a lifelong pattern of use consume cannabis over a relatively brief period of time just prior to psychosis onset. Additional key factors determining the clinical and neurobiological manifestation of psychosis as well as course and outcome in cannabis users include: underlying genetic and developmental vulnerability to schizophrenia-spectrum disorders; and whether or not CU ceases or continues after the onset of psychosis. Finally, methodological guidelines are presented for future research aimed at both elucidating the pathways that lead from cannabis to psychosis and clarifying the long-term outcome of the disorder in those who have a history of using cannabis.
    Full-text · Article · Oct 2013 · Frontiers in Psychiatry
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    • "The robust decrease in CB1R mRNA expression in layer II from early life to adulthood in our human cohort agrees with previous findings in primate [67] and suggests strong regulation of neurotransmission by CB1Rs early in life (Figure 8). It is tempting to speculate that this CB1R down-regulation results in a gradual reduction in CB1R-mediated suppression of inhibitory presynaptic neurotransmission. "
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    ABSTRACT: Endocannabinoids provide control over cortical neurotransmission. We investigated the developmental expression of key genes in the endocannabinoid system across human postnatal life and determined whether they correspond to the development of markers for inhibitory interneurons, which shape cortical development. We used microarray with qPCR validation and in situ hybridisation to quantify mRNA for the central endocannabinoid receptor CB1R, endocannabinoid synthetic enzymes (DAGLα for 2-arachidonylglycerol [2-AG] and NAPE-PLD for anandamide), and inactivating enzymes (MGL and ABHD6 for 2-AG and FAAH for anandamide) in human dorsolateral prefrontal cortex (39 days - 49 years). CB1R mRNA decreases until adulthood, particularly in layer II, after peaking between neonates and toddlers. DAGLα mRNA expression is lowest in early life and adulthood, peaking between school age and young adulthood. MGL expression declines after peaking in infancy, while ABHD6 increases from neonatal age. NAPE-PLD and FAAH expression increase steadily after infancy, peaking in adulthood. Stronger endocannabinoid regulation of presynaptic neurotransmission in both supragranular and infragranular cortical layers as indexed through higher CB1R mRNA may occur within the first few years of human life. After adolescence, higher mRNA levels of the anandamide synthetic and inactivating enzymes NAPE-PLD and FAAH suggest that a late developmental switch may occur where anandamide is more strongly regulated after adolescence than earlier in life. Thus, expression of key genes in the endocannabinoid system changes with maturation of cortical function.
    Full-text · Article · Jul 2012 · BMC Neuroscience
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    • "All remaining animals were unperfused and experimentally naı¨ve. Monkeys were assigned to age groups (Supplementary Table S3) that were established by previous studies (Hashimoto et al. 2009; Eggan et al. 2010). RNA was isolated from the frontal pole (PFC area 10) due to the availability of existing tissue. "
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    ABSTRACT: Certain cognitive deficits in schizophrenia have been linked to dysfunction of prefrontal cortical (PFC) γ-aminobutyric acid (GABA) neurons and appear neurodevelopmental in nature. Since opioids suppress GABA neuron activity, we conducted the first study to determine 1) whether the μ opioid receptor (MOR), δ opioid receptor (DOR), and opioid ligand proenkephalin are altered in the PFC of a large cohort of schizophrenia subjects and 2) the postnatal developmental trajectory in monkey PFC of opioid markers that are altered in schizophrenia. We used quantitative polymerase chain reaction to measure mRNA levels from 42 schizophrenia and 42 matched healthy comparison subjects; 18 monkeys chronically exposed to haloperidol, olanzapine, or placebo; and 49 monkeys aged 1 week–11.5 years. We found higher levels for MOR mRNA (+27%) in schizophrenia but no differences in DOR or proenkephalin mRNAs. Elevated MOR mRNA levels in schizophrenia did not appear to be explained by substance abuse, psychotropic medications, or illness chronicity. Finally, MOR mRNA levels declined through early postnatal development, stabilized shortly before adolescence and increased across adulthood in monkey PFC. In schizophrenia, higher MOR mRNA levels may contribute to suppressed PFC GABA neuron activity and might be attributable to alterations in the postnatal developmental trajectory of MOR signaling.
    Preview · Article · Aug 2011 · Cerebral Cortex
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