title: Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia.
abstract: Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose-time-effect relationship should be central.
authors.affiliation: Rudolf Magnus Institute of Neuroscience, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Matthijs G
authors.initials: MG
authors.lastname: Bossong
authors.forename: Raymond J M
authors.initials: RJ
authors.lastname: Niesink
mesh_terms: D000293:Adolescent; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development* / Q000503:physiopathology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D002188:Cannabis / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology; D006801:Humans; D002189:Marijuana Abuse / Q000503:physiopathology; D008959:Models, Neurological; D009415:Nerve Net / Q000187:drug effects; D009446:Neurobiology; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000139:chemically induced* / Q000503:physiopathology*; D013569:Synapses / Q000502:physiology
chemical_list: D063385:Cannabinoid Receptor Modulators; D018377:Neurotransmitter Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013759:Dronabinol