Susceptibility of the adolescent brain to cannabinoids

Long-term hippocampal effects and relevance to schizophrenia

K. A. Gleason, S. G. Birnbaum, A. Shukla, S. Ghose

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Clinical studies report associations between cannabis use during adolescence and later onset of schizophrenia. We examined the causal relationship between developmental cannabinoid administration and long-term behavioral and molecular alterations in mice. Mice were administered either WIN 55,212-2 (WIN), a cannabinoid receptor 1 (CB1) agonist or vehicle (Veh) during adolescence (postnatal day 30-35) or early adulthood (postnatal day 63-70). Behavioral testing was conducted after postnatal day 120 followed by biochemical assays. Adolescent cannabinoid treatment (ACU) leads to deficits in prepulse inhibition and fear conditioning in adulthood. Metabotropic glutamate receptors type 5 (mGluR5), a receptor critically involved in fear conditioning and endocannabinoid (eCB) signaling, is significantly reduced in the ACU mouse hippocampus. Next, we examined expression profiles of genes involved in eCB synthesis (diacylglycerol lipase (DGL)) and uptake (monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH)) in the experimental mice. We find evidence of increased MGL and FAAH in ACU mice, reflecting increases in eCB uptake and degradation. These data suggest that administration of cannabinoids during adolescence leads to a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations in sensorimotor gating and hippocampal-dependent learning and memory deficits. Further, these deficits are associated with a reduction in hippocampal mGluR5 and a sustained change in eCB turnover, suggesting reduced eCB signaling in the ACU hippocampus. These data suggest that significant cannabis use during adolescence may be a contributory causal factor in the development of certain features of schizophrenia and may offer mGluR5 as a potential therapeutic target.

Original languageEnglish (US)
Article numbere199
JournalTranslational Psychiatry
Volume2
DOIs
StatePublished - 2012

Fingerprint

Endocannabinoids
Cannabinoids
Metabotropic Glutamate 5 Receptor
Schizophrenia
Monoacylglycerol Lipases
Brain
Cannabis
Fear
Hippocampus
Sensory Gating
Cannabinoid Receptor Agonists
Lipoprotein Lipase
Memory Disorders
Transcriptome
Rodentia
Learning
Phenotype
Therapeutics

Keywords

  • adolescence
  • cannabis
  • endocannabinoid
  • hippocampus
  • mGluR5

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience

Cite this

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title = "Susceptibility of the adolescent brain to cannabinoids: Long-term hippocampal effects and relevance to schizophrenia",
abstract = "Clinical studies report associations between cannabis use during adolescence and later onset of schizophrenia. We examined the causal relationship between developmental cannabinoid administration and long-term behavioral and molecular alterations in mice. Mice were administered either WIN 55,212-2 (WIN), a cannabinoid receptor 1 (CB1) agonist or vehicle (Veh) during adolescence (postnatal day 30-35) or early adulthood (postnatal day 63-70). Behavioral testing was conducted after postnatal day 120 followed by biochemical assays. Adolescent cannabinoid treatment (ACU) leads to deficits in prepulse inhibition and fear conditioning in adulthood. Metabotropic glutamate receptors type 5 (mGluR5), a receptor critically involved in fear conditioning and endocannabinoid (eCB) signaling, is significantly reduced in the ACU mouse hippocampus. Next, we examined expression profiles of genes involved in eCB synthesis (diacylglycerol lipase (DGL)) and uptake (monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH)) in the experimental mice. We find evidence of increased MGL and FAAH in ACU mice, reflecting increases in eCB uptake and degradation. These data suggest that administration of cannabinoids during adolescence leads to a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations in sensorimotor gating and hippocampal-dependent learning and memory deficits. Further, these deficits are associated with a reduction in hippocampal mGluR5 and a sustained change in eCB turnover, suggesting reduced eCB signaling in the ACU hippocampus. These data suggest that significant cannabis use during adolescence may be a contributory causal factor in the development of certain features of schizophrenia and may offer mGluR5 as a potential therapeutic target.",
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T2 - Long-term hippocampal effects and relevance to schizophrenia

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AU - Shukla, A.

AU - Ghose, S.

PY - 2012

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N2 - Clinical studies report associations between cannabis use during adolescence and later onset of schizophrenia. We examined the causal relationship between developmental cannabinoid administration and long-term behavioral and molecular alterations in mice. Mice were administered either WIN 55,212-2 (WIN), a cannabinoid receptor 1 (CB1) agonist or vehicle (Veh) during adolescence (postnatal day 30-35) or early adulthood (postnatal day 63-70). Behavioral testing was conducted after postnatal day 120 followed by biochemical assays. Adolescent cannabinoid treatment (ACU) leads to deficits in prepulse inhibition and fear conditioning in adulthood. Metabotropic glutamate receptors type 5 (mGluR5), a receptor critically involved in fear conditioning and endocannabinoid (eCB) signaling, is significantly reduced in the ACU mouse hippocampus. Next, we examined expression profiles of genes involved in eCB synthesis (diacylglycerol lipase (DGL)) and uptake (monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH)) in the experimental mice. We find evidence of increased MGL and FAAH in ACU mice, reflecting increases in eCB uptake and degradation. These data suggest that administration of cannabinoids during adolescence leads to a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations in sensorimotor gating and hippocampal-dependent learning and memory deficits. Further, these deficits are associated with a reduction in hippocampal mGluR5 and a sustained change in eCB turnover, suggesting reduced eCB signaling in the ACU hippocampus. These data suggest that significant cannabis use during adolescence may be a contributory causal factor in the development of certain features of schizophrenia and may offer mGluR5 as a potential therapeutic target.

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