Elsevier

Life Sciences

Volume 92, Issues 8–9, 19 March 2013, Pages 446-452
Life Sciences

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Brain regional differences in CB1 receptor adaptation and regulation of transcription

https://doi.org/10.1016/j.lfs.2012.08.023Get rights and content

Abstract

Cannabinoid CB1 receptors (CB1Rs) are expressed throughout the brain and mediate the central effects of cannabinoids, including Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana. Repeated THC administration produces tolerance to cannabinoid-mediated effects, although the magnitude of tolerance varies by effect. Consistent with this observation, CB1R desensitization and downregulation, as well as induction of immediate early genes (IEGs), vary by brain region. Zif268 and c-Fos are induced in the forebrain after acute THC administration. Phosphorylation of the cAMP response-element binding protein (CREB) is increased in a region-specific manner after THC administration. Results differ between acute versus repeated THC injection, and suggest that tolerance to IEG activation might develop in some regions. Repeated THC treatment produces CB1R desensitization and downregulation in the brain, although less adaption occurs in the striatum as compared to regions such as the hippocampus. Repeated THC treatment also induces expression of ΔFosB, a very stable isoform of FosB, in the striatum. Transgenic expression of ∆FosB in the striatum enhances the rewarding effects of several drugs, but its role in THC-mediated effects is not known. The inverse regional relationship between CB1R desensitization and ∆FosB induction suggests that these adaptations might inhibit each other, although this possibility has not been investigated. The differential regional expression of individual IEGs by acute or repeated THC administration suggests that regulation of target genes and effects on CB1R signaling will contribute to the behavioral effects of THC.

Introduction

Cannabinoid type 1 receptors (CB1Rs) are potential therapeutic targets for numerous disorders but also mediate the psychoactive, motor and memory-impairing effects of cannabinoids, which limit their clinical use. The psychoactive effects of Δ9-tetrahydrocanabinol (THC), the main psychoactive constituent of marijuana, also contribute to its popularity as an illicit drug. Repeated marijuana use can produce tolerance and withdrawal symptoms, which are included in the DSMIV criteria for cannabis use disorder (American Psychiatric Association, 2000). Understanding the molecular mechanisms that underlie these cannabinoid properties is critical to developing strategies to overcome these adverse effects. Studies have shown that tolerance to repeated cannabinoid agonist administration occurs concurrently with CB1R desensitization (attenuated receptor-mediated G-protein and effector activity) and downregulation (loss of receptors). Studies from our laboratory and others have revealed that CB1R desensitization and downregulation vary by brain region in rodents treated with THC or synthetic cannabinoids (Sim-Selley, 2003). Similar regional differences in CB1R downregulation occur in the human brain (Villares, 2007, Hirvonen et al., 2011). CB1R desensitization and downregulation recover within days to weeks following cessation of treatment (Sim-Selley et al., 2006, Hirvonen et al., 2011), suggesting that long-lasting neurobiological changes produced by cannabinoids are mediated by additional mechanisms. Immediate Early Genes (IEGS) provide candidate mechanisms to regulate both short and longer-term adaptations to cannabinoids. IEGs are transcription factors that can be constitutively expressed or induced by stimuli to regulate the expression of target genes. Inducible IEGs, including zif268 (also called krox24 or egr1) and Fos (c-Fos, FosB, fos-related antigen 1 (Fra-1), Fra-2 and ΔFosB) and Jun (c-Jun, JunB and junD) families of transcription factors can be regulated by cannabinoids. Cannabinoids also regulate cAMP response element binding protein (CREB), which is constitutively expressed and its binding to DNA is regulated by phosphorylation by upstream kinases. This review will discuss cannabinoid-mediated regulation of these transcription factors in the brain and consider the possible functional consequences.

Section snippets

CNS expression of CB1Rs and IEGs

Co-distribution of CB1Rs and IEGs in the brain provides for potential interactions that could influence a variety of in vivo responses. CB1Rs are widely expressed in the brain, with high density in the prefrontal cortex, globus pallidus, substantia nigra, hippocampus, striatum (caudate-putamen and nucleus accumbens) and molecular layer of the cerebellum. Lower expression occurs in the hypothalamus, periaqueductal gray and basolateral amygdala. This expression profile corresponds with acute

Cannabinoid-regulated immediate early genes

The effect of cannabinoid administration on specific IEGs is discussed in the following sections. As shown in Table 1, acute versus repeated cannabinoid administration can regulate IEGs differently. As reported for other measures, differences in the drug and dose administered, timing of administration and species examined can produce different results between laboratories. The time between cannabinoid administration and tissue collection can also influence results, because many IEGs are only

Zif268

Expression of zif268 in the brain has been implicated in the regulation of neural plasticity, the proteosome complex and long term potentiation/memory formation (James et al., 2006). Acute cannabinoid administration enhances zif268 expression, whereas repeated treatment reduces expression. Mailleux et al. (1994) reported that zif268 mRNA increased in the cingulate cortex, fronto-parietal cortex and caudate-putamen of rats 20 min after acute THC (5 mg/kg) injection. Separate studies in the

CREB

Several drugs of abuse increase CREB activity, measured as CREB phosphorylation (pCREB) or total CREB bound to DNA (Nestler, 2004). Initial studies showed no changes in CREB bound to DNA in the caudate-putamen or cerebellum of rats that received THC (5–40 mg/kg b.i.d.) for 5 days with brain collection 21 days after the last injection (Rubino et al., 2003). Subsequent studies using acute THC (15 mg/kg) administration found increased pCREB levels in the caudate-putamen, hippocampus and cerebellum,

c-Fos

Fos (c-Fos, FosB, fos-related antigen 1 (Fra-1), Fra-2 and ΔFosB) and Jun (c-Jun, JunB and junD) families of transcription factors form AP-1 complexes that bind to AP-1 consensus sites on target genes. Mailleux et al. (1994) showed that c-Fos-ir and c-Jun-ir cells increased in the cingulate cortex when measured 20 min after THC (5 mg/kg) injection, whereas only c-Fos-ir cells increased in the fronto-parietal cortex and caudate-putamen. Subsequent studies showed an increase in c-Fos-ir cells in

FosB and ΔFosB

Fewer studies have assessed FosB and its truncated isoforms (ΔFosB, Fra-1 and Fra-2) following cannabinoid treatment. Fos antigens are generally induced rapidly and transiently after acute drug administration (e.g. c-Fos). However, ∆FosB, a C-terminally truncated splice variant of FosB, is stable and accumulates with repeated induction over time (e.g. during repeated drug treatment), and can be detected in neurons for several weeks after cessation of drug treatment (Chen et al., 1997, Perrotti

CB1R desensitization and downregulation

Studies have shown that CB1Rs in the caudate-putamen and its projection areas (globus pallidus and substantia nigra) show the least magnitude of CB1R desensitization and downregulation, whereas CB1Rs in the hippocampus exhibit the greatest magnitude of desensitization and downregulation in response to repeated THC administration (Sim-Selley, 2003). Similarly, CB1R adaptations in the striatum develop more slowly and recover more quickly than in regions such as the hippocampus (Breivogel et al.,

Conclusions

Acute administration of THC induces IEGs, including zif268, pCREB and c-Fos, in a brain region-dependent manner, with most studies reporting induction in the striatum, hippocampus and cortex. Repeated THC administration appears to produce less induction of CREB and zif268 in certain regions, suggesting the possible development of tolerance to this effect. The caudate-putamen and nucleus accumbens are of particular interest for their role in motivation and motor behaviors. CB1Rs in these regions

Conflict of Interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

These studies were supported by USPHS grants DA014277 (LJS) and F31-DA030227 (MFL).

References (67)

  • A. Miyamoto et al.

    Desensitization of Fos protein induction in rat striatum and nucleus accumbens following repeated administration of delta9-tetrahydrocannabinol

    Brain Res

    (1997)
  • A. Miyamoto et al.

    Roles of dopamine D1 receptors in delta 9-tetrahydrocannabinol-induced expression of Fos protein in the rat brain

    Brain Res

    (1996)
  • E.J. Nestler

    Molecular mechanisms of drug addiction

    Neuropharmacology

    (2004)
  • M.C. Peakman et al.

    Inducible, brain region-specific expression of a dominant negative mutant of c-Jun in transgenic mice decreases sensitivity to cocaine

    Brain Res

    (2003)
  • T. Rubino et al.

    Modulation of extracellular signal-regulated kinases cascade by chronic delta 9-tetrahydrocannabinol treatment

    Mol Cell Neurosci

    (2004)
  • T. Rubino et al.

    CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour

    Neuropharmacology

    (2008)
  • L.J. Sim-Selley et al.

    Effect of DeltaFosB overexpression on opioid and cannabinoid receptor-mediated signaling in the nucleus accumbens

    Neuropharmacology

    (2011)
  • J. Villares

    Chronic use of marijuana decreases cannabinoid receptor binding and mRNA expression in the human brain

    Neuroscience

    (2007)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders: DSM-IV-TR

    (2000)
  • J.A. Bibb et al.

    Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons

    Nature

    (1999)
  • C. Blazquez et al.

    Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease

    Brain

    (2011)
  • A.A. Boucher et al.

    Chronic treatment with Delta(9)-tetrahydrocannabinol impairs spatial memory and reduces zif268 expression in the mouse forebrain

    Behav Pharmacol

    (2009)
  • C.S. Breivogel et al.

    Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain

    J Neurochem

    (1999)
  • C. Capper-Loup et al.

    Concurrent activation of dopamine D1 and D2 receptors is required to evoke neural and behavioral phenotypes of cocaine sensitization

    J Neurosci

    (2002)
  • J. Chen et al.

    Chronic Fos-related antigens: stable variants of deltaFosB induced in brain by chronic treatments

    J Neurosci

    (1997)
  • J. Chen et al.

    Transgenic animals with inducible, targeted gene expression in brain

    Mol Pharmacol

    (1998)
  • D.C. D'Souza et al.

    Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis

    Neuropsychopharmacology

    (2008)
  • V. De Chiara et al.

    Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum

    J Neurosci

    (2010)
  • P. Derkinderen et al.

    Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus

    J Neurosci

    (2003)
  • N. Fan et al.

    Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Delta9-THC exposure-impaired hippocampal synaptic plasticity

    J Neurochem

    (2010)
  • S. Ghozland et al.

    Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors

    J Neurosci

    (2002)
  • M. Glass et al.

    Induction of the Krox 24 transcription factor in striosomes by a cannabinoid agonist

    Neuroreport

    (1995)
  • M. Haney et al.

    Marijuana withdrawal in humans: effects of oral THC or divalproex

    Neuropsychopharmacology

    (2004)
  • Cited by (0)

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