MinireviewBrain regional differences in CB1 receptor adaptation and regulation of transcription
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).
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