Effects of long-term exposure to Δ9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions

Zhuang, Shou-Yuan; Kittler, Josef T.; Grigorenko, Elena; Kirby, Michael; Sim, Laura J.; Hampson, Robert E.; Childers, Steven R.; Deadwyler, Sam A.

doi:10.1016/s0169-328x(98)00232-0

Cited by 101 publications

(70 citation statements)

References 31 publications

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“…In striatum/GP, however, CB 1 receptor mRNA was significantly decreased by ⌬ 9 -THC at 1 day after treatment. Both of these results are in agreement with previously published findings on brain region-dependent effects of long-term cannabinoid administration on CB 1 receptor transcription (Rubino et al, 1994;Zhuang et al, 1998). Although decreased CB 1 receptor mRNA in striatum/GP could contribute to CB 1 receptor down-regulation, the time course of recovery of CB 1 mRNA in this region (3 days) did not match the normalization rate of CB 1 receptor protein or binding (7 days).…”

Section: Discussionsupporting

confidence: 90%

“…Likewise, Cichewicz et al (2001) reported no decrease in CB 1 receptor protein in midbrain or spinal cord of mice administered oral THC for 6.5 days. Moreover, Zhuang et al (1998) reported that the time course of changes in CB 1 receptor mRNA during long-term THC treatment did not correspond well with the time course of changes in CB 1 receptor binding sites. Thus, it remains to be determined whether down-regulation of CB 1 receptor binding sites is mediated by a reduction in CB 1 receptor protein and, if so, to what extent transcriptional regulation plays a role in this adaptive response.…”

mentioning

confidence: 99%

“…Moreover, studies have demonstrated the time-dependent nature of the development of down-regulation and desensitization, with CB 1 receptors in hippocampus and cerebellum exhibiting greater magnitude and more rapid adaptations than those in basal ganglia (Breivogel et al, 1999). Changes in CB 1 receptor mRNA also occur in these regions, but the magnitude and direction of change vary with treatment duration (Zhuang et al, 1998). Studies have also characterized temporal characteristics of the development of tolerance to cannabinoid-mediated memory impairment (Deadwyler et al, 1995), hypomotility (Bass and Martin, 2000;Whitlow et al, 2002), antinociception (Bass and Martin, 2000), and hypothermia (Whitlow et al, 2002) and showed differences in the rate of tolerance development to these effects.…”

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confidence: 99%

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Prolonged Recovery Rate of CB₁ Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Sim‐Selley

Schechter²,

Rorrer³

et al. 2006

Mol Pharmacol

102

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Long-term cannabinoid administration produces region-dependent CB 1 receptor desensitization and down-regulation. This study examined the time course for normalization of CB 1 receptors and G-protein activation using 35 S]GTP␥S binding were decreased in both regions 1 day after treatment. WIN55,212-2-stimulated G-protein activation in striatum/GP returned to control level at 3 days after cessation of treatment with either drug but did not return to control level in hippocampus until 14 days. CB 1 receptor binding did not recover to control levels until day 7 or 14 after treatment in striatum/GP and hippocampus, respectively. The mechanism of CB 1 binding site down-regulation was investigated after long-term ⌬ 9 -THC treatment. Analysis of CB 1 receptor mRNA in hippocampus and striatum/GP showed that transcriptional regulation could not explain prolonged recovery rates from CB 1 receptor down-regulation. In contrast, CB 1 receptor protein, as determined by immunoblot analysis, matched the down-regulation and recovery rates of CB 1 receptor binding sites relatively closely. These data demonstrate that cannabinoid-induced decreases in CB 1 receptor function persist for relatively long time periods after cessation of long-term drug treatment and that CB 1 receptor signaling recovers more quickly in striatum/GP than hippocampus. Moreover, down-regulation of CB 1 receptor binding sites does not seem to result mainly from transcriptional regulation, suggesting that adaptive regulation of CB 1 receptors in brain primarily occurs at the protein level.

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Section: Discussionsupporting

confidence: 90%

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confidence: 99%

mentioning

confidence: 99%

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Prolonged Recovery Rate of CB₁ Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Sim‐Selley

Schechter²,

Rorrer³

et al. 2006

Mol Pharmacol

102

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“…Under these experimental conditions, CB1R expression was enhanced specifically on the CD11b -(P5) cells, but not on the CD11b + (P4) cells. This result correlates with that obtained for Cb1r mRNA expression under similar THC treatment conditions in rat cerebellum (41). This microglial activation was not associated with cellular stress, as revealed by the Fluoro-Jade B assay.…”

Section: Discussionsupporting

confidence: 90%

Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

et al. 2013

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Chronic cannabis exposure can lead to cerebellar dysfunction in humans, but the neurobiological mechanisms involved remain incompletely understood. Here, we found that in mice, subchronic administration of the psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), activated cerebellar microglia and increased the expression of neuroinflammatory markers, including IL-1β. This neuroinflammatory phenotype correlated with deficits in cerebellar conditioned learning and fine motor coordination. The neuroinflammatory phenotype was readily detectable in the cerebellum of mice with global loss of the CB1 cannabinoid receptor (CB1R, Cb1 -/-mice) and in mice lacking CB1R in the cerebellar parallel fibers, suggesting that CB1R downregulation in the cerebellar molecular layer plays a key role in THC-induced cerebellar deficits. Expression of CB2 cannabinoid receptor (CB2R) and Il1b mRNA was increased under neuroinflammatory conditions in activated CD11b-positive microglial cells. Furthermore, administration of the immunosuppressant minocycline or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1 -/-and THC-withdrawn mice. Our results suggest that cerebellar microglial activation plays a crucial role in the cerebellar deficits induced by repeated cannabis exposure.

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“…A 1 ml-aliquot of the cDNA suspension was used as a PCR template. In most experiments, 28S rRNA was employed as the internal standard to assay changes in relative expression levels of a specific transcript and coamplified with the target transcript of interest, 25,26 because (1) 28S rRNA levels in the brain were reported not to be affected by drugs such as cannabinoid, 26 and (2) similar MAP-induced expressional changes were obtained by this quantitative method and the competitive PCR described below (data not shown). An appropriate portion (70-90%) of the added primers specific for the 28S rRNA sequence was phosphorylated at their 3 0 ends so that the target and the control amplicon will have similar amplification kinetics and their exponential phases will overlap.…”

Section: Rna Fingerprintingmentioning

confidence: 99%

A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex

et al. 2003

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Single or repeated exposure to psychostimulants such as amphetamines and cocaine after postnatal week 3 leads to an enduring enhancement in the psychotomimetic responses elicited by a subsequent challenge of a stimulant in rodents. This behavioral sensitization phenomenon has been considered to be the neural consequences of stimulant-induced alterations in gene expression in the brain after a critical period of postnatal development. Using a differential cloning technique, RNA arbitrarily primed PCR, we have now identified from the rat neocortex a novel and developmentally regulated methamphetamine (MAP)-inducible gene mrt1 (MAP responsive transcript 1). mrt1 encodes two major types of PDZ-and PX-domains containing proteins of approximately 62 kDa in size with different carboxy termini, Mrt1a and Mrt1b. The mrt1 mRNAs for Mrt1a, mrt1a, and for Mrt1b, mrt1b, are predominantly expressed in various brain regions and the testes, respectively. Acute MAP injection upregulated mrt1b expression in the neocortex after postnatal week 3 in a D1 receptor antagonist-sensitive manner without affecting mrt1a expression. This upregulation was mimicked by another stimulant, cocaine, whereas pentobarbital and D1 antagonist failed to change the mrt1b transcript levels. Moreover, repeated daily treatment of MAP, but not MAP plus D1 antagonist, for 5 days caused an augmentation of the basal expression of mrt1b 2 and 3 weeks after the drug discontinuation. These late-developing, cocaine-crossreactive, D1 antagonist-sensitive and long-term regulations of mrt1b by MAP are similar to the pharmacological profiles of stimulant-induced behavioral sensitization, and therefore may be associated with the initiation and/or maintenance of the long-term neuronal adaptation.

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Effects of long-term exposure to Δ9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions

Cited by 101 publications

References 31 publications

Prolonged Recovery Rate of CB₁ Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Prolonged Recovery Rate of CB₁ Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex

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Effects of long-term exposure to Δ9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions

Cited by 101 publications

References 31 publications

Prolonged Recovery Rate of CB1 Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Prolonged Recovery Rate of CB1 Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex

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Prolonged Recovery Rate of CB₁ Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Prolonged Recovery Rate of CB₁ Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration