Acute Effects of Δ⁹-Tetrahydrocannabinol on the Auditory Evoked Mismatch Negativity are Modulated by the NRG1 Gene

• Introduction
• Materials and Methods
• Results
• Discussion
• References

Reduced amplitudes of auditory mismatch negativity (MMN) are a robust finding in schizophrenia, indicating deficient auditory information processing. Cannabis-induced psychotic states may resemble schizophrenic disorders. Yet, as previously reported, Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the main psychoactive constituent of cannabis, has no effect on MMN generation. The aim of this study was to investigate whether variations in the potential susceptibility gene for schizophrenia, neuregulin 1 (NRG1), modulate the effects of Δ⁹-THC on MMN generation in 22 healthy subjects. Our analysis showed that NRG1 (rs783406) was significantly associated with the MMN amplitude, particularly at central electrodes. These data indicate that variations within NRG1 may alter the sensitivity to the cognitive effects of cannabinoids.

Introduction

The mismatch negativity (MMN) is a negative component of the auditory event-related brain potential (ERP) which is elicited by any discriminable change of a repetitive sound indicating auditory information processing [9]. Reduced amplitudes of auditory evoked mismatch negativity (MMN) are a characteristic finding in schizophrenic patients [12]. Based on the close relationship between cannabis, the endogenous cannabinoid system, and schizophrenia [3], our group investigated the acute effects of cannabinoids on MMN values in healthy subjects [7]. Contrary to our expectation, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) as the primary psychoactive constituent of the Cannabis sativa plant had no effect on MMN generation. The activity of Δ⁹-THC is mediated by agonistic effects at central cannabinoid (CB1) receptors [8].

Since cortical N-methyl-d-aspartate (NMDA) receptor functioning seems to be involved in MMN generation [6], we hypothesized that there is a Δ⁹-THC-induced modulation of MMN amplitude by genetic variations in a potential susceptibility gene for schizophrenia, the human neuregulin 1 (NRG1) gene, within the same study sample [7]. In the brain, NRG1 may influence glutamatergic neurotransmission by multiple post- and presynaptic mechanisms, including the modulation of NMDA receptors and the regulation of NMDA-dependent glutamatergic synaptic plasticity [5]. Two single nucleotide polymorphisms (SNPs) were of specific interest for this study. NRG1 rs6994992 is a functional promoter variation associated with a genetic predisposition for schizophrenia and NRG1 type IV isoform expression [11], whereas NRG1 rs7834206, another promoter polymorphism, has been unexplored so far.

Materials and Methods

As previously described in more detail [7], 22 healthy, right-handed, non-smoking and normal hearing Caucasian subjects (11 male, 11 female, mean age 28.0±6.0 years) were orally administered with either Δ⁹-THC (total dose of 10 mg) or placebo. Auditory ERPs were elicited within an auditory oddball paradigm. The MMNs were measured in the difference waves obtained by subtracting the ERPs to the standard stimuli from the ERPs to the deviant stimuli per subject during the 130 B 250 ms latency range after stimulus onset. Deoxyribonucleic acid (DNA) was extracted from peripheral leukocytes by standard procedures. Single nucleotide polymorphisms (SNPs) rs6994992 and rs7834206 in the NRG1 gene were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. For PCR, the following primers were used: rs6994992 (forward: 5′-AGAGGCCAGGACGCG-3′, reverse: 5′-AGGCGAGTTTGGTCCAAG-3′), rs7834206 (forward: 5′-CAACTTGCAGAATCTTGGGCT-3′, reverse: 5′-TGCAGTTTGGAGGGACAGG-3′). The digested PCR products were resolved on 2% agarose gels stained with ethidium bromide. MMN amplitude and latency under the different drug conditions were compared for the different genotype groups using ANOVA multivariate analysis with post-hoc Bonferroni correction for multiple comparisons.

Results

Group comparisons revealed a significantly reduced MMN amplitude for the NRG1 rs7834206 C/C genotype compared to the C/A genotype at Cz (F=5.096, p=0.016, [Fig. 1]) and C4 (F=4.340, p=0.033) under the Δ⁹-THC condition. NRG1 rs6994992 showed no association with the MMN amplitude. Moreover, there was no association of MMN amplitude with NRG1 under the placebo condition. Regarding the MMN latency, no significant differences at frontal or central electrodes were observed for both polymorphisms.

Discussion

The results of the present study demonstrate that the acute effects of Δ⁹-THC on MMN generation in healthy subjects may depend on a specific genetic polymorphism within the NRG1 gene. In particular, smaller amplitudes for the NRG1 rs7834206 C/C genotype at central electrodes could be detected. Although the functional consequences of this polymorphism have been unexplored so far, it can be speculated that it may influence glutamatergic neurotransmission, presumably by modulation of NMDA receptors and regulation of NMDA-dependent glutamatergic synaptic plasticity [5]. Analogous results were obtained in a recent animal study that investigated the acute behavioural effects of Δ⁹-THC modulated by dysfunction in the NRG1 gene [2]. The authors demonstrated that heterozygous NRG1 knock-out mice were more sensitive to the acute effects of Δ⁹-THC on different behavioural animal models of schizophrenia in comparison to wild type-like mice.

A close relationship between the endogenous cannabinoid system and glutamatergic neurotransmission has been found. For example, CB1 agonists exhibited similar disruptive effects on glutamatergic neurotransmission like the NMDA receptor antagonist ketamine in the hippocampus as well as in the prefrontal cortex of the rat brain [4] [10]. As some psychotogenic effects of NMDA receptor antagonists could be counteracted by a selective CB1 receptor antagonist, it has been suggested that Δ⁹-THC-induced disruption of NMDA-related glutamatergic neurotransmission could be mediated by a CB1 receptor mechanism [1].

In conclusion, our data suggest that the acute effects of Δ⁹-THC on MMN generation may depend on the NRG1 rs7834206 polymorphism. It therefore appears that this polymorphism may alter the sensitivity to the cognitive effects of Δ⁹-THC. Since NRG1 has been known to modulate NMDA receptor functioning that seems to play a major role in MMN generation, it can be suggested that the disruptive effects of Δ⁹-THC on MMN amplitude may be mediated by the NMDA receptor, presumably due to a CB1 receptor mechanism. Further studies with greater sample sizes and additional SNPs are required to replicate our findings.

References

• 1 Ballmaier M, Bortolato M, Rizzetti C. et al . Cannabinoid receptor antagonists counteract sensorimotor gating deficits in the phencyclidine model of psychosis.  Neuropsychopharmacology. 2007;  32 2098-2107
  CrossrefPubMedSearch in Google Scholar
• 2 Boucher AA, Arnold JC, Duffy L. et al . Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Δ⁹-tetrahydrocannabinol.  Psychopharmacology. 2007;  192 325-336
  CrossrefPubMedSearch in Google Scholar
• 3 D’Souza DC. Cannabinoids and psychosis.  Int Rev Neurobiol. 2007;  78 289-326
  PubMedSearch in Google Scholar
• 4 Ferraro L, Tomasini MC, Gessa GL. et al . The cannabinoid receptor agonist WIN 55 212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study.  Cereb Cortex. 2001;  11 728-733
  CrossrefPubMedSearch in Google Scholar
• 5 Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.  Mol Psychiatry. 2005;  10 40-68
  CrossrefPubMedSearch in Google Scholar
• 6 Javitt DC, Steinschneider M, Schroeder CE. et al . Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia.  Proc Natl Acad Sci USA. 1996;  93 11962-11967
  CrossrefPubMedSearch in Google Scholar
• 7 Juckel G, Roser P, Nadulski T. et al . Acute effects of Δ⁹-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity.  Schizophr Res. 2007;  97 109-117
  CrossrefPubMedSearch in Google Scholar
• 8 Matsuda LA, Lolait SJ, Brownstein MJ. et al . Structure of a cannabinoid receptor and functional expression of the cloned cDNA.  Nature. 1990;  346 561-564
  CrossrefPubMedSearch in Google Scholar
• 9 Näätänen R. The mismatch negativity: a powerful tool for cognitive neuroscience.  Ear Hear. 1995;  16 6-18
  CrossrefPubMedSearch in Google Scholar
• 10 Shen M, Piser TM, Seybold VS. et al . Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures.  J Neurosci. 1996;  16 4322-4334
  PubMedSearch in Google Scholar
• 11 Tan W, Wang Y, Gold B. et al . Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia.  J Biol Chem. 2007;  282 24343-24351
  CrossrefPubMedSearch in Google Scholar
• 12 Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis.  Schizophr Res. 2005;  76 1-23
  CrossrefPubMedSearch in Google Scholar

Correspondence

P. RoserMD 

Department of Psychiatry

Ruhr-University Bochum

LWL University Hospital

Alexandrinenstraße 1

44791 Bochum

Germany

Phone: +49/234/5077 153

Fax: +49/234 /5077 234

Email: patrik.roser@rub.de

References

• 1 Ballmaier M, Bortolato M, Rizzetti C. et al . Cannabinoid receptor antagonists counteract sensorimotor gating deficits in the phencyclidine model of psychosis.  Neuropsychopharmacology. 2007;  32 2098-2107
  CrossrefPubMedSearch in Google Scholar
• 2 Boucher AA, Arnold JC, Duffy L. et al . Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Δ⁹-tetrahydrocannabinol.  Psychopharmacology. 2007;  192 325-336
  CrossrefPubMedSearch in Google Scholar
• 3 D’Souza DC. Cannabinoids and psychosis.  Int Rev Neurobiol. 2007;  78 289-326
  PubMedSearch in Google Scholar
• 4 Ferraro L, Tomasini MC, Gessa GL. et al . The cannabinoid receptor agonist WIN 55 212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study.  Cereb Cortex. 2001;  11 728-733
  CrossrefPubMedSearch in Google Scholar
• 5 Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.  Mol Psychiatry. 2005;  10 40-68
  CrossrefPubMedSearch in Google Scholar
• 6 Javitt DC, Steinschneider M, Schroeder CE. et al . Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia.  Proc Natl Acad Sci USA. 1996;  93 11962-11967
  CrossrefPubMedSearch in Google Scholar
• 7 Juckel G, Roser P, Nadulski T. et al . Acute effects of Δ⁹-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity.  Schizophr Res. 2007;  97 109-117
  CrossrefPubMedSearch in Google Scholar
• 8 Matsuda LA, Lolait SJ, Brownstein MJ. et al . Structure of a cannabinoid receptor and functional expression of the cloned cDNA.  Nature. 1990;  346 561-564
  CrossrefPubMedSearch in Google Scholar
• 9 Näätänen R. The mismatch negativity: a powerful tool for cognitive neuroscience.  Ear Hear. 1995;  16 6-18
  CrossrefPubMedSearch in Google Scholar
• 10 Shen M, Piser TM, Seybold VS. et al . Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures.  J Neurosci. 1996;  16 4322-4334
  PubMedSearch in Google Scholar
• 11 Tan W, Wang Y, Gold B. et al . Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia.  J Biol Chem. 2007;  282 24343-24351
  CrossrefPubMedSearch in Google Scholar
• 12 Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis.  Schizophr Res. 2005;  76 1-23
  CrossrefPubMedSearch in Google Scholar

Correspondence

P. RoserMD 

Department of Psychiatry

Ruhr-University Bochum

LWL University Hospital

Alexandrinenstraße 1

44791 Bochum

Germany

Phone: +49/234/5077 153

Fax: +49/234 /5077 234

Email: patrik.roser@rub.de