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Reduced type III neuregulin 1 expression does not modulate the behavioural sensitivity of mice to acute Δ9-tetrahydrocannabinol (D9-THC).
Pharmacol Biochem Behav. 2018 07; 170:64-70.PB

Abstract

Mice with a mutation in the transmembrane domain of the schizophrenia risk gene, neuregulin 1 (Nrg1 TM HET), are more susceptible to the neuro-behavioural effects of Δ9-tetrahydrocannabinol (D9-THC), the principal psychoactive component in cannabis. However, NRG1 is transcriptionally complex with over 30 different isoforms, most of which carry a transmembrane domain, raising the question which NRG1 isoform(s) may contribute to this phenotype. Type III NRG1/Nrg1 is the most brain abundant isoform and brain studies have identified increased levels of type III NRG1 mRNA in humans carrying a NRG1 risk haplotype for schizophrenia. To investigate whether mice heterozygous for type III Nrg1 (i.e. knockout: type III Nrg1+/-) are more susceptible to the behavioural effects of acute doses of D9-THC, we injected male mice with either vehicle or D9-THC (3 or 10 mg/kg) before testing them for locomotion, anxiety, social interaction, and sensorimotor gating. Acute D9-THC led to reduced locomotion and reduced social interaction, but increased anxiety in mice. Furthermore, type III Nrg1 males displayed a robust deficit in sensorimotor gating and demonstrated reduced following during social interaction across drug conditions. However, they did not show a change in behavioural susceptibility to acute D9-THC compared to controls. These results reinforce the validity of type III Nrg1+/- mice for schizophrenia research and suggest that loss of function of type III Nrg1 may not be responsible for the exaggerated response to acute D9-THC observed in heterozygous Nrg1 TM mice. This highlights the importance of careful consideration of Nrg1 isoform type differences.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Lloyd D
Neuroscience Research Australia (NeuRA), Randwick, Australia; School of Psychiatry, University of New South Wales, Kensington, Australia.
Talmage D
Pharmacological Sciences, School of Medicine, Stony Brook University, New York, USA.
Shannon Weickert C
Neuroscience Research Australia (NeuRA), Randwick, Australia; School of Psychiatry, University of New South Wales, Kensington, Australia.
Karl T
Neuroscience Research Australia (NeuRA), Randwick, Australia; School of Medicine, Western Sydney University, Campbelltown, Australia. Electronic address: t.karl@westernsydney.edu.au.

MeSH

AnimalsBehavior, AnimalDronabinolExploratory BehaviorMaleMiceMice, Inbred C57BLMotor ActivityNeuregulin-1Prepulse InhibitionReflex, StartleSocial Behavior

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29750976

Citation

Lloyd, David, et al. "Reduced Type III Neuregulin 1 Expression Does Not Modulate the Behavioural Sensitivity of Mice to Acute Δ9-tetrahydrocannabinol (D9-THC)." Pharmacology, Biochemistry, and Behavior, vol. 170, 2018, pp. 64-70.
Lloyd D, Talmage D, Shannon Weickert C, et al. Reduced type III neuregulin 1 expression does not modulate the behavioural sensitivity of mice to acute Δ9-tetrahydrocannabinol (D9-THC). Pharmacol Biochem Behav. 2018;170:64-70.
Lloyd, D., Talmage, D., Shannon Weickert, C., & Karl, T. (2018). Reduced type III neuregulin 1 expression does not modulate the behavioural sensitivity of mice to acute Δ9-tetrahydrocannabinol (D9-THC). Pharmacology, Biochemistry, and Behavior, 170, 64-70. https://doi.org/10.1016/j.pbb.2018.05.003
Lloyd D, et al. Reduced Type III Neuregulin 1 Expression Does Not Modulate the Behavioural Sensitivity of Mice to Acute Δ9-tetrahydrocannabinol (D9-THC). Pharmacol Biochem Behav. 2018;170:64-70. PubMed PMID: 29750976.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reduced type III neuregulin 1 expression does not modulate the behavioural sensitivity of mice to acute Δ9-tetrahydrocannabinol (D9-THC). AU - Lloyd,David, AU - Talmage,David, AU - Shannon Weickert,Cynthia, AU - Karl,Tim, Y1 - 2018/05/08/ PY - 2017/12/15/received PY - 2018/04/12/revised PY - 2018/05/07/accepted PY - 2018/5/12/pubmed PY - 2019/3/23/medline PY - 2018/5/12/entrez KW - Cannabis KW - Neuregulin 1 (Nrg1) type III KW - Schizophrenia KW - Sensorimotor gating (PPI) KW - Social behaviours KW - Δ(9)-Tetrahydrocannabinol (D(9)-THC) SP - 64 EP - 70 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol Biochem Behav VL - 170 N2 - Mice with a mutation in the transmembrane domain of the schizophrenia risk gene, neuregulin 1 (Nrg1 TM HET), are more susceptible to the neuro-behavioural effects of Δ9-tetrahydrocannabinol (D9-THC), the principal psychoactive component in cannabis. However, NRG1 is transcriptionally complex with over 30 different isoforms, most of which carry a transmembrane domain, raising the question which NRG1 isoform(s) may contribute to this phenotype. Type III NRG1/Nrg1 is the most brain abundant isoform and brain studies have identified increased levels of type III NRG1 mRNA in humans carrying a NRG1 risk haplotype for schizophrenia. To investigate whether mice heterozygous for type III Nrg1 (i.e. knockout: type III Nrg1+/-) are more susceptible to the behavioural effects of acute doses of D9-THC, we injected male mice with either vehicle or D9-THC (3 or 10 mg/kg) before testing them for locomotion, anxiety, social interaction, and sensorimotor gating. Acute D9-THC led to reduced locomotion and reduced social interaction, but increased anxiety in mice. Furthermore, type III Nrg1 males displayed a robust deficit in sensorimotor gating and demonstrated reduced following during social interaction across drug conditions. However, they did not show a change in behavioural susceptibility to acute D9-THC compared to controls. These results reinforce the validity of type III Nrg1+/- mice for schizophrenia research and suggest that loss of function of type III Nrg1 may not be responsible for the exaggerated response to acute D9-THC observed in heterozygous Nrg1 TM mice. This highlights the importance of careful consideration of Nrg1 isoform type differences. SN - 1873-5177 UR - https://www.unboundmedicine.com/medline/citation/29750976/Reduced_type_III_neuregulin_1_expression_does_not_modulate_the_behavioural_sensitivity_of_mice_to_acute_��9_tetrahydrocannabinol__D9_THC__ DB - PRIME DP - Unbound Medicine ER -