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Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice.
PLoS One. 2012; 7(4):e34129.Plos

Abstract

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes.

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Authors+Show Affiliations

Long LE
Schizophrenia Research Institute, Darlinghurst, New South Wales, Australia.
Chesworth R
No affiliation info available
Huang XF
No affiliation info available
Wong A
No affiliation info available
Spiro A
No affiliation info available
McGregor IS
No affiliation info available
Arnold JC
No affiliation info available
Karl T
No affiliation info available

MeSH

AnimalsAnxietyBehavior, AnimalCannabidiolCell MembraneExploratory BehaviorFemaleLocomotionMaleMiceMutationNeuregulin-1Protein Structure, TertiaryReceptor, Serotonin, 5-HT2ASensory GatingTime Factors

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

22509273

Citation

Long, Leonora E., et al. "Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice." PloS One, vol. 7, no. 4, 2012, pp. e34129.
Long LE, Chesworth R, Huang XF, et al. Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. PLoS One. 2012;7(4):e34129.
Long, L. E., Chesworth, R., Huang, X. F., Wong, A., Spiro, A., McGregor, I. S., Arnold, J. C., & Karl, T. (2012). Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. PloS One, 7(4), e34129. https://doi.org/10.1371/journal.pone.0034129
Long LE, et al. Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice. PLoS One. 2012;7(4):e34129. PubMed PMID: 22509273.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. AU - Long,Leonora E, AU - Chesworth,Rose, AU - Huang,Xu-Feng, AU - Wong,Alexander, AU - Spiro,Adena, AU - McGregor,Iain S, AU - Arnold,Jonathon C, AU - Karl,Tim, Y1 - 2012/04/03/ PY - 2011/11/23/received PY - 2012/02/22/accepted PY - 2012/4/18/entrez PY - 2012/4/18/pubmed PY - 2012/8/21/medline SP - e34129 EP - e34129 JF - PloS one JO - PLoS One VL - 7 IS - 4 N2 - The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22509273/Distinct_neurobehavioural_effects_of_cannabidiol_in_transmembrane_domain_neuregulin_1_mutant_mice_ L2 - https://dx.plos.org/10.1371/journal.pone.0034129 DB - PRIME DP - Unbound Medicine ER -