Browsing by Author "Arnold, JC"

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    Adolescent rats find repeated Δ9-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure
    (Springer Nature, 2007-06-20) Quinn, HR; Matsumoto, I; Callaghan, PD; Long, LE; Arnold, JC; Gunasekaran, N; Thompson, MR; Dawson, B; Mallet, PE; Kashem, MA; Matsda-Matsumoto, H; Iwazki, T; McGregor, IS
    The current study examined whether adolescent rats are more vulnerable than adult rats to the lasting adverse effects of cannabinoid exposure on brain and behavior. Male Wistar rats were repeatedly exposed to Δ9-tetrahydrocannabinol (Δ(9)-THC, 5 mg/kg i.p.) in a place-conditioning paradigm during either the adolescent (post-natal day 28+) or adult (post-natal day 60+) developmental stages. Adult rats avoided a Δ(9)-THC-paired environment after either four or eight pairings and this avoidance persisted for at least 16 days following the final Δ(9)-THC injection. In contrast, adolescent rats showed no significant place aversion. Adult Δ(9)-THC-treated rats produced more vocalizations than adolescent rats when handled during the intoxicated state, also suggesting greater drug-induced aversion. After a 10-15 day washout, both adult and adolescent Δ(9)-THC pretreated rats showed decreased social interaction, while onlyΔ (9)-THC pretreated adolescent rats showed significantly impaired object recognition memory. Seventeen days following their last Δ(9)-THC injection, rats were euthanised and hippocampal tissue processed using two-dimensional gel electrophoresis proteomics. There was no evidence of residual Δ(9)-THC being present in blood at this time. Proteomic analysis uncovered 27 proteins, many involved in regulating oxidative stress/mitochondrial functioning and cytoarchitecture, which were differentially expressed in adolescent Δ(9)-THC pretreated rats relative to adolescent controls. In adults, only 10 hippocampal proteins were differentially expressed in Δ(9)-THC compared to vehicle-pretreated controls. Overall these findings suggest that adolescent rats find repeated Δ(9)-THC exposure less aversive than adults, but that cannabinoid exposure causes greater lasting memory deficits and hippocampal alterations in adolescent than adult rats. © 2018 Springer Nature
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    The differential binding of antipsychotic drugs to the ABC transporter P-glycoprotein predicts cannabinoid–antipsychotic drug interactions
    (Springer, 2017-03-08) Brzozowska, NI; de Tonnerre, EJ; Li, KM; Wang, XS; Boucher, AA; Callaghan, PD; Kuligowski, M; Wong, A; Arnold, JC
    Cannabis use increases rates of psychotic relapse and treatment failure in schizophrenia patients. Clinical studies suggest that cannabis use reduces the efficacy of antipsychotic drugs, but there has been no direct demonstration of this in a controlled study. The present study demonstrates that exposure to the principal phytocannabinoid, Δ9-tetrahydrocannabinol (THC), reverses the neurobehavioral effects of the antipsychotic drug risperidone in mice. THC exposure did not influence D2 and 5-HT2A receptor binding, the major targets of antipsychotic action, but it lowered the brain concentrations of risperidone and its active metabolite, 9-hydroxy risperidone. As risperidone and its active metabolite are excellent substrates of the ABC transporter P-glycoprotein (P-gp), we hypothesized that THC might increase P-gp expression at the blood–brain barrier (BBB) and thus enhance efflux of risperidone and its metabolite from brain tissue. We confirmed that the brain disposition of risperidone and 9-hydroxy risperidone is strongly influenced by P-gp, as P-gp knockout mice displayed greater brain concentrations of these drugs than wild-type mice. Furthermore, we demonstrated that THC exposure increased P-gp expression in various brain regions important to risperidone’s antipsychotic action. We then showed that THC exposure did not influence the neurobehavioral effects of clozapine. Clozapine shares a very similar antipsychotic mode of action to risperidone, but unlike risperidone is not a P-gp substrate. Our results imply that clozapine or non-P-gp substrate antipsychotic drugs may be better first-line treatments for schizophrenia patients with a history of cannabis use. © 2017 American College of Neuropsychopharmacology, published by Springer Nature Limited.
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    Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex
    (Frontiers, 2014-09-29) Chohan, TW; Nguyen, AP; Todd, SM; Bennett, MR; Callaghan, PD; Arnold, JC
    Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1) and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs) which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET) and wild-type (WT) mice using [3H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV) and the dentate gyrus (DG) of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL) subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However, in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex. © 2014 Chohan, Nguyen, Todd, Bennett, Callaghan and Arnold this is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)