%0 Journal Article
%~ PubMed
%A Long, Leonora E
%A Chesworth, Rose
%A Huang, Xu-Feng
%A McGregor, Iain S
%A Arnold, Jonathon C
%A Karl, Tim
%T Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence.
%B International Journal of Neuropsychopharmacology
%D 2013
%C United Kingdom
%I Cambridge University Press
%V 16
%N 1
%P 163-175
%@ 1469-5111
%X 
%Z FOR Codes: 111599


%0 Journal Article
%~ PubMed
%A Spencer, Jarrah R
%A Darbyshire, Keturah M E
%A Boucher, Aurelie A
%A Arnold, Jonathon C
%T Adolescent neuregulin 1 heterozygous mice display enhanced behavioral sensitivity to methamphetamine.
%B Progress in Neuro-psychopharmacology & Biological Psychiatry
%D 2012
%C United States
%I Elsevier Inc.
%V 39
%N 2
%P 376-381
%@ 1878-4216
%X Methamphetamine use triggers psychosis in genetically vulnerable individuals, however the exact nature of this genetic predisposition requires elucidation. In addition, adolescence may be a particular period of neurodevelopmental vulnerability to the actions of methamphetamine; interestingly, this period coincides with a higher likelihood of onset of schizophrenia and drug experimentation. In the current study we investigated whether adolescent mice heterozygous for the schizophrenia susceptibility gene neuregulin 1 (Nrg1 HET mice) exhibit altered behavioural responses to methamphetamine (0.6 or 2.4mg/kg) in schizophrenia-relevant paradigms. The responses measured were locomotor activity in the open field test and sensorimotor gating function in the prepulse inhibition of startle paradigm (PPI). Adolescent Nrg1 HET mice displayed a subtle, transient, novelty-induced baseline locomotor hyperactivity over days, and a selective PPI deficit at the prepulse intensity-interstimulus interval (ISI) combination of 82dB-64ms. Adolescent Nrg1 HET mice were more sensitive to the locomotor stimulatory effects of an acute, low-dose of methamphetamine (0.6mg/kg) relative to wild-type (WT) controls. The augmented response to acute methamphetamine observed in Nrg1 HET mice disappeared with repeated, daily dosing over 7days. Methamphetamine did not affect average PPI (total or across different prepulse intensities), however 0.6mg/kg methamphetamine triggered a PPI deficit selectively in Nrg1 HET mice but not WT mice at 82dB-256ms. Our results show that locomotor hyperactivity in Nrg1 HET mice, albeit subtle, can manifest much earlier than previously reported and that Nrg1 may confer vulnerability to the acute actions of methamphetamine, a drug known to trigger psychotic reactions in humans.
%Z FOR Codes: 111599


%0 Journal Article
%~ PubMed
%A Arnold, Jonathon C
%A Hone, Phoebe
%A Holland, Michelle L
%A Allen, John D
%T CB(2) and TRPV(1) receptors mediate cannabinoid actions on MDR1 expression in multidrug resistant cells.
%B Pharmacological Reports
%D 2012
%C Poland
%I Polska Akademia Nauk * Instytut Farmakologii
%V 64
%N 3
%P 751-757
%@ 1734-1140
%X Background: Cannabis is the most widely used illicit drug in the world that is often used by cancer patients in combination with conventional anticancer drugs. Multidrug resistance (MDR) is a major obstacle in the treatment of cancer. An extensively characterized mechanism of MDR involves overexpression of P-glycoprotein (P-gp), which reduces the cellular accumulation of cytotoxic drugs in tumor cells. Methods: Here we examined the role of cannabinoid receptors and transient receptor potential vanilloid type 1 (TRPV(1)) receptors in the effects of plant-derived cannabinoids on MDR1 mRNA expression in MDR CEM/VLB(100) cells which overexpress P-gp due to MDR1 gene amplification. Results: We showed that both cannabidiol (CBD) and ??(9)-tetrahydrocannabinol (??(9)-THC) (10 ??M) transiently induced the MDR1 transcript in P-gp overexpressing cells at 4 but not 8 or 48 h incubation durations. CBD and THC also concomitantly increased P-gp activity as measured by reduced accumulation of the P-gp substrate Rhodamine 123 in these cells with a maximal inhibitory effect observed at 4 h that slowly diminished by 48 h. CEM/VLB(100) cell lines were shown to express CB(2) and TRPV(1) receptors. ??(9)-THC effects on MDR1 expression were mediated by CB(2) receptors. The effects of CBD were not mediated by either CB(2) or TRPV(1) receptors alone, however, required activation of both these receptors to modulate MDR1 mRNA expression. Conclusion: This is the first evidence that CB(2) and TRPV(1) receptors cooperate to modulate MDR1 expression.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Long, Leonora E
%A Chesworth, Rose
%A Huang, Xu-Feng
%A Wong, Alexander
%A Spiro, Adena
%A McGregor, Iain S
%A Arnold, Jonathon C
%A Karl, Tim
%T Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice.
%B PLoS One
%D 2012
%C United States
%I Public Library of Science
%V 7
%N 4
%P e34129
%@ 1932-6203
%X 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, ??(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.
%Z FOR Codes: 111599


%0 Journal Article
%~ PubMed
%A Spiro, Adena S
%A Wong, Alexander
%A Boucher, Aur??lie A
%A Arnold, Jonathon C
%T Enhanced brain disposition and effects of Δ9-tetrahydrocannabinol in P-glycoprotein and breast cancer resistance protein knockout mice.
%B PLoS One
%D 2012
%C United States
%I Public Library of Science
%V 7
%N 4
%P e35937
%@ 1932-6203
%X The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis ??(9)-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice. Abcb1a/b (-/-), Abcg2 (-/-) and wild-type (WT) mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b (-/-) and Abcg2 (-/-) mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (-/-) mice. ABC transporter knockout mice were more sensitive to THC-induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis.
%Z FOR Codes: 111599


%0 Journal Article
%~ PubMed
%A Wong, A
%A Gunasekaran, N
%A Hancock, D P
%A Denyer, G S
%A Meng, L
%A Radford, J L
%A McGregor, I S
%A Arnold, J C
%T The Major Plant-derived Cannabinoid Δ9-Tetrahydrocannabinol Promotes Hypertrophy and Macrophage Infiltration in Adipose Tissue.
%B Hormone and Metabolic Research
%D 2012
%C Germany
%I Georg Thieme Verlag
%V 44
%N 2
%P 105-113
%@ 1439-4286
%X Synthetic cannabinoid receptor agonists activate lipoprotein lipase and the formation of lipid droplets in cultured adipocytes. Here we extend this work by examining whether ??9-tetrahydrocannabinol (THC), a major plant-derived cannabinoid, increases adipocyte size in vivo. Further, possibly as a consequence of hypertrophy, we hypothesize that THC exposure promotes macrophage infiltration into adipose tissue, an inflammatory state observed in obese individuals. Rats repeatedly exposed to THC in vivo had reduced body weight, fat pad weight, and ingested less food over the drug injection period. However, THC promoted adipocyte hypertrophy that was accompanied by a significant increase in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) expression, an enzyme important in packaging triglycerides. We also showed that THC induced macrophage infiltration and increased expression of the inflammatory cytokine tumor necrosis factor alpha (TNF-??) in adipose tissue but did not induce apoptosis as measured by TUNEL staining. That THC increased adipocyte cell size in the absence of greater food intake, body weight and fat provides a unique model to explore mechanisms underlying changes in adipocyte size associated with a mild inflammatory state in fat tissue.
%Z FOR Codes: 111506


%0 Journal Article
%~ PubMed
%A Arnold, J C
%A Boucher, A A
%A Karl, T
%T The Yin and Yang of Cannabis-induced Psychosis: the Actions of ∆(9)-Tetrahydrocannabinol and Cannabidiol in Rodent Models of Schizophrenia.
%B Current Pharmaceutical Design
%D 2012
%C Netherlands
%I Bentham Science Publishers Ltd.
%V 18
%N 32
%P 5113-5130
%@ 1873-4286
%X The link between cannabis and psychosis has often been debated with polarized views on the topic. There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and ???(9)-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms. In the present review we will first focus on how traditional rodent models of schizophrenia have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. We will also review novel rodent models used to address genetic vulnerability to cannabis-induced schizophrenia and show that specific genes are being uncovered that modulate cannabinoid action (e.g. the schizophrenia susceptibility gene neuregulin 1). We will also review rodent studies that have addressed interactions between THC and CBD. These animal studies underscore great complexity with some studies showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD might potentiate the actions of THC. Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors or that CBD inhibits proteins that regulate THC disposition and metabolism (e.g. ABC transporters such as P-glycoprotein).
%Z FOR Codes: 111599


%0 Journal Article
%~ PubMed
%A Karl, Tim
%A Cheng, David
%A Garner, Brett
%A Arnold, Jonathon C
%T The therapeutic potential of the endocannabinoid system for Alzheimer's disease.
%B Expert Opinion on Therapeutic Targets
%D 2012
%C United Kingdom
%I Informa Healthcare
%V 16
%N 4
%P 407-420
%@ 1744-7631
%X INTRODUCTION: Dementia currently affects over 35 million people worldwide. The most common form of dementia is Alzheimer''s disease (AD). Currently, treatments for AD do not stop or reverse the progression of the disease and they are accompanied by side effects. AREAS COVERED: The main features of AD pathology, treatment options currently available, the endocannabinoid system and its functionality in general and its role in AD pathology in detail will be outlined. A particular focus will be on the therapeutic potential of the phytocannabinoid cannabidiol. EXPERT OPINION: Based on the complex pathology of AD, a preventative, multimodal drug approach targeting a combination of pathological AD symptoms appears ideal. Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects. Thus, the cannabinoid system should be a prime target for AD therapy. The cannabinoid receptor 2 appears to be a promising candidate but its role in AD has to be investigated cautiously. Furthermore, the phytocannabinoid cannabidiol is of particular interest as it lacks the psychoactive and cognition-impairing properties of other cannabinoids. In conclusion, future research should focus on the evaluation of the effects of manipulations to the endocannabinoid system in established animal models for AD, combined with early-phase studies in humans.
%Z FOR Codes: 111599 110904


%0 Journal Article
%~ PubMed
%A Bowen, Michael T
%A Carson, Dean S
%A Spiro, Adena
%A Arnold, Jonathon C
%A McGregor, Iain S
%T Adolescent oxytocin exposure causes persistent reductions in anxiety and alcohol consumption and enhances sociability in rats.
%B PloS One
%D 2011
%C United States
%I Public Library of Science
%V 6
%N 11
%P e27237
%@ 1932-6203
%X Previous studies have suggested that administration of oxytocin (OT) can have modulatory effects on social and anxiety-like behavior in mammals that may endure beyond the time of acute OT administration. The current study examined whether repeated administration of OT to male Wistar rats (n???=???48) during a key developmental epoch (early adolescence) altered their physiology and behavior in later-life. Group housed rats were given intraperitoneal injections of either 1 mg/kg OT or vehicle during early adolescence (post natal-days [PND] 33-42). OT treatment caused a transient inhibition of body weight gain that recovered quickly after the cessation of treatment. At PND 50, the rats pre-treated with OT displayed less anxiety-like behavior on the emergence test, while at PND 55 they showed greater levels of social interaction. A subgroup of OT pre-treated rats examined at PND 63 showed a strong trend towards increased plasma OT levels, and also displayed significantly increased OT receptor mRNA in the hypothalamus. Rats pre-treated with OT and their controls showed similar induction of beer intake in daily 70 min test sessions (PND 63 onwards) in which the alcohol concentration of beer was gradually increased across days from 0.44% to 4.44%. However, when given ad libitum access to beer in their home cages from PND 72 onwards (early adulthood), consumption of beer but not water was significantly less in the OT pre-treated rats. A "booster" shot of OT (1 mg/kg) given after 25 days of ad libitum access to beer had a strong acute inhibitory effect on beer intake without affecting water intake. Overall these results suggest that exogenous OT administered during adolescence can have subtle yet enduring effects on anxiety, sociability and the motivation to consume alcohol. Such effects may reflect the inherent neuroplasticity of brain OT systems and a feed-forward effect whereby exogenous OT upregulates endogenous OT systems.
%Z FOR Codes: 111599


%0 Journal Article
%~ PubMed
%A Klein, Charlotte
%A Karanges, Emily
%A Spiro, Adena
%A Wong, Alexander
%A Spencer, Jarrah
%A Huynh, Thanh
%A Gunasekaran, Nathan
%A Karl, Tim
%A Long, Leonora E
%A Huang, Xu-Feng
%A Liu, Kelly
%A Arnold, Jonathon C
%A McGregor, Iain S
%T Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats.
%B Psychopharmacology
%D 2011
%C Germany
%I Springer
%V 218
%N 2
%P 443-57
%@ 0033-3158
%X The interactions between ??(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models.
%Z FOR Codes: 111599 110999


%0 Journal Article
%~ PubMed
%A Sokolic, Ljiljana
%A Long, Leonora E
%A Hunt, Glenn E
%A Arnold, Jonathon C
%A McGregor, Iain S
%T Disruptive effects of the prototypical cannabinoid Δ9-tetrahydrocannabinol and the fatty acid amide inhibitor URB-597 on go/no-go auditory discrimination performance and olfactory reversal learning in rats.
%B Behavioural Pharmacology
%D 2011
%C United States
%I Lippincott Williams & Wilkins
%V 22
%N 3
%P 191-202
%@ 1473-5849
%X The effects of ??-tetrahydrocannabinol (??-THC; 0.3, 1, 3 and 10 mg/kg), and the fatty acid amide hydrolysis inhibitor URB-597 (0.1 and 0.3 mg/kg), on auditory and olfactory go/no-go discrimination tasks were examined in rats. The aims were to assess (i) whether simple olfactory and auditory discrimination tasks are sensitive to cannabinoid interference and (ii) whether manipulation of endogenous cannabinoid levels with URB-597 might have adverse effects on perceptual and cognitive functions. Thirsty rats were trained to nose poke at a ''sniff port'', where odours were briefly presented. After one odour (S+, lemon), licks made at an adjacent tube were rewarded with water, whereas licks after a second odour (S-, strawberry) were unrewarded. In an analogous auditory task, nose pokes produced an auditory S+ (beep) or S- (white noise). ??-THC and URB-597 impaired performance on the auditory but not the olfactory discrimination task. Auditory performance was still affected on the day after ??-THC (3 and 10 mg/kg) and URB-597 (0.3 mg/kg) exposure. ??-THC and URB-597 markedly impaired olfactory discrimination reversals without disrupting acquisition of the original discrimination. Rimonabant (CB1 antagonist; 3 mg/kg) reversed all ??-THC and URB-597 effects on auditory discriminations and olfactory discrimination reversals. These results confirm impairment of cognitive flexibility (reversal learning) by cannabinoids and show remarkable sensitivity of auditory discrimination performance to ??-THC and the augmented endocannabinoid signalling produced by URB-597.
%Z FOR Codes: 1109 1115


%0 Journal Article
%~ PubMed
%A Boucher, A A
%A Arnold, J C
%A Hunt, G E
%A Spiro, A
%A Spencer, J
%A Brown, C
%A McGregor, I S
%A Bennett, M R
%A Kassiou, M
%T Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test.
%B Neuroscience
%D 2011
%C United Kingdom, France
%I Pergamon
%V 189
%N 2011
%P 170-7
%@ 0306-4522
%X There is considerable evidence suggesting genetic factors play an important role in the pathophysiology of depression, possibly by increasing susceptibility to repeated environmental stressors. Recent linkage studies have associated a polymorphism of the gene coding for the P2X7 receptor (P2X7R) with both major depressive disorder and bipolar disorder. Here we assessed whether P2X7 deletion affected the behavioural and neural response to repeated stress. P2X7R knockout (P2X7-/-) mice were subjected to the forced swim test for three consecutive days and neuronal activation in response to the third exposure was assessed using c-Fos immunohistochemistry. In addition, anxiety was evaluated in another group of P2X7-/- mice using the elevated plus maze (EPM) and light dark emergence (LDE) tests. Equivalent levels of immobility were observed in P2X7-/- mice and wild-type (WT) mice on the first exposure to forced swim, but much greater immobility was seen in WT mice on second and third exposures. This suggests that P2X7-/- mice exhibit an impaired adaptive coping response to repeated stress. Reinforcing this view, c-Fos expression in the dentate gyrus of the hippocampus and in the basolateral amygdala was seen in WT mice but not P2X7-/- mice following repeated forced swim. In addition, decreased locomotor activity was detected in P2X7-/- mice without any specific effects on anxiety in the LDE test. However, P2X7-/- mice showed greater anxiety-like behaviour in the EPM. These data suggest that the P2X7R may be involved in the adaptive mechanisms elicited by exposure to repeated environmental stressors that leads to the development of depression-like behaviours. This suggests that P2X7R antagonists may be useful therapeutics for the treatment of major depression, possibly by increasing resilience in the face of repeated stress.
%Z FOR Codes: 111599 110999


%0 Journal Article
%~ PubMed
%A Long, Leonora E
%A Chesworth, Rose
%A Arnold, Jonathon C
%A Karl, Tim
%T A follow-up study: acute behavioural effects of Delta(9)-THC in female heterozygous neuregulin 1 transmembrane domain mutant mice.
%B Psychopharmacology
%D 2010
%C Germany
%I Springer
%V 211
%N 3
%P 277-289
%@ 0033-3158
%X Heavy cannabis use is linked with an increased risk for schizophrenia. We showed previously that male heterozygous neuregulin 1 transmembrane domain (Nrg1 HET) mice are more sensitive to some effects of the psychotropic cannabis constituent Delta(9)-tetrahydrocannabinol (THC). We report data from a follow-up study in female Nrg1 HET mice, investigating THC effects on behaviours with some relevance to schizophrenia.
%Z FOR Codes: 170101


%0 Journal Article
%~ PubMed
%A Arnold, Jonathon C
%A Dielenberg, Robert A
%A McGregor, Iain S
%T Cannabinoids increase conditioned ultrasonic vocalisations and cat odour avoidance in rats: Strain differences in drug-induced anxiety.
%B Life sciences
%D 2010
%C United States
%I Elsevier Inc.
%V 87
%N 17-18
%P 572-8
%@ 1879-0631
%X Genetic disposition modulates the psychoactive effects of cannabis. Cannabinoids have a greater impact on brain regions that subserve anxiety in Wistar compared to Lewis strain rats. Here we aim to show that this correlates with strain differences in cannabinoid-induced anxiety-related behaviour.
%Z FOR Codes: 111599


%0 Journal Article
%~ PubMed
%A van Nieuwenhuijzen, Petra S
%A Long, Leonora E
%A Hunt, Glenn E
%A Arnold, Jonathon C
%A McGregor, Iain S
%T Residual social, memory and oxytocin-related changes in rats following repeated exposure to gamma-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination.
%B Psychopharmacology
%D 2010
%C Germany
%I Springer
%V 212
%N 
%P 663-74
%@ 0033-3158
%X There has been little investigation of the possible lasting adverse effects of ??-hydroxybutyrate (GHB).
%Z FOR Codes: 111501 110903 170101


%0 Journal Article
%~ PubMed
%A Carson, Dean S
%A Hunt, Glenn E
%A Guastella, Adam J
%A Barber, Lachlan
%A Cornish, Jennifer L
%A Arnold, Jonathon C
%A Boucher, Aurelie A
%A McGregor, Iain S
%T Systemically administered oxytocin decreases methamphetamine activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus.
%B Addiction biology
%D 2010
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 15
%N 4
%P 448-63
%@ 1369-1600
%X Recent preclinical evidence indicates that the neuropeptide oxytocin may have potential in the treatment of drug dependence and drug withdrawal. Oxytocin reduces methamphetamine self-administration, conditioned place preference and hyperactivity in rodents. However, it is unclear how oxytocin acts in the brain to produce such effects. The present study examined how patterns of neural activation produced by methamphetamine were modified by co-administered oxytocin. Male Sprague-Dawley rats were pretreated with either 2 mg/kg oxytocin (IP) or saline and then injected with either 2 mg/kg methamphetamine (IP) or saline. After injection, locomotor activity was measured for 80 minutes prior to perfusion. As in previous studies, co-administered oxytocin significantly reduced methamphetamine-induced behaviors. Strikingly, oxytocin significantly reduced methamphetamine-induced Fos expression in two regions of the basal ganglia: the subthalamic nucleus and the nucleus accumbens core. The subthalamic nucleus is of particular interest given emerging evidence for this structure in compulsive, addiction-relevant behaviors. When administered alone, oxytocin increased Fos expression in several regions, most notably in the oxytocin-synthesizing neurons of the supraoptic nucleus and paraventricular nucleus of the hypothalamus. This provides new evidence for central actions of peripheral oxytocin and suggests a self-stimulation effect of exogenous oxytocin on its own hypothalamic circuitry. Overall, these results give further insight into the way in which oxytocin might moderate compulsive behaviors and demonstrate the capacity of peripherally administered oxytocin to induce widespread central effects.
%Z FOR Codes: 110999 111501 170101


%0 Journal Article
%~ PubMed
%A Boucher, Aurélie A
%A Hunt, Glenn E
%A Micheau, Jacques
%A Huang, Xufeng
%A McGregor, Iain S
%A Karl, Tim
%A Arnold, Jonathon C
%T The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids.
%B The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
%D 2010
%C United Kingdom
%I Cambridge University Press
%V 14
%N 
%P 631-43
%@ 1469-5111
%X Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of ??9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FosB/??FosB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, Nrg1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FosB/??FosB expression in the lateral septum, ventral part (LSV) of Nrg1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in Nrg1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1-cannabinoid interactions.
%Z FOR Codes: 111501 110903


%0 Journal Article
%~ Isi
%A Boucher, A. A.
%A Vivier, L.
%A Metna-Laurent, M.
%A Brayda-Bruno, L.
%A Mons, N.
%A Arnold, J. C.
%A Micheau, J.
%T Chronic treatment with Delta(9)-tetrahydrocannabinol impairs spatial memory and reduces zif268 expression in the mouse forebrain
%B Behavioural Pharmacology
%D 2009
%C United States, Unit
%I Lippincott Williams & Wilkins
%V 20
%N 1
%P 45-55
%@ 0955-8810
%X 
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Gunasekaran, N
%A Long, L E
%A Dawson, B L
%A Hansen, G H
%A Richardson, D P
%A Li, K M
%A Arnold, J C
%A McGregor, I S
%T Reintoxication: the release of fat-stored Delta(9)-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure.
%B British Journal of Pharmacology
%D 2009
%C United Kingdom
%I John Wiley & Sons Ltd.
%V 158
%N 5
%P 1330-1337
%@ 0007-1188
%X BACKGROUND AND PURPOSE: Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in adipose tissue where it is stored for long periods of time. Here we investigated whether conditions that promote lipolysis can liberate THC from adipocytes to yield increased blood levels of THC. EXPERIMENTAL APPROACH: In vitro studies involved freshly isolated rat adipocytes that were incubated with THC before exposure to the lipolytic agent adrenocorticotrophic hormone (ACTH). A complementary in vivo approach examined the effects of both food deprivation and ACTH on blood levels of THC in rats that had been repeatedly injected with THC (10 mg.kg(-1)) for 10 consecutive days. Lipolysis promoted by ACTH or food deprivation was indexed by measurement of glycerol levels. KEY RESULTS: ACTH increased THC levels in the medium of THC-pretreated adipocytes in vitro. ACTH also enhanced THC release from adipocytes in vitro when taken from rats repeatedly pretreated with THC in vivo. Finally, in vivo ACTH exposure and 24 h food deprivation both enhanced the levels of THC and its metabolite, (-)-11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH) in the blood of rats that had been pre-exposed to repeated THC injections. CONCLUSIONS AND IMPLICATIONS: The present study shows that lipolysis enhances the release of THC from fat stores back into blood. This suggests the likelihood of ''reintoxication'' whereby food deprivation or stress may raise blood THC levels in animals chronically exposed to the drug. Further research will need to confirm whether this can lead to functional effects, such as impaired cognitive function or ''flashbacks''.
%Z FOR Codes: 1115


%0 Journal Article
%~ PubMed
%A Jiwane, Ashish
%A Holland, Andrew Ja
%A Soundappan, Soundappan Sv
%A Arnold, John
%T An unusual case of bilious vomiting in a neonate
%B Journal of Paediatrics and Child Health
%D 2008
%C United Kingdom
%I Wiley-Blackwell
%V 44
%N 12
%P 747-749
%@ 1440-1754
%X 
%Z FOR Codes: 111403


%0 Journal Article
%~ PubMed
%A Holland, Michelle L
%A Allen, John D
%A Arnold, Jonathon C
%T Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1).
%B European journal of pharmacology
%D 2008
%C Netherlands
%I Elsevier BV
%V 591
%N 
%P 128-31
%@ 0014-2999
%X The ATP-binding cassette (ABC) transporter ABCC1, or multidrug resistance-related protein 1 (MRP1) is implicated in Phase II metabolism and multidrug resistance as it effluxes substrate anticancer drugs. As cannabinoids inhibit two related ABC transporters, P-glycoprotein and ABCG2, here we examined whether they also inhibit ABCC1. Indeed, the cannabinoids enhanced the intracellular accumulation of two ABCC1 substrates, Fluo3 and vincristine, in ovarian carcinoma cells over-expressing ABCC1 (2008/MRP1) with a rank order of potency: cannabidiol>cannabinol>Delta(9)-tetrahydrocannabinol. Cannabinoid inhibition of ABCC1 was confirmed using insect cell membrane MRP1 ATPase assays. These results demonstrate that cannabinoids inhibit ABCC1.
%Z FOR Codes: 110502


%0 Journal Article
%~ PubMed
%A Quinn, Heidi R
%A Matsumoto, Izuru
%A Callaghan, Paul D
%A Long, Leonora E
%A Arnold, Jonathon C
%A Gunasekaran, Nathan
%A Thompson, Murray R
%A Dawson, Bronwyn
%A Mallet, Paul E
%A Kashem, Mohammed A
%A Matsuda-Matsumoto, Haruka
%A Iwazaki, Takeshi
%A McGregor, Iain S
%T Adolescent Rats Find Repeated Delta(9)-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure.
%B Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
%D 2007
%C United Kingdom
%I Nature Publishing Group
%V 33
%N 0
%P 1113-26
%@ 0893-133X
%X 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 Delta-9-tetrahydrocannabinol (Delta(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 Delta(9)-THC-paired environment after either four or eight pairings and this avoidance persisted for at least 16 days following the final Delta(9)-THC injection. In contrast, adolescent rats showed no significant place aversion. Adult Delta(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 Delta(9)-THC pretreated rats showed decreased social interaction, while only Delta(9)-THC pretreated adolescent rats showed significantly impaired object recognition memory. Seventeen days following their last Delta(9)-THC injection, rats were euthanased and hippocampal tissue processed using two-dimensional gel electrophoresis proteomics. There was no evidence of residual Delta(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 Delta(9)-THC pretreated rats relative to adolescent controls. In adults, only 10 hippocampal proteins were differentially expressed in Delta(9)-THC compared to vehicle-pretreated controls. Overall these findings suggest that adolescent rats find repeated Delta(9)-THC exposure less aversive than adults, but that cannabinoid exposure causes greater lasting memory deficits and hippocampal alterations in adolescent than adult rats.
%Z FOR Codes: 111505


%0 Journal Article
%~ PubMed
%A McGregor, I S
%A Arnold, J C
%T Cannabis reward: biased towards the fairer sex?
%B British journal of pharmacology
%D 2007
%C United Kingdom
%I Nature Publishing Group
%V 152
%N 5
%P 562-4
%@ 0007-1188
%X In contrast to drugs such as alcohol, amphetamine and cocaine, cannabis use in humans has proven difficult to model in laboratory animals. Recent breakthrough discoveries of intravenous THC self-administration in rhesus monkeys and self-administration of the synthetic cannabinoid agonist WIN 55,212-2 in rats have allowed new studies of the genetic, neural and environmental determinants of cannabis use. In the present issue of BJP, Fattore and colleagues further demonstrate genetic (strain) differences in WIN 55,212-2 self-administration in rats, with Long Evans (LE) and Lister Hooded (LH), but not Sprague-Dawley, rats self-administering this drug. They then show that female LE and LH rats self-administer more WIN 55,212-2 than male rats. Ovariectomy abolished this sex difference, suggesting a permissive role for oestrogen in cannabis reward. This accompanying Commentary reviews recent progress in animal models of cannabis use and highlights the role of genetic, developmental and endocrine factors in driving cannabis use and dependence.
%Z FOR Codes: 111505


%0 Journal Article
%~ PubMed
%A Boucher, A A
%A Arnold, J C
%A Duffy, L
%A Schofield, P R
%A Micheau, J
%A Karl, T
%T Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol.
%B Psychopharmacology
%D 2007
%C Germany
%I Springer
%V 192
%N 3
%P 325-336
%@ 0033-3158
%X RATIONALE: Cannabis use may precipitate schizophrenia especially if the individual has a genetic vulnerability to this mental disorder. Human and animal research indicates that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia. OBJECTIVES: The aim of this study was to investigate whether dysfunction in the Nrg1 gene modulates the behavioural effects of Delta(9)-tetrahydrocannabinol (THC), the major psychotropic component of cannabis. MATERIALS AND METHODS: Heterozygous Nrg1 transmembrane-domain knockout mice (Nrg1 HET) were treated with acute THC (0, 5 or 10 mg/kg i.p.) 30 min before being tested using open field (OF), hole board (HB), light-dark (LD), elevated plus maze (EPM), social interaction (SI) and prepulse inhibition (PPI) tests. RESULTS: Nrg1 HET mice showed differences in baseline behaviour with regard to locomotor activity, exploration and anxiety. More importantly, they were more sensitive to the locomotor suppressant actions of THC compared to wild type-like (WT) mice. In addition, Nrg1 HET mice expressed a greater THC-induced enhancement in % PPI than WT mice. The effects of THC on anxiety-related behaviour were task-dependent, with Nrg1 HET mice being more susceptible than WT mice to the anxiogenic effects of THC in LD, but not in the EPM, SI and OF tests. CONCLUSIONS: Nrg1 HET mice were more sensitive to the acute effects of THC in an array of different behaviours including those that model symptoms of schizophrenia. It appears that variation in the schizophrenia-related neuregulin 1 gene alters the sensitivity to the behavioural effects of cannabinoids.
%Z FOR Codes: 111505


%0 Journal Article
%~ PubMed
%A Boucher, A A
%A Hunt, G E
%A Karl, T
%A Micheau, J
%A McGregor, I S
%A Arnold, J C
%T Heterozygous neuregulin 1 mice display greater baseline and Delta(9)-tetrahydrocannabinol-induced c-Fos expression.
%B Neuroscience
%D 2007
%C Netherlands, France
%I Elsevier BV
%V 149
%N 4
%P 861-70
%@ 0306-4522
%X Cannabis use may increase the risk of developing schizophrenia by precipitating the disorder in genetically vulnerable individuals. Neuregulin 1 (NRG1) is a schizophrenia susceptibility gene and mutant mice heterozygous for the transmembrane domain of this gene (Nrg1 HET mice) exhibit a schizophrenia-related phenotype. We have recently shown that Nrg1 HET mice are more sensitive to the behavioral effects of the main psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC). In the present study, we examined the effects of THC (10 mg/kg i.p.) on neuronal activity in Nrg1 HET mice and wild type-like (WT) mice using c-Fos immunohistochemistry. In the lateral septum, THC selectively increased c-Fos expression in Nrg1 HET mice with no corresponding effect being observed in WT mice. In addition, THC promoted a greater increase in c-Fos expression in Nrg1 HET mice than WT mice in the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. Consistent with Nrg1 HET mice exhibiting a schizophrenia-related phenotype, these mice expressed greater drug-free levels of c-Fos in two regions thought to be involved in schizophrenia, the shell of the nucleus accumbens and the lateral septum. Interestingly, the effects of genotype on c-Fos expression, drug-free or following THC exposure, were only observed when animals experienced behavioral testing prior to perfusion. This suggests an interaction with stress was necessary for the promotion of these effects. These data provide neurobiological correlates for the enhanced behavioral sensitivity of Nrg1 HET mice to THC and reinforce the existence of cannabinoid-neuregulin 1 interactions in the CNS. This research may enhance our understanding of how genetic factors increase individual vulnerability to schizophrenia and cannabis-induced psychosis.
%Z FOR Codes: 110903 110502 110999


%0 Journal Article
%~ PubMed
%A Holland, M L
%A Lau, D T T
%A Allen, J D
%A Arnold, J C
%T The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids.
%B British journal of pharmacology
%D 2007
%C United Kingdom
%I Nature Publishing Group
%V 152
%N 5
%P 815-24
%@ 0007-1188
%X Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and delta 9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2.
%Z FOR Codes: 111505


%0 Journal Article
%~ Isi
%A Karl, T.
%A Duffy, L.
%A Boucher, A.
%A Arnold, J.
%A Schofield, P.
%T Genetic animal models for neuregulin 1 - valuable tools for schizophrenia research?
%B Australian and New Zealand Journal of Psychiatry
%D 2006
%C United Kingdom
%I Taylor & Francis Ltd.
%V 40
%N 
%P A115-A115
%@ 0004-8674
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Holland, M L
%A Panetta, J A
%A Hoskins, J M
%A Bebawy, M
%A Roufogalis, B D
%A Allen, J D
%A Arnold, J C
%T The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells.
%B Biochemical pharmacology
%D 2006
%C United States
%I Elsevier Inc.
%V 71
%N 8
%P 1146-54
%@ 0006-2952
%X Cannabis is the most widely used illicit drug in the world. Cannabinoids are used therapeutically by some patients as they have analgesic, anti-emetic and appetite stimulant properties which palliate adverse symptoms. Use of these agents in an oncology setting raises the question of whether they act to modulate the effectiveness of concurrently administered anti-cancer drugs. The transporter, P-glycoprotein (P-gp) confers multiple drug resistance (MDR) by effluxing a diverse array of anti-cancer agents. This study was undertaken to examine the effect of cannabinoids on P-gp. Unlike the known P-gp inhibitor, PSC833, short 1h exposure to three plant-derived cannabinoids, cannabinol (CBN), cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC) and the synthetic cannabinoid receptor agonist, WIN55, 212-2 (WIN) did not inhibit the efflux of the P-gp substrate Rhodamine 123 (Rh123) in either a drug-selected human T lymphoblastoid leukaemia cell line (CEM/VLB(100)) or in a mouse fibroblast MDR1 transfected cell line (77.1). However, in CEM/VLB(100) cells, prolonged 72 h exposure to the cannabinoids, THC and CBD, decreased P-gp expression to a similar extent as the flavonoid, curcumin (turmeric). This correlated with an increase in intracellular accumulation of Rh123 and enhanced sensitivity of the cells to the cytotoxic actions of the P-gp substrate, vinblastine. Taken together, these results provide preliminary evidence that cannabinoids do not exacerbate P-gp mediated MDR. Further, plant-derived cannabinoids are moderately effective in reversing MDR in CEM/VLB(100) cells by decreasing P-gp expression.
%Z FOR Codes: 110502