Recently, a novel paradigm has been designed to assess social investigative behaviour in pairs of Sprague–Dawley rats, which involves physical separation whilst ensuring they are able to maintain contact through other social cues. We have modified this set-up in order to assess not just social behaviour but also locomotor activity of the rats. Results showed that the MK-801- (0.3 mg/kg) treated rats displayed reduced social investigative behaviour, hyperactivity as well as reduced attention span. Pretreatment with the phytocannabinoid cannabidiol (3 mg/kg) not only normalised social investigative behaviour but increased it beyond control levels. Pretreatment with clozapine (1, 3 mg/kg) also normalised social investigative behaviour. Both cannabidiol and clozapine inhibited MK-801-induced hyperactivity. However, there were no effects of pretreatment on impairments to attention span. Our findings reinforce several aspects of the validity of the MK-801-induced model of social withdrawal and hyperactivity and also support the use of this novel set-up for further investigations to assess the antipsychotic potential of novel compounds.
AhnaouAMegensAADrinkenburgWH (2003) The atypical antipsychotics risperidone, clozapine and olanzapine differ regarding their sedative potency in rats. Neuropsychobiology48: 47–54.
2.
BeckerAGreckschG (2004) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Test of predictive validity. Prog Neuropsychopharmacol Biol Psychiatry28: 1267–1277.
3.
BekkedalMYPankseppJRossiJ3rd (1998) Long-term changes in rat social behavior following treatment with trimethylolpropane. Neurotoxicol Teratol20: 307–316.
4.
BekkedalMYRossiJ3rdPankseppJ (1999) Fetal and neonatal exposure to trimethylolpropane phosphate alters rat social behavior and emotional responsivity. Neurotoxicol Teratol21: 435–443.
5.
BoguszewskiPZagrodzkaJ (2002) Emotional changes related to age in rats – a behavioral analysis. Behav Brain Res133: 323–332.
6.
BoulayDDepoortereRLouisC. (2004) SSR181507, a putative atypical antipsychotic with dopamine D2 antagonist and 5-HT1A agonist activities: improvement of social interaction deficits induced by phencyclidine in rats. Neuropharmacology46: 1121–1129.
7.
BoulayDPichatPDargazanliG. (2008) Characterisation of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia. Pharmacol Biochem Behav91: 47–58.
8.
BubserMKesebergUNotzPK. (1992) Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur J Pharmacol229: 75–82.
DaiHCareyRJ (1994) The NMDA antagonist MK-801 can impair attention to exteroceptive stimuli. Behav Brain Res62: 149–156.
11.
DeakTArakawaHBekkedalMY. (2009) Validation of a novel social investigation task that may dissociate social motivation from exploratory activity. Behav Brain Res199: 326–333.
12.
DeianaSWatanabeAYamasakiY. (2012) Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl)219: 859–873.
13.
GattazWFSchummerBBehrensS (1994) Effects of zotepine, haloperidol and clozapine on MK-801-induced stereotypy and locomotion in rats. J Neural Transm Gen Sect96: 227–232.
14.
GuimarãesVMZuardiAWDel BelEA. (2004) Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum. Life Sci75: 633–638.
15.
GururajanAMaloneDTTaylorDA (2009a) Advances in cannabidiol research as an antipsychotic. Current Topics Pharmacol13: 17–24.
16.
GururajanATaylorDAMaloneDT (2009b) Effect of testing conditions on the propsychotic action of MK-801 on prepulse inhibition, social behaviour and locomotor activity. Physiol Behav99: 131–138.
17.
GururajanATaylorDAMaloneDT (2010) Current pharmacological models of social withdrawal in rats: relevance to schizophrenia. Behav Pharmacol21: 690–709.
18.
GururajanATaylorDAMaloneDT (2011) Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia. Behav Brain Res222: 299–308.
19.
HayakawaKMishimaKHazekawaM. (2008) Cannabidiol potentiates pharmacological effects of delta9-tetrahydrocannabinol via CB1 receptor-dependent mechanism. Brain Res1188: 157–164.
20.
HoffmanDC (1992) Typical and atypical neuroleptics antagonize MK-801-induced locomotion and stereotypy in rats. J Neural Transm Gen Sect89: 1–10.
21.
IzzoAABorrelliFCapassoR. (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci30: 515–527.
22.
LataneBCappellHJoyV (1970) Social deprivation, housing density, and gregariousness in rats. J Comp Physiol Psychol70: 221–227.
23.
LongLE (2006) Neuropharmacological Studies of the Effect of Cannabinoids on Some Behavioural and Molecular Correlates of Psychosis. Victorian College of Pharmacy. Dept. of Pharmaceutical Biology and Pharmacology. Melbourne: Monash University, 236.
24.
LongLEChesworthRHuangXF. (2009) A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int J Neuropsychopharmacol13: 861–876.
25.
LoscherWHonackD (1992) The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems. Eur J Pharmacol215: 199–208.
26.
MaloneDTJongejanDTaylorDA (2009) Cannabidiol reverses the reduction in social interaction produced by low dose Delta(9)-tetrahydrocannabinol in rats. Pharmacol Biochem Behav93: 91–96.
27.
MatheJMNomikosGGHildebrandBE. (1996) Prazosin inhibits MK-801-induced hyperlocomotion and dopamine release in the nucleus accumbens. Eur J Pharmacol309: 1–11.
28.
MoreiraFAGuimaraesFS (2005) Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol512: 199–205.
29.
MorimotoTHashimotoKYasumatsuH. (2002) Neuropharmacological profile of a novel potential atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)- 6H-[1]benzothieno[2,3-b][1,5] benzodiazepine maleate). Neuropsychopharmacol26: 456–467.
OuagazzalANieoullonAAmalricM (1993) Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats. Psychopharmacology111: 427–434.
32.
PankseppJNelsonEBekkedalM (1997) Brain systems for the mediation of social separation-distress and social-reward. Evolutionary antecedents and neuropeptide intermediaries. Ann N Y Acad Sci807: 78–100.
33.
RungJPCarlssonAMarkinhuhtaKR. (2005a) The dopaminergic stabilizers (−)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats. Prog Neuropsychopharmacol Biol Psych29: 833–839.
34.
RungJPCarlssonARyden MarkinhuhtaK. (2005b) (+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia. Prog Neuropsychopharmacol Biol Psych29: 827–832.
35.
Sams-DoddF (1996) Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia. Behav Pharmacol7: 3–23.
36.
SteinpreisRESokolowskiJDPapanikolaouA. (1994) The effects of haloperidol and clozapine on PCP- and amphetamine-induced suppression of social behavior in the rat. Pharmacol Biochem Behav47: 579–585.
37.
van ReeJMNiesinkRJNirI (1984) delta 1-Tetrahydrocannabinol but not cannabidiol reduces contact and aggressive behavior of rats tested in dyadic encounters. Psychopharmacology84: 561–565.
38.
VarvelSAWileyJLYangR. (2006) Interactions between THC and cannabidiol in mouse models of cannabinoid activity. Psychopharmacology186: 226–234.
39.
WedzonyKMackowiakMZajaczkowskiW. (2000) WAY 100135, an antagonist of 5-HT1A serotonin receptors, attenuates psychotomimetic effects of MK-801. Neuropsychopharmacol23: 547–559.
40.
ZuardiAWCrippaJAHallakJE. (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res39: 421–429.
41.
ZuardiAWMoraisSLGuimaraesFS. (1995) Antipsychotic effect of cannabidiol. J Clin Psychiat56: 485–486.
