Ketamine-induced behavioural and brain oxidative changes
in mice: an assessment of possible beneficial effects of zinc
as mono- or adjunct therapy
Olakunle James Onaolapo
Olayemi Quyyom Ademakinwa
Temitayo Opeyemi Olalekan
Adejoke Yetunde Onaolapo
Received: 19 January 2017 /Accepted: 29 May 2017 / Published online: 14 June 2017
Springer-Verlag GmbH Germany 2017
Rationale We studied the influence of zinc, haloperidol or
olanzapine on neurobehaviour (open-field, radial arm maze
and elevated plus maze) and brain antioxidant status in
vehicle- or ketamine-treated mice, with the aim of ascertaining
the potentials of zinc in counteracting ketamine’seffects.
Objectives Experiment 1 assessed the effects of zinc in
healthy animals and the relative degrees of modulation of
ketamine’s effects by zinc, haloperidol or olanzapine, respec-
tively. Experiment 2 assessed the modulation of ketamine’s
effects following co-administration of zinc with haloperidol
Methods Male mice weighing 18–20geachwereused.
Animals were pretreated with ketamine (except vehicle, zinc,
haloperidol and olanzapine controls) for 10 days before com-
mencement of 14-day treatment (day 11–24) with vehicle,
zinc, haloperidol or olanzapine (alone or in combination).
Ketamine injection also continued alongside zinc and/or stan-
dard drugs in the ketamine-treated groups. Zinc, haloperidol
and olanzapine were administered by gavage. Treatments
were given daily and behaviours assessed on days 11 and
24. On day 24, animals were sacrificed and whole brain ho-
mogenates used for estimation of glutathione, nitric oxide and
malondialdehyde (MDA) levels.
Results Ketamine increased open-field behaviours, nitric ox-
ide and MDA levels, while it decreased working memory,
social interaction and glutathione. Administration of zinc
alone or in combination with haloperidol or olanzapine was
associated with variable degrees of reversal of these effects.
Conclusion Zinc may have the potential of a possible thera-
peutic agent and/or adjunct in the reversal of schizophrenia-
like changes in behaviour and brain oxidative status.
Mental health disorders (like schizophrenia) contribute signif-
icantly to overall disease burden worldwide (Nestler and
Hyman 2010). Schizophrenia, a chronic debilitating disorder
known to affect about 1% of the world population (McGrath
et al. 2004), is characterised by clusters of symptoms which
could be positive, negative or related to loss of memory and/or
executive functioning (Larson et al. 2010). The age of onset of
schizophrenia, which is generally between adolescence and
young adulthood (age 15–35) (Thomsen 1996; Kessler et al.
2007), further increases the disease burden. Therefore, there is
an ever-increasing need to continually examine, evaluate and
develop novel treatments for this disorder, not only for the
direct benefit of the patients but also for the society at large
(Arroll et al. 2014).
Experimental models have assisted in the understanding of
the different hypotheses relating to schizophrenia pathogene-
sis, the development of new drugs and repurposing of old
drugs (Steeds et al. 2015). Pharmacological models using N-
-aspartate glutamate receptor (NMDA-R) antagonist
like phencyclidine, MK801 and ketamine have been found
* Olakunle James Onaolapo
* Adejoke Yetunde Onaolapo
Department of Pharmacology, Ladoke Akintola University of
Technology, Osogbo, Osun State, Nigeria
Department of Anatomy, Ladoke Akintola University of Technology,
Ogbomoso, Oyo State, Nigeria
Psychopharmacology (2017) 234:2707–2725