Pro-cognitive effect of 1MeTIQ on recognition memory in the ketamine model of schizophrenia in rats: the behavioural and neurochemical effects
Psychopharmacology
https://doi.org/10.1007/s00213-020-05484-1
ORIGINAL INVESTIGATION
Pro-cognitive effect of 1MeTIQ on recognition memory
in the ketamine model of schizophrenia in rats: the behavioural
and neurochemical effects
Magdalena Białoń 1 & Marcelina Żarnowska 1 & Lucyna Antkiewicz-Michaluk 1 & Agnieszka Wąsik 1
Received: 19 November 2019 / Accepted: 12 February 2020
# The Author(s) 2020
Abstract
Rationale Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this
disease, there is evidence that the noradrenergic system also plays a role in its major symptoms.
Objectives In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ)
an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats.
Methods We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel
object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies
allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum.
Results Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances
memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully
increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical
effect.
Conclusions 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in
the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an
important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated
the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its
possible participation in negative symptoms of the schizophrenia.
Keywords Schizophrenia . Novel object recognition (NOR) . 1,2,3,4-Tetrahydroisoquinoline (1MeTIQ) . Ketamine . Olanzapine
Introduction
Schizophrenia is a devastating mental disorder that can result
in cognitive deficits, including memory deficits, attentional
deficits and executive functioning impairments, in addition
to positive and negative symptoms (Heinrichs and Zakzanis
1998). These symptoms generally appear years before a clinical diagnosis (Lesh et al. 2011) and strongly influence patient
quality of life; therefore, it is necessary to explore effective
* Agnieszka Wąsik
1
Department of Neurochemistry, Maj Institute of Pharmacology,
Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland
treatments for related cognitive impairments. Studies of memory in patients with schizophrenia have reported large deficits
in verbal and visual features (Faraone et al. 2000) of recognition (Danion et al. 1999) and episodic memory (Krabbendam
et al. 2001; Toulopoulou et al. 2003), both of which are part of
declarative memory (Riedel and Blokland 2015). One of the
most popular methods for investigating declarative memory
processes in rodents is the novel object recognition (NOR)
test—a non-rewarded, ethologically relevant paradigm that
is based on the spontaneous exploratory behaviours of rodents
and that does not require external motivation, punishment or
training (Ennaceur and Delacour 1988; Ennaceur 2010;
Cadinu et al. 2018). NOR test gained popularity as it is simple
and cheap behavioural assay of memory that relies primarily
on a rodent’s innate exploratory behaviour in the absence of
Psychopharmacology
externally applied rules, reinforcement or stressful training
(Silvers et al. 2007; Reger et al. 2009; Mathiasen and
DiCamillo 2010; Antunes and Biala 2012; Cadinu et al.
2018) . A preference for the novel object is evidence that the
familiar object has been remembered by the animal. This form
of memory is considered to be the rodent equivalent of human
declarative (episodic) memory (Ennaceur 2010). In humans,
the analogous task used to study declarative memory is a
visual-paired comparison task (Sivakumaran et al. 2018), in
which patients with schizophrenia show less accuracy in recognizing previously seen objects (Heckers et al. 2000). There
are evidence that atypical antipsychotic drugs, such as
olanzapine, improve cognitive functions, including memory
(Wolff and Leander 2003; He et al. 2005; Mahmoud et al.
2019; Desamericq et al. 2014; Guo et al. 2011; Gurpegui
et al. 2007; Meltzer and McGurk 1999; McGurk et al. 2004;
Mutlu et al. 2011; Rajagopal et al. 2014; Babic et al. 2018)
while other authors have shown that olanzapine can impair
memory (Skarsfeldt 1996; Purdon et al. 2000; Levin et al.
2005).
Many theories of the molecular origins of schizophrenia
symptoms have arisen, although the aetiology of the illness
remains uncertain. Many networks and neurotransmitters may
be involved in the pathophysiology of schizophrenia; however, no single neurotransmitter or system can explain the full
picture of the heterogeneity of schizophrenia symptoms (Yang
and Tsai 2017). In addition to the engagement of dopaminergic, serotonergic and noradrenergic systems, there is strong
evidence from many research disciplines indicating the role
of the hypofunction of N-methyl-D-aspartate receptors
(NMDARs) as a primary neurophysiological contributor to
schizophrenia (Weickert et al. 2013; Nakazawa et al. 2017;
Bubeniková-Valesová et al. 2008; Duncan et al. 1999;
Brandao-Teles et al. 2017; Balu 2016; Krystal et al. 1999).
NMDAR antagonists such as ketamine, dizocilpine (MK801) and phencyclidine (PCP), as well as transgenic animals,
have become useful preclinical tools to model the illness
(Gilmour et al. 2012; Neill et al. 2010; Coyle 2012; Bondi
et al. 2012). 1-Methyl-1,2,3,4-tetrahydroisoquinoline
(1MeTIQ) is an endogenous amine present and synthesised
in the mammalian brain in low concentrations (AntkiewiczMichaluk et al. 2014; Wąsik and Antkiewicz-Michaluk 2017).
The 1MeTIQ present in the brain is a mixture of (R)- and (S)enantiomers enzymatically synthesised from 2phenylethylamine and pyruvate by 1MeTIQ-synthesizing enzyme, a membrane-bound protein localised in the mitochondrial synaptosomal fraction (Yamakawa et al. 1999). Previous
studies have shown that 1MeTIQ has affinity for the agonistic
form of dopamine receptors and acts as a reversible monoamine oxidase (MAOA and MAOB) inhibitor with neuroprotective, anti-depressive (Antkiewicz-Michaluk et al. 2001,
2006, 2007; Patsenka and Antkiewicz-Michaluk 2004;
Wąsik et al. 2016) and a (...truncated)
