Abstract
RationaleSchizophrenia 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.ObjectivesIn 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.MethodsWe 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.ResultsOur 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.Conclusions1MeTIQ, 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.
Highlights
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)
We observed statistically significant differences in the exploration times for the novel object (NO) and FO in groups treated with 1MeTIQ (p < 0.001), combined 1MeTIQ and ketamine (p < 0.05), olanzapine (p < 0.01) and combined olanzapine and ketamine (p < 0.05) (Fig. 1b)
Olanzapine given with ketamine did not produce significant changes in the discrimination index (DI) (Fig. 2a)
Summary
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; it is necessary to explore effective. 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). 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)
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