1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound that is constantly present in the brain, and that exhibits neuroprotective activity. Our earlier study has suggested that 1MeTIQ may play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. It is well known that
central nervous system stimulants such as:
amphetamine,
cocaine,
phencyclidine, and selective
NMDA receptor antagonists, e.g.,
MK-801 produce neuropsychotoxicity (
psychosis, addiction) that is indistinguishable from paranoid type
schizophrenia. In rodents,
phencyclidine and
MK-801 are often used to evoke
schizophrenia-like behavioral abnormalities which are inhibited by
neuroleptics. The present study was designed to further investigate potential
antipsychotic properties of 1MeTIQ by using both behavioral and neurochemical studies in the rat. We investigated the influence of 1MeTIQ (25 and 50 mg/kg ip) on locomotor hyperactivity, disruptions of prepulse inhibition (PPI), and working memory impairment induced by the
NMDA receptor antagonist,
MK-801 (0.2-0.3 mg/kg ip). In addition in the biochemical study, we analyzed the effect of 1MeTIQ on the changes in
dopamine metabolism in different brain structures and in extraneuronal release of
dopamine and
glutamate in the rat frontal cortex, produced by
MK-801. The concentration of
dopamine (DA) and its metabolites:
3,4-dihydroxyphenylacetic acid (
DOPAC),
3-methoxytyramine (3-MT), and
homovanillic acid (HVA), as well as the extraneuronal concentration of
dopamine and
glutamate were established by HPLC.
MK-801 (0.25 mg/kg ip) evoked significant disruptions of PPI and working memory impairment, and co-administration of 1MeTIQ at two investigated doses of 25 and 50 mg/kg ip did not antagonize these effects. On the other hand hyperactivity evoked by
MK-801 as well as a rise in
dopamine metabolism in specific brain structures and
glutamate release in the frontal cortex was completely antagonized by pretreatment with 1MeTIQ. If the hyperlocomotion elicited by acutely administered
MK-801 is a valid model of at least some aspects of
schizophrenia, these results indicate that 1MeTIQ will show efficacy in treating this condition. In conclusions, the present study suggests that 1MeTIQ, an endogenous neuroprotective compound, exhibits also
antipsychotic-like efficacy in some animal tests, and may be useful in clinical practice as a
psychosis-attenuating
drug in schizophrenic patients. However, 1MeTIQ did not attenuate sensorimotor gating deficit or working memory impairment evoked by
MK-801 which may be served as a model of negative symptoms of
schizophrenia.