Review Article - (2018) Volume 8, Issue 5
1metiq, an Endogenous Compound Present in the Mammalian Brain Displays Neuroprotective, Antiaddictive and Antidepressant-Like Activity in Animal Models of theCentral Nervous System Disorders
- Corresponding Author:
- Lucyna Antkiewicz-Michaluk
Institute of Pharmacology PAS, Department of Neurochemistry, SmÃÂtna Str.12, 31-052 Krakow, Poland
Tel: +48 12 6623-203
The review manuscript raises some important aspects concerning the pharmacology, clinical applications of an endogenous amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), a unsubstituted non-catechol tetrahydroisoquinoline which is present in the mammalian brain. The manuscript is focused on the mechanisms of action of 1MeTIQ in behavioral, neurochemical and molecular studies on rodents. The neuroprotective, antiaddictive and antidepressant properties of 1MeTIQ will be described.
Findings implicate 1MeTIQ in unique and complex mechanisms of neuroprotection in various neurodegenerative diseases of the central nervous system. We believe that MAO inhibition, free radical scavenging properties and antagonism to the glutamatergic system may play an essential role in neuroprotection. At the same time all demonstrated results strongly support the view that 1MeTIQ has a considerable potential as an antidepressant and antiaddictive drug demonstrated in the animal models of depression (forced swim test, tail suspension test, reserpine and clonidine model) and addiction (morphine and cocaine addiction).
Introduced data have shown that therapeutic effects of 1MeTIQ may be coupling with gentle activation of the monoaminergic system (dopaminergic, noradrenergic and serotoninergic) in the brain structures, the simultaneous inhibition of MAO-dependent oxidation and reduction of the glutamate system activity in the brain.
1MeTIQ, Mechanism of action, Brain dopamine metabolism, Neuroprotection, Addiction, Antidepressant-like activity, Rat
Tetrahydroisoquinolines (TIQs) are a big family of compounds widespread in plant and animal kingdoms [1,2]. In general, TIQs can be formed by condensation of biogenic amines (phenylethylamines and catecholamines) with aldehydes or α-keto acids in the so-called Pictet- Spengler reaction [1,3], although some of them (e.g. 1-methyl-1,2,3,4-tetrahydroisoquinoline, 1MeTIQ) are also synthesized enzymatically in the mammalian brain [4-6]. Depending on the chemical structure of biogenic amines participating in these reactions, TIQs family can be divided into compounds with catechol and non-catechol structures. The presence of two noncatechol TIQs that is 1MeTIQ and 1BnTIQ, in the brains of humans, monkeys and rodents as well as in the cerebrospinal fluid (CSF) of parkinsonian patients and healthy controls [7-11] has been detected by means of chromatographic methods. 1MeTIQ is considered to be a potential neuroprotective compound, while 1BnTIQ is suspected of displaying neurotoxic properties [12-17]. Interestingly, the amount of 1MeTIQ in parkinsonian patients was reduced and tended to decrease with aging . Additionally, in old rats a 50% reduction in the amount of 1MeTIQ was found in the substantia nigra . As it was demonstrated by others authors 1MeTIQ synthesis is inhibited by different compounds that induce experimental parkinsonism [19,20]. Basing on introduced findings the 1MeTIQ concentration in the brain plays an important role in the pathogenesis of the toxin-induced parkinsonism. What more, the degeneration of the dopaminergic neurons may proceed as a result of the loss of neuroprotection afforded by 1MeTIQ. It is well known that oxidative stress provides a universal mechanism for inducing cell death . In the brain, MOA-mediated deamination of monoamines (especially dopamine) constitutes the main source of toxic .OH formation and H2O2 generation. 1MeTIQ, in contrast to neurotoxic tetrahydroisoquinolines (e.g. salsolinol, 1BnTIQ) (Figure 1), is a reversible inhibitor of MAO A and B activities and possesses antioxidant properties . 1MeTIQ exhibits intrinsic structure-related antioxidant properties, as indicated by the effects of 1MeTIQ on inhibiting free radical formation and abolishing .OH generation resulting from dopamine oxidation via the Fenton reaction in the abiotic system . In this light 1MeTIQ seems to be an endogenous compound protecting especially dopamine neurons against oxidation stress produced by free radicals. Moreover, 1MeTIQ exists in two stereoisomeric forms, R- and S-enantiomers. Their proportion in the mouse brain amounts to 0.60, implying that 1MeTIQ could be synthesized, at least partially, using an enzymatic pathway . As it was demonstrated in our earlier paper, both stereo enantiomers, similarly to racemate (R,S- 1MeTIQ), possess neuroprotective activity against rotenone-induced impairment of dopamine release in the rat brain .
Neuroprotection- the effect of 1MeTIQ against rotenone and glutamate-evoked neurotoxicity
Rotenone, an environmental toxin shows selective neurotoxicity towards dopaminergic neurons . It is a classical, lipophilic inhibitor of mitochondrial complex I, and such mechanism of action was postulated to be the cause of rotenone-induced neurodegeneration . Rotenone also triggers dopamine release, as evidenced by microdialysis and biochemical data , and this activity may further contribute to the degeneration of dopaminergic cells. In our study repeated administration of rotenone produced many defects in general behavior of rats, considerable mortality and dramatic increases of dopamine metabolism. One ought to underline that rotenone increased many times dopamine oxidative catabolic pathway and in the same time strongly depressed COMT-dependent methylation and its main product the extracellular dopamine metabolite, 3-methoxytyramine (3-MT). These behavioral and biochemical changes were effectively counteracted by administration of 1MeTIQ before each dose of rotenone . Additionally, rotenone administered intracerebrally to the left medial forebrain bundle (MFB) produced neurodegeneration of dopamine neurons, and also in this case peripheral administration of 1MeTIQ before rotenone, and then during 21 days significantly reduced the fall of striatal dopamine concentration . These data demonstrated that 1MeTIQ is able to counteract the damaging action of rotenone, a dopaminergic neurotoxin, and seems to be a potential neuroprotective agent. Also, our in vitro experiments (granular cell cultures obtained from seven day old rats) was found that 1MeTIQ (in concentration-related manner) prevented glutamate-induced cell death and 45Ca2+ influx . Such profile of 1MeTIQ action suggested specific effects of this compound on an excitatory amino acid receptor. What is more, 1MeTIQ prevents kainite-induced release of excitatory amino acids from the rat frontal cortex observed in an in vivo microdialysis study . The results presented above suggest that 1MeTIQ may exhibit anticonvulsant activity. In fact, 1MeTIQ exerts anticonvulsant effects by increasing the threshold for electro-convulsions and potentiation of the antiseizure action of carbamazepine and valproate against maximal electroshock in rodents .
Conclusions: 1MeTIQ offers a unique and complex mechanism of neuroprotection, in which reversible inhibitory effect on monoamine oxidase (MAO A and B), scavenging properties of free radicals, and antagonism to the glutamateinduced excitotoxicity seems to play a very important role.
Drug addiction is one of the most difficult medical and social problems, as no effective pharmacotherapy has been available so far. Drug addiction is a chronically relapsing disorder that is characterized by compulsion to take the drug and loss of control in limiting intake. The neurobiological changes that accompany drug addiction have not been understood till now; however, drugs of abuse are unique in terms of their reinforcing properties. Dopaminergic mechanisms are traditional targets in the research into addiction [29-31]. A question arises about the neurobiological substrate of reward. The nucleus accumbens (NAc), as a part of the ventral striatum, as well as dorsal striatum, hippocampus and frontal cortex are considered to be a crucial points of integration of information by receiving emotional and cognitive inputs (frontal cortex, hippocampus), and by projecting to motor output regions (dorsal and ventral striatum) . Early theories on drugs of abuse and natural rewards suggested that activation of dopamine cells in the ventral tegmental area (VTA) and the release of dopamine in target structures signaled reward, especially in the NAc [32,33]. How it was recently demonstrated the glutamate system and its release are also important factors in drug addiction and that imbalance in glutamate homeostasis which is responsible for neuroplasticity may impair communication between the prefrontal cortex and the NAc [34-36].
Morphine addiction – the effect of 1MeTIQ
Morphine activates opioid μ-receptors and produces the antinociceptive effect called analgesia. In the same time morphine affects the dopamine reward system in the nucleus accumbens leading to the development of morphine addiction [32,37]. As it is well known calcium plays an important role in nociception. Activation of opioid μ-receptors is closely related to the inhibition of calcium uptake and this process is mainly responsible for opioid-induced analgesia . 1MeTIQ co-administered with morphine strongly potentiated its analgesic effect [39-41]. Additionally, as it was demonstrated 1MeTIQ administered before each morphine injection completely inhibited the development of morphine tolerance and prevented naloxoneinduced precipitation of the abstinence syndrome: body weight loss and head-twitches in morphine-dependent rats . Moreover, it has been shown that 1MeTIQ is also effective in prevention of morphine-induced placepreference and alcohol intake .
A question arises as to the mechanism of action responsible for that clinically interesting effect of 1MeTIQ. As mentioned above, 1MeTIQ as a neuroprotective substance inhibits the main dopamine oxidative enzyme MAO and simultaneously possesses free radical scavenging properties. 1MeTIQ has also affinity for NMDA receptor as its antagonist and prevents glutamateinduced cell death . Such mechanism of action could be partially responsible for its antinociception and antiaddictive effects [16,43]. Taken together it was demonstrated that complex mechanism of action of 1MeTIQ in the brain leads to its profitable and clinically wanted effects in morphine sensitization and addiction.
Cocaine addiction – the effect of 1MeTIQ
The essential role of the mesolimbic dopaminergic system in addiction has been well established [44,45]. In search of an effective therapy several antidopaminergic drugs were tested as potential anti-abuse agents [46,47]. While neuroleptics have been found not to be useful in that respect, partial agonists of the dopamine D2 and D3 receptors offer some hope [48,49]. Studies of partial agonists with an antidopaminergic profile of action different from that of classical neuroleptics seem justified, and taking into account the data mentioned above, 1MeTIQ is especially an interesting candidate for future clinical studies. In animal studies exogenously administered 1MeTIQ antagonized cocaine-induced locomotor sensitization as well as cocaine self-administration. What is more, 1MeTIQ significantly antagonized cocaineinduced reinstatement of seeking-behavior [50, 51]. Possible anti-abuse properties of 1MeTIQ are particularly interesting, as it has been suggested that this compound acts as a regulator of brain homeostatsis [52-54]. There is a long established view that depression of dopaminergic activity in the limbic structures may be responsible for craving [55,56]. In cocaine-dependent rats administered 1MeTIQ stabilizes dopamine function in the limbic brain structures, and it may be assumed that blockade of reinstatement by 1MeTIQ is related to this effect . Another biochemical action of 1MeTIQ, possibly related to its anticraving effect, may be connected with the activation of the noradrenergic system in the brain. Such effect may be associated with the antagonistic action of 1MeTIQ on alpha-2 adrenergic receptors [58,40,41]. The ability of 1MeTIQ to increase the level of the main metabolite of noradrenaline in the CNS, 3-methoxy4-hydroxyphenylglicol (MHPG), as well as its extraneuronal metabolite, normetanephrine (NM), reflects the antagonistic effect of 1MeTIQ on the alpha-2-adrenoceptors .
Conclusions: To explain the mechanism of the antiaddictive effects of 1MeTIQ, its wide spectrum of action in the CNS should be considered. Functional studies have shown that 1MeTIQ acts as an antidopaminergic agent but in contrast to typical neuroleptics, it induces no catalepsy in animals. Moreover, 1MeTIQ is involved in a direct interaction with the agonistic conformation of dopamine receptors and thus acts as partial dopamine agonist. On the other hand, it also displays a moderate effect on the NMDA receptor and the glutaminergic system as well as offers neuroprotection against glutamateinduced excitotoxicity in the rat. The presented results strongly support the view that 1MeTIQ is a compound which has a considerable potential to combat drug addiction, particularly through attenuation of the abstinence syndrome and craving.
Antidepressant-like activity of 1MeTIQ
Recently, depression has been recognized as a major public health problem. Despite intensive research, the etiology and pathogenesis of depression remains unclear. Preclinical and clinical studies suggest that monoamine neurotransmitters: dopamine, noradrenaline and serotonin in the central nervous system play a key role in the pathophysiology of depression [60-63]. These studies have been focused largely on the levels of monoamines and their receptors, and have led to putting forward several theories of depression, including the monoamine depletion and receptor sensitivity hypothesis [61,64,65]. Effective drugs for depression act as MAO inhibitors and/or 5-HT and NA reuptake inhibitors [65-67]. Although a lot of efforts have been invested in the development of new drugs in the last years the situation is still far from satisfactory. To address these needs, antidepressants with a novel mechanism of action and without side effects are in great demand.
1,2,3,4-Tetrahydroisoquinoline (TIQ) and its methyl derivative, 1MeTIQ there are members of tetrahydroisoquinoline family (TIQs). They are the most widespread alkaloids occurring in plants, a variety of food products as well as in the human, primate and rodent brain [1,2,7]. TIQ and 1MeTIQ show high affinity for the brain tissue and easily penetrate into the brain or are actively transported by the organic cation transporter system . What is particularly interesting, the concentration of TIQs in the brain was several-fold higher than in plasma both after acute and chronic treatment . Additionally, it was demonstrated that TIQ and 1MeTIQ in low micro molar concentrations inhibit enzymatic activity of both isoforms of monoamine oxidase (MAO A and B). Consequently, TIQ and 1MeTIQ inhibit MAO-dependent oxidative deamination of dopamine, the main catabolic pathway leading to the generation of free oxygen radicals [13,69]. In the same time both compounds shift dopamine catabolism towards COMTdependent O-methylation, what is extremely significant in view of their neuroprotective effects [13,70]. It is widely known that preclinical and clinical trials are being conducted to evaluate antidepressive potential of several MAO A and MAO B inhibitors and some of them, such as brofaromine and moclobemide are already used as antidepressants .
Our latest research have demonstrated antidepressant-like potential of both investigated compounds, TIQ and 1MeTIQ, in behavioral tests involving rodent models of depression [59,72,73]. The behavioral despair tests, like forced swim test (FST) in mice and rats and tail suspension test (TST) in mice, are widely used as useful models for probing pathological mechanism of depression and for evaluation of antidepressant drugs, and possess a high predictive validity for antidepressant efficacy in human depression [74,75]. Recently, a behavioral individual response category was developed including immobility, swimming and climbing . Selective serotonin reuptake inhibitors increase swimming behavior, while drugs acting primarily on elevating extracellular levels of NA or DA increase climbing behavior [77,78]. Clonidine, as alpha2 adrenoceptor agonist, which inhibits release of noradrenaline and suppresses noradrenergic activity was also employed as a useful and well known animal model of depression [79-81]. Another interesting model of depression was obtained by chronic administration of a low dose of reserpine (0.2 mg/kg), which was based on and monoamine depleting action in the brain, and its inhibitory effect on the vesicular monoamine transporter 2 (VMAT2). In fact, behavioral studies have revealed that chronic treatment with a low dose of reserpine induced a distinct depressivelike behavior in the FST as well as significant decrease in the level of dopamine, noradrenaline and serotonin in the rat brain . Reserpine interferes with the storage of monoamines by blocking the ATP-dependent uptake mechanism in the storage organelles . How it was shown by other authors the VMAT2 deficient animals showed progressive loss of dopamine terminals, accumulation of α-synuclein, and an increased oxidative stress, [83,84]. It is important to mention that many studies have indicated that depression is characterized by a significantly decreased antioxidant status, as evidenced by a lowered tryptophan, tyrosine, vitamin E, zinc concentration, and a reduced glutathione level, which are all antioxidants [85-87]. Recently, a new hypothesis was formulated which postulating that the activation of oxidative stress pathways and inflammation may be pathophysiological factors leading to the depression [67,86].
In all of the above introduced animal models of depression, both investigated compounds (TIQ and 1MeTIQ) completely antagonized behavioral and neurochemical syndromes of depressive-like behavior in rodents displaying therapeutic potential similar to a classical antidepressant, imipramine [59,88,89].
Conclusions: Summing up, our studies provide evidence that 1,2,3,4-tetrahydroisoquinoline and its methyl derivative, 1MeTIQ show a potent antidepressant-like effects and their pharmacological activity may be connected with affecting monoaminergic systems (dopamine, noradrenaline and serotonin). Great hopes are placed in the application of 1MeTIQ in antidepressive treatment as a safe drug with clinically useful mechanism of action that has been recently described as a neuroprotectant with antiaddictive potency .
1MeTIQ, a compound with high affinity for the brain tissue inhibits the oxidative MAOdependent dopamine catabolism and activated the COMT-dependent pathway and antagonizes glutamate-induced excitotoxicity such complex mechanism of action of 1MeTIQ may be responsible for its beneficial neuroprotective, antiaddictive and antidepressant-like properties in rodents.
Conflict of Interest
The authors declare no conflict of interest.
- Rommelspacher H, Susilo R. Tetrahydroisoquinolines and β-carbolines: putative natural substances in plants and mammals. Prog. Drug. Res 29(1), 415-459 (1985).
- McNaught KS, Carrupt PA, Altomare C, et al. Isoquinoline derivateves as endogenous neurotoxins in the aetiology of Parkinson’s disease. Bichem. Pharmacol 56(8), 921-933 (1998).
- Nagatsu T. Isoquinoline neurotoxins in the brain and Parkinson’s disease. Neurosci. Res 29(2), 99-111 (1997).
- Yamakawa T, Ohta S. Isolation of 1-methyl 1,2,3,4-tetrahydroisoquinoline-synthesizing enzyme from rat brain: a possible Parkinson’s disease-preventing enzyme. Biochem. Biophys. Res. Commun 236(1), 676-681 (1997).
- Yamakawa T, Kotake Y, Fulitani M, et al. Regional distribution of parkinsonism-preventing endogenous tetrahydroisoquinoline derivatives and an endogenous parkinsonism-preventing substance-synthesizing enzyme in monkey brain. Neurosci. Lett 276(1), 68-70 (1999).
- Naoi M, Maruyama W, Nagy GM. Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurance, metabolizm and function In human brains. Neurotoxicology 25(1-2), 193-204 (2004).
- Makino Y, Ohta S, Tachikawa O, et al. Presence of tetrahydroisoquinoline and 1-methyl –tetrahydro-isoquinoline in foods: compounds related to Parkinson’s disease. Life. Sci 43(4), 373-378 (1988).
- Ayala A, Parrado J, Cano J, et al. Reduction of 1-methyl 1,2,3,4-tetrahydroisoquinoline level In substantia nigra of the aged rat. Brain. Res 638(1-2), 334-336 (1994).
- Kotake Y, Tasaki Y, Makino Y, et al. 1-Benzyl-1,2,3,4- tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel endogenous amine in mouse brain and parkinsonian CSF. J. Neurochem 65(6), 2633-2638 (1995).
- Kotake Y, Tasaki Y, Hirobe M, et al. Deprenyl decreases an endogenous parkinsonism-inducing compound, 1-benzyl-1,2,3,4- tetrahydroisoquinoline in mice: in vivo and in vitro studies. Brain. Res 787(2), 341-343 (1998).
- Inoue H, Matsubara D, Tsuruta Y. Simultaneous analysis of 1,2,3,4-tetrahydroisoquinolines by high-performance liquid chromatography using 4-(5,6-dimethoxy-2-phthalimidinyl-2-methoxyphenylsulfonyl chloride as a fluorescent labeling reagent. J. Chromatogr. B. Analayt. Technol. Biomed. Life. Sci 867(1), 32-36 (2008).
- Tasaki Y, Makino Y, Ohta S, et al. 1-Methyl 1,2,3,4-tetrahydroisoquinoline, decreasing in 1-methyl-4-phenyl-1,2,3,6-tetrtahydropyrdine-treated mouse, prevents parkinsonism-like behavior abnormalities. J. Neurochem 57(6), 1940-1943 (1991).
- Antkiewicz-Michaluk L, Michaluk J, Mokrosz M, et al. Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties. J. Neurochem 78(1), 100-108 (2001).
- Antkiewicz-Michaluk L, Karolewicz B, Romanska I, et al. 1-Methyl-1,2,3,4-tetrahydroisoquinoline protects against rotenone-induced mortality and biochemical changes in rat brain. Eur. J. Pharmacol 466(3), 263-269 (2003).
- Antkiewicz-Michaluk L, Wardas J, Michaluk J et al. Protective effect of 1-methyl 1,2,3,4-tetrahydroisoquinoline against dopaminergic neurodegeneration in the extrapyramidal structures produced by intracerebral injection of rotenone. Int. J. Neuropsychopharmacol 7(2), 155-163 (2004).
- Antkiewicz-Michaluk L, Lazarewicz JW, Patsenka A, et al. The mechanism of 1,2,3,4-tetrahydroisoquinolines neuroprotection: the importance of free radicals scavenging properties and inhibition of glutamate-induced excitotoxicity.J. Neurochem 97(3), 846-856 (2006).
- Wąsik A, Romańska I, Antkiewicz-Michaluk L. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous parkinsonism-inducing toxin, strongly potentiates MAO-dependent dopamine oxidation and impairs dopamine release: ex vivo and in vivo neurochemical studies. Neurotox. Res 15(1), 15-23 (2009).
- Ohta S, Kohno M, Makino Y, et al. Tetrahydroisoquinoline and 1-methyl –tetrahydroisoquinoline are present in the human brain: relation to Parkinson’s disease. Biomed. Res 8(6), 453-456 (1987).
- Igarashi K, Sugiyama Y, kasuya F, et al. Determination of 1-methyl-1,2,3,4-tetrahydroisoquinoline in mouse brain after treatment with haloperidol by gas chromatography-selected ion monitoring. J. Chromatogr. B. Biomed. Sci Appl 731(1), 53-58 (1999).
- Yamakawa T, Ohta S. Biosynthesis of a parkinsonism-preventing substance, 1- methyl-1,2,3,4-tetrahydroisoquinoline, is inhibited by parkinsonism-inducing compounds in rat brain mitochondrial fraction. Neurosci. Lett 259(3), 157-160 (1999).
- Dykens JA. Free radicals and mitochondria dysfunction in excitotoxicity and neurodegenerative disease. In: Koliatsos VE, Rata RR (eds) Death and diseases of the nervous system. Humana Press, Totowa (1999).
- Patsenka A, Antkiewicz-Michaluk L. Inhibition of rodent brain monoamine oxidase and tyrosine hydroxylase by endogenous compounds - 1,2,3,4-tetrahydroisoquinoline alkaloids. Pol. J. Pharmacol 56(6), 727-734 (2004).
- Makino Y, Tasaki Y, Ohta S, et al. Confirmation of the enantiomers of 1-methyl 1,2,3,4-tetrahydroisoquinoline in the mouse brain and foods applying gas chromatography/mass spectrometry with negative ion chemical ionization. Biomed. Environ Mass. Spectrom 19(7), 415-419 (1990).
- Antkiewicz-Michaluk L, Wasik A, Romanska I et al. Both stereoselective (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinoline enantiomers protect striatal terminals against rotenone-induced suppression of dopamine release. Neurotox. Res 20(2), 134-149 (2011).
- Marey-Semper I, Gelman M, Levi-Strauss M. The high sensitivity to rotenone of striatal dopamine uptake suggests the existence of a constitutive metabolic deficiency in dopaminergic neurons from the substantia nigra. Eur. J. Neurosci 5(8), 1029-1034 (1993).
- Greenamyre JT, Betarbet R, Sherer T, et al. Parkinson’s disease, pesticides and mitochondrial dysfunction. Trends. Neurosci 24(5), 247 (2001).
- Thiffault C, Langston JW, Di Monte DA. Increased striatal dopamine turnover following acute administration of rotenone to mice. Brain. Res 885(2), 283-288 (2000).
- Luszczki JJ, Antkiewicz-Michaluk L, Czuczwar SJ. 1-Methyl-1,2,3,4-tetrahydroisoquinoline enhances the anticonvulsant action carbamazepine and valproate in the mouse maximal electroshock seizure model. Neuropharmacology 50(2), 133-142 (2006).
- Beridge K, Robinson T. What is the role dopamine in reward: hedonic impact, reward learning, or incentive salience?. Brain. Res. Rev 28(3), 309-369 (1998).
- Kelley AE. Memory and addiction: shared neuronal circuitry and molecular mechanisms. Neuron 44(1), 161-179 (2004).
- Kelley AE. Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci. Biobehav. Rev 27(8), 765-776 (2004).
- Chiara DG. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav. Brain. Res 137(1-2), 75-114 (2002).
- Ungless MA. Dopamine: the salient issue. Trends. Neurosci 27(12), 702-706 (2004).
- Kalivas PW. Interaction between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants. Drug. Alcohol. Depend 37(2), 95-100 (1995).
- Ma YY, Guo CY, Yu P, et al. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats. Exp. Neurol 200(2), 343-355 (2006).
- Nagy J. The NR2B subtype of NMDA receptor: a potentialtarget for the treatment of alcohol dependence. Curr. Drug. Targets. CNS. Neurol. Disord 3(3), 169-179 (2004).
- Di Chiara G, Bassareo V, Fenu S, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47(1), 227-241 (2004).
- Kamikubo K, Niwa M, Fugimura H, et al. Morphine inhibits depolarization-dependent calcium uptake by synaptosomes. Eur. J. Pharmacol 95(1-2), 149-150 (1983).
- Wąsik A, Romanska I, Antkiewicz-Michaluk L. The effect of an endogenous compound 1-methyl-1,2,3,4-tetrahydroisoquinoline on morphine-induced analgesia, dependence and neurochemical changes in dopamine metabolism in rat brain structures. J. Physiol. Pharmacol 58(2), 235-252 (2007).
- Vetulani J, Antkiewicz-Michaluk L, Michaluk J. Modification of morphine analgesia, tolerance by 1,2,3,4-tetrahydroisoquinoline. Eur. Neuropsychopharmacol 113(1), S29-S30 (2003).
- Vetulani J, Antkiewicz-Michaluk L, Nalepa I, et al. A possibile physiological role for cerebral tetrahydroisoquinolines. Neurotox. Res 5(1-2), 147-155 (2003).
- Antkiewicz-Michaluk L, Filip M, Kostowski W, et al. 1-Methyl-1,2,3,4-tetrahydroisoquinoline attenuates ethanol, cocaine and morphine addiction in behavioral models: neurochemical correlates. Acta. Neurobiol. Exp 65(1), 301-321 (2005).
- Vanderschuren LJ, Kalivas PW. Alteration in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151(2-3), 99-120 (2000).
- Goldstein RZ, Volkov ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am. J. Psychiatry 159(10), 1642-1652 (2002).
- Grimm JW, Lu L, Hayashi T, et al. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J. Neurosci 23(3), 742-747 (2003).
- Berger SP, Hall S, Mickalian JD, et al. Haloperidol antagonism of cue-elicited cocaine craving. Lancet 347(1), 504-508 (1996).
- Smelson DA, Williams J, Ziedonis D, et al. A double-blind placebo-controlled pilot study of risperidone for decreasing cue-elicited craving in recently withdrawn cocaine dependent patients. J. Subst. Abuse. Treat 27(1), 45-49 (2004).
- Le Foll B, Goldberg SR, Sokoloff P. The dopamine D3 receptor and drug dependence: effects on reward or beyond?. Neuropharmacology 49(4), 525-541 (2005).
- Mach UR, Hackling AE, Perachon S, et al. development of novel 1,2,3,4-tetrahydroisoquinoline derivatives and closely related compounds as potent and selective dopamine D3 receptor ligands. Chem. Biochem 5(4), 508-518 (2004).
- Filip M, Antkiewicz-Michaluk L, Zaniewska M, et al. Effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline on the behavioral effects of cocaine in rats. J Physiol Pharmacol. 58, 625-639 (2007).
- Wasik A, Romanska I, Antkiewicz-Michaluk L. Important role of 3-methoxytyramine in the inhibition of cocaine sensitizatiopn by 1- methyl-1,2,3,4-tetrahydroisoquinoline: an in vivo microdialysis study. Pharmacol Rep. 62, 983-997 (2010).
- Antkiewicz-Michaluk L, Michaluk J, Romańska I et al. Antidopaminergic effects of 1,2,3,4-tetrahydroisoquinoline and salsolinol. J Neural Transm. 107, 1009-1019 (2000).
- Antkiewicz-Michaluk L, Romańska I, Papla I, et al. Neurochemical changes induced by acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline and salsolinol in dopaminergic structures of rat brain. Neuroscience 96(1), 59-64 (2000).
- Vetulani J, Nalepa I, Antkiewicz-Michaluk L, et al. Opposite effect of simple tetrahydroisoquinolines on amphetamine- and morphine-stimulated locomotor activity in mice. J. Neural. Transm 108(5), 513-526 (2001).
- Rossetti ZL, Hmaidan Y, Gessa GL. Marked inhibition of meso-limbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. Eur. J. Pharmacol 221(2-3), 227-234 (1992).
- Little KY, Pate UN, Clark TB, et al. Alteration of brain dopamine and serotonin levels in cocaine users: a preliminary report. Am. J. Psychiatry 153(9), 1216-1218 (1996).
- Antkiewicz-Michaluk L, Filip M, Michaluk J, et al. An endogenous neuroprotectant substance, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), prevents the behavioral and neurochemical effects of cocaine reinstatement in drug-dependent rats. J. Neural. Transm 114(3), 307-317 (2007).
- Michaluk J, Krygowska-Wajs A, Karolewicz B, et al. Role of noradrenergic system In the mechanizm of action of endogenous neurotoxin 1,2,3,4-tetrahydroisoquinoline: biochemical and functional studies. Pol. J. Pharmacol 54(1), 19-25 (2002).
- Mozdzen E, Wasik A, Romanska I, et al. Antidepressant-like effect of 1,2,3,4-tetrahydroisoquinoline and its methyl derivative in animal models of depression. Pharmacol. Rep 69(3), 566-574 (2017).
- Maj J, Przegalinski E, Mogilnicka E. Hypotheses concerning the mechanism of action of antidepressant drugs. Rev. Physiol. Biochem. Pharmacol 100(4), 1-74 (1984).
- Antkiewicz-Michaluk L. Action of antidepressant neuroleptics chlorprothixene and levomepromazine of the central noradrenergic system comparison with other antidepressants. Pol. J. Pharmacol. Pharm 37(5), 667-677 (1985).
- Colpaert FC. Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in rats. Neuropharmacology 26(9), 1431-1440 (1987).
- Cantello R, Aguggia M, Gilli M, et al. Major depression in Parkinson’s disease and the mood response to intravenous methylphenidate: possible role of the hedonic dopamine synapse. J. Neurol. Neurosurg. Psychiatry 52(6), 724-731 (1989).
- Sulser F. New perspectives on the molecular pharmacology of affective disorders. Eur. Arch. Psych. Neurol 238(5-6), 231-239 (1989).
- Richelson E. Pharmacology of antidepressants – characteristics of the ideal drug. Mayo. Clinic. Proc 69(11), 1069-1081 (1994).
- Bourin M. Is it possible to predict the activity of a new antidepressant in animals with simple psychopharmacological test. Fund. Clin. Pharmacol 4(1), 49-64 (1990).
- Vetulani J, Nalepa I. Antidepressants: past, present and future. Eur. J. Pharmacol 405(1), 351-363 (2000).
- Lorenc-Koci E, Wójcikowski J, Kot M, et al. Disposition of 1,2,3,4-tetrahydroisoquinoline in the brain of male Wistar and Dark Agouti rats. Brain. Res 996(2), 168-179 (2004).
- Maruyama W, Nakahara D, Dostert P, et al. Naturally-occuring isoquinolines perturb monoamine metabolism in the brain: studied by in vivo micridialysis. J. Neural. Gen. Sect 94(2), 91-102 (1993).
- Możdżeń E, Papp M, Gruca P, et al. 1,2,3,4-Tetrahydroisoquinoline produces an antidepressant-like effect in the forced swim test and chronic mild stress model of depression in the rat: neurochemical correlates. Eur. J. Pharmacol 729(1), 107-115 (2014).
- Kitamura Y, Kitagawa K, Kimoto S, et al. Selegilin exerts antidepressant-like effects during the forced swim test in adrenocorticotropic hormone-treatedrats. J. Pharmacol. Sci 106(4), 639-644 (2008).
- Antkiewicz-Michaluk L, Wasik A, Możdżeń E, et al. Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: behavioral and neurochemical studies in the rat. Neurotox. Res 26(1), 85-98 (2014).
- Wąsik A, Romanska I, Antkiewicz-Michaluk L. Comparison of the effects of acute and chronic administration of tetrahydroisoquinoline amines on the in vivo dopaminę release: a microdialysis study in the rat striatum. Neurotox. Res 30(4), 648-657 (2016).
- Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch. Int. Pharmacodyn. Ther 229(2), 327-336 (1977).
- Steru L, Chermat R, Thierry B, et al. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85(3), 367-370 (1985).
- Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially produced by serotoninergic and noradrenergic antidepressants. Psychopharmacol 121(1), 66-72 (1995).
- Borsini F. Role of the serotonergic system in the forced swimming test. Neurosci. Biobehav. Rev 19(3), 377-395 (1995).
- Detke MJ, Lucki I. Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the: the effects of water depth. Behav. Brain. Res 73(1-2), 43-46 (1996).
- Enginar N, Eroǧlu L. The long-term clonidine treatment induced behavioral depression in rats. Pol. J. Pharmacol. Pharm 42(5), 409-415 (1990).
- Kostowski W, Obersztyn M. Chronic administration of desipramine and imipramine but not zimelidine attenuates clonidine-induced depression of avoidance behavior in rats. Pol. J. Pharmacol. Pharm 40(4), 341-349 (1988).
- Parale MP, Kulkarni SK. Clonidine-induced behavioural despair in mice: reversal by antidepressats. Psychopharmacol (Berl) 89(2), 171-174 (1986).
- Nagakura Y, Oe T, Aoki T, et al. Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: a putative animal model of fibromyalgia. Pain 146(1-2), 26-33 (2009).
- Caudle WM, Richardson JR, Wang MZ, et al. Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J. Neurosci 27(30), 8138-8148 (2007).
- Caudle WM, Colebrooke RE, Emson PC, et al. Altered vesicular dopamine storage in Parkinson`s disease: a premature demise. Trends. Neurosci 31(6), 303-308 (2008).
- Kodydkova J, Vavrova L, Zeman M, et al. Antoxidative enzymes and increased oxidative stress in depressive women. Clin. Biochem 42(13-14), 1368-1374 (2009).
- Maes M. The cytokine hypothesis of depression: inflammation, oxidative and nitrosative stress and leaky gut as a new targets for adjunctive treatments in depression. Neuro. Endocrinol. Lett 29(3), 287-191 (2008).
- Maes M, Galecki P, Chang YS, et al. A review on the oxidative and nitrosative stress pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog. Neuropsychopharmacol. Biol. Psychiatry 35(3), 676-692 (2011).
- Antkiewicz-Michaluk L, Romańska I, Wasik A, et al. Antidepressant –like effect of the endogenous neuroprotective amine, 1MeTIQ in clonidine-induced depression: behavioral and neurochemical studies in rats. Neurotox. Res 32(1), 94-106 (2017).
- Antkiewicz-Michaluk L, Wasik A, Michaluk J. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine with unexpected mechanism of action: new vistas of therapeutic application. Neurotox. Res 25(1), 1-12 (2014).