1-Methyl-1,2,3,4-tetrahydroisoquinoline, an Endogenous Neuroprotectant and MAO Inhibitor with Antidepressant-Like Properties in the Rat

The main finding of this paper is that the endogenous neuroprotective compound, 1MeTIQ administered systemically to rats produced antidepressant-like effect in the FST. This effect was intensified by combined administration of 1MeTIQ and desipramine, a classic tricyclic antidepressant. Neurochemical data showed that this effect was connected with the activation of all monoaminergic (dopaminergic, serotoninergic, and noradrenergic) systems.

Desipramine is a well-known tricyclic antidepressant which acts as a selective noradrenaline reuptake inhibitor (Grunewald et al. 1979; Javaid et al. 1979; Wroblewski et al. 1996). In rodents, desipramine induced a significant decrease in the immobility time in the forced swimming test (Redrobe et al. 1996; Lucki et al. 2001; Holmes 2003; Kim et al. 2010) with simultaneous elevation of the climbing time. The modified FST measures the frequency of different types of active behaviors: swimming, which is sensitive to serotoninergic compounds, such as SSRIs, and climbing, which is sensitive to tricyclic antidepressants and drugs with selective effects on catecholamine transmission (Cryan and Lucki 2000; Cryan et al. 2005; Detke et al. 1995). As shown by Detke et al. (1995), the increase in climbing activity is connected with an enhanced noradrenergic system activation.

Our present data from the behavioral experiments demonstrated that acute systemic administration of 1MeTIQ in a low dose (10 mg/kg i.p.) produced antidepressant-like effect by reducing the immobility time (Fig. 1a) with simultaneous elevation of the climbing time (Fig. 1c). This effect was similar to the influence induced by desipramine given in a lower dose (10 mg/kg i.p.) (Fig. 1a, c). The higher dose of desipramine produced a stronger decrease in the immobility time (Fig. 1a) with simultaneous powerful elevation of the climbing time (Fig. 1c). In the combination group, when 1MeTIQ was given together with a lower dose of desipramine, the reduction of the immobility time was slightly stronger than in the 1MeTIQ group with a significant increase in the swimming time (Fig. 1a, b). These data coming from the behavioral FST suggest that 1MeTIQ (given alone in a low dose), similarly to desipramine, influences mainly the catecholaminergic system. In opposite to this, when 1MeTIQ was administered in combination with desipramine, the activation of serotoninergic system seemed to be the dominant which was reflected by the swimming behavior in this group (Fig. 1b).

In our earlier studies, we demonstrated that 1MeTIQ was a reversible, short-acting and moderate inhibitor of both MAO-A and MAO-B activity (Antkiewicz-Michaluk et al. 2001; Patsenka and Antkiewicz-Michaluk 2004). There are evidences that MAO inhibitors have several particularly useful therapeutic properties, such as the blockade of the oxidation pathway (leading to reduced free radical production) in monoamine catabolism (Youdim et al. 2006) and the increase in the concentration of monoamines in the brain by inhibition of their catabolism (Alvarez et al. 1999; Haefely et al. 1992). This mechanism of action is responsible not only for neuroprotective effects but also for antidepressant-like activity of MAO inhibitors (e.g., selegiline or moclobemide) in different animal models (Cryan et al. 2005; Kitamura et al. 2008; Miura et al. 1996; Youdim and Bakhle 2006). In order to exclude the psychostimulating activity of 1MeTIQ, we have examined the influence of its administration (alone and combined with desipramine) on locomotor activity of rats. 1MeTIQ administered in a dose of 10 mg/kg i.p. or desipramine (10 mg/kg i.p.) induced a significant decrease in locomotor activity (Fig. 2). An even stronger reducing effect on motility was observed in the combination group (Fig. 2). These results clearly show that 1MeTIQ, like desipramine, did not have psychostimulant properties and the prolonged climbing or swimming time (in the combination group) in the forced swimming test was the result of an increased motivation to escape from the stressful situation, i.e., placing the animal in the cylinder with water.

The results from behavioral experiments were confirmed by the neurochemical data. For presentation the neurochemical results we selected two brain structures: connected with monoaminergic function: the striatum—as a representative of the dopaminergic system and motor function, and the hypothalamus for noradrenergic system. It should be borne in mind that serotonin nerve endings are present in large numbers in both analyzed brain structures. Some authors demonstrated that striatal dopamine play an important role in the pathophysiology of depression by modulating emotional and motor symptoms (Byrum et al. 1999; Newberg et al. 2007; Rogers et al. 1998). Additionally, Amsterdam et al. (2012) suggested that greater striatal dopamine transporter density may represent a putative biomarker of depression. Also Shah et al. (1997) reported a decrease in dopamine function in the striatum of patients with major depression. Moreover, evidence from animal and human studies showed that stressful life events and the consequent hypothalamic–pituitary–adrenal (HPA) axis hyperactivity are among the most potent factors of depressive episodes (Swaab et al. 2005; Wang et al. 2010). As demonstrated in Table 1, 1MeTIQ in contrast to desipramine, significantly affected the dopaminergic system. It produced a significant elevation (P < 0.05) of the dopamine concentration in the hypothalamus. Additionally, 1MeTIQ induced a significant reduction (P < 0.01) in the level of the interneuronal dopamine metabolite, DOPAC with simultaneous elevation (P < 0.01) of the concentration of extraneuronal dopamine metabolite, 3-MT (Table 1). At the same time, the rate of dopamine oxidation expressed as the [DOPAC]/[DA] ratio was significantly (P < 0.01) decreased (Fig. 3a), and the marker of dopamine reuptake inhibition, i.e., the [3-MT]/[DOPAC] ratio was strongly increased (P < 0.01) (Fig. 3b). This is a very important property of 1MeTIQ because it not only induced elevation of the dopamine concentration in the synaptic cleft but also by blocking the activity of MAO it caused the reduction of free radical production in the dopaminergic neurons (Antkiewicz-Michaluk et al. 2001; Patsenka and Antkiewicz-Michaluk 2004). 1MeTIQ, as a moderate and reversible inhibitor of MAO-A and MAO-B (Patsenka and Antkiewicz-Michaluk 2004) seems to be safe and effective in clinic what can be important from practical point of view. The formation of free radicals leads to oxidative stress. Oxidative stress is a universal mechanism of inducing cell death (Dykens 1999). Maes et al. (2009) postulated a new theory of depression, which was called “the inflammatory and neurodegenerative hypothesis of depression” which suggests that the activation of inflammatory and oxidative stress pathways is the cause of development of depression (Maes et al. 2008). 1MeTIQ given concomitantly with desipramine produced a significant elevation (P < 0.01) of the concentration of dopamine with simultaneous reduction of the DOPAC level (P < 0.05) (Table 1). In the combination group, we observed a significant decrease in the rate of dopamine oxidation pathway expressed as the [DOPAC]/[DA] ratio of the magnitude similar to the 1MeTIQ group (Fig. 3a), however, the marker of dopamine reuptake inhibition; i.e., the [3-MT]/[DOPAC] ratio elevated by 1MeTIQ returned to control values in the combined treatment group (Fig. 3b). Simultaneously, the rate of total dopamine metabolism measured as the [HVA]/[DA] × 100 ratio was significantly (P < 0.05) decreased (Fig. 3c).

Similarly to desipramine, 1MeTIQ did not influence the level of noradrenaline but induced a significant (P < 0.01) elevation of the NMN concentration in the hypothalamus (Table 2). As shown in Fig. 4, 1MeTIQ produced an increase (P < 0.01) in the rate of noradrenaline release measured as [NMN]/[NA] × 100 with the same effectiveness like desipramine. However, in the frontal cortex, 1MeTIQ acted more strongly than desipramine and significantly (P < 0.01) increased the concentration of both, noradrenaline and NMN (Table 2). This effects of 1MeTIQ may be associated with its ability to inhibit the noradrenaline reuptake process. Noradrenaline released into the synaptic cleft is catabolized by COMT to NMN by the process of methylation. The increased amount of NMN indicates the elevated release of noradrenaline or the inhibition its uptake into the neuron. 1MeTIQ given in combination with desipramine produced a significant increase in the concentration of noradrenaline (P < 0.05) and its direct metabolite, NMN (P < 0.01) (Table 2). At the same time, the rate of extraneuronal noradrenaline catabolism expressed as [NMN]/[NA] × 100 was strongly elevated (more than in the groups treated with each drug alone) (Fig. 4). The strongest activation of noradrenergic system was observed in the combined treatment group in the hypothalamus where both, the concentration of noradrenaline and its metabolite, NMN was significantly elevated (Table 2).

The present data demonstrated that desipramine given in a dose (10 mg/kg i.p.) did not affect the concentration of serotonin and its metabolite, 5-HIAA (Table 3). Also the rate of serotonin metabolism measured as [5-HIAA]/[5-HT] × 100 was not changed by desipramine (Fig. 5). In contrast to desipramine, 1MeTIQ produced a significant elevation (P < 0.01) of the serotonin concentration in the hypothalamus (Table 3). Additionally, the rate of serotonin metabolism estimated as [5-HIAA]/[5-HT] × 100 was significantly (P < 0.01) decreased in this group (Fig. 5). The observed neurochemical changes in the serotoninergic system are the result of the inhibition of MAO activity in the rat brain by 1MeTIQ (Patsenka et al. 2004). The neurochemical data demonstrated that in the hypothalamus, the concentration of serotonin was significantly increased (P < 0.01) in the combined treatment group (Table 3). Simultaneously, the rate of serotonin metabolism measured as [5-HIAA]/[5-HT] × 100 was significantly decreased (P < 0.01) in this group (Fig. 5).

Our present data demonstrate that 1MeTIQ is characterized by a wide spectrum of actions on all monoaminergic systems in the rat brain. Thanks to its ability to inhibit both MAO-A and MAO-B activity (Patsenka and Antkiewicz-Michaluk 2004) and to scavenge free radicals (Antkiewicz-Michaluk et al. 2006); 1MeTIQ may be useful not only for the therapy of neurodegenerative disease but also in the treatment of depression.