Remediation of chronic immobilization stress-induced negative affective behaviors and altered metabolism of monoamines in the prefrontal cortex by inactivation of basolateral amygdala.

Exposure to chronic stress precipitates depression and anxiety. Stress-induced responses are differentially regulated by the prefrontal cortex (PFC) and basolateral amygdala (BLA). For instance, repeated stress leads to hypertrophy of BLA, resulting in the emergence of affective symptoms. Chronic stress-induced changes in the metabolism of monoamines are central in the manifestation of affective symptoms. Interestingly, BLA via its reciprocal connections modulates prefrontal cortical monoaminergic responses to acute stress. However, the effects of BLA inactivation on chronic stress-induced affective behaviors and monoaminergic changes in the PFC are relatively unknown. Thus, we hypothesized that inactivation of BLA might prevent chronic immobilization stress (CIS)-induced depressive-, anxiety-like behaviors, and associated monoaminergic alterations in the prelimbic (PrL) and anterior cingulate cortex (ACC) subregions of PFC. We used two different BLA silencing strategies, namely ibotenic acid lesion and reversible temporary inactivation using lidocaine. We found that CIS precipitates depressive- and anxiety-like behaviors. Further, CIS-induced negative affective behaviors were associated with decreased levels of 5-HT, DA, and NE, and increased 5-HIAA/5-HT, DOPAC + HVA/DA, and MHPG/NE ratio in the PrL and ACC, suggesting enhanced metabolism. Interestingly, BLA lesion prior to CIS blocked the emergence of depressive- and anxiety-like behaviors. Moreover, the lesion of BLA prior to CIS was sufficient to prevent alterations in levels of monoamines and their metabolites in the PrL and ACC. Thereafter, we evaluated whether the effects of BLA lesion could be mirrored by temporary inactivation of BLA, specifically during stress. Remarkably, temporary inactivation of BLA during stress recapitulated the effects of lesion. Our results have implications for understanding the role of BLA in chronic stress-induced metabolic alterations in prefrontal cortical monoaminergic systems, and associated mood and anxiety disorders. The current study supports the hypothesis that combating amygdalar hyperactivity might be a viable strategy for the management of stress and associated affective disorders.

Antidepressant-like effect of 1,2,3,4-tetrahydroisoquinoline and its methyl derivative in animal models of depression.

BACKGROUND: Most of the currently used antidepressant drugs are monoamine-based compounds, acting by the inhibition of re-uptake or metabolism of noradrenaline (NA) and/or serotonin (5-HT), because these neurotransmitters play a key role in the pathophysiology of depression. The aim of this study was to investigate the potential antidepressant-like activity of an endogenous amine, 1,2,3,4-tetrahydroisoquinoline (TIQ) and its close derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ). METHODS: The experiments were carried out on male C57BL6J mice. The antidepressant-like activity of TIQs was evaluated in the behavioral tests: the forced swim test (FST) and tail suspension test (TST) and neurochemical analysis. TIQ and 1MeTIQ were administrated in three differences doses of 10, 25 or 50mg/kg. Imipramine (IMI; 15 or 30mg/kg) was used as a reference drug. In the neurochemical ex vivo study, the levels of NA, 5-HT and their metabolites, the rate of monoamine metabolism and their neuronal activity in different mouse brain structures were determined by HPLC with electrochemical detection. RESULTS: The results of this study have demonstrated that TIQ and 1MeTIQ produced antidepressant-like effect in the FST and TST because they significantly decreased the immobility time comparably to IMI. Biochemical data have demonstrated that administration of TIQs led to the activation of NA and 5-HT systems. CONCLUSIONS: The results reported in this paper indicate that TIQ and 1MeTIQ possess a distinct antidepressant activity. In the light of these findings, we suggest that both tested compounds may be effective for the depression therapy in a clinical setting with better tolerance of side effects.

Antidepressant-Like Effect of the Endogenous Neuroprotective Amine, 1MeTIQ in Clonidine-Induced Depression: Behavioral and Neurochemical Studies in Rats.

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders especially depression. Animal models are widely used to study antidepressant-like effect in rodents; however, it should be taken into account that pharmacological models do not always answer to the complexity of the disease processes. This study verified the behavioral (forced swim test (FST), locomotor activity test) and neurochemical effects (monoamines metabolism) of a low dose of clonidine (0.1 mg/kg i.p.) which was used as an experimental model of depression. In such pharmacological model, we investigated the antidepressant-like effect of an endogenous neuroprotective amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) administered in a dose of 25 mg/kg (i.p.) before clonidine in the behavioral and neurochemical tests carried out in rats. The behavioral study has shown that clonidine produced depression in the locomotor activity test but did not cause pro-depressive effect in the FST. 1MeTIQ produced antidepressant-like effect in the FST and completely antagonized clonidine-induced sedation in the locomotor activity test. Neurochemical data demonstrated that clonidine produced a significant inhibition of monoamine metabolism in the central nervous system. The release of dopamine, noradrenaline, and serotonin as well as the rate of their metabolism were diminished in the investigated brain structures (frontal cortex, hypothalamus, and striatum). 1MeTIQ completely antagonized the clonidine-induced depression of monoaminergic systems and restored their levels to the control values. 1MeTIQ as an endogenous neuroprotective compound with a distinct antidepressant-like activity in rodents produces hope on the efficiency of antidepressant medicines for future practical clinical use.

Withdrawal from repeated administration of a low dose of reserpine induced opposing adaptive changes in the noradrenaline and serotonin system function: a behavioral and neurochemical ex vivo and in vivo studies in the rat.

Reserpine is an inhibitor of the vesicular monoamine transporter 2 (VMAT2) and monoamine releaser, so it can be used as a pharmacological model of depression. In the present paper, we investigated the behavioral and neurochemical effects of withdrawal from acute and repeated administration of a low dose of reserpine (0.2 mg/kg) in Wistar Han rats. We demonstrated the behavioral and receptor oversensitivity (postsynaptic dopamine D1) during withdrawal from chronic reserpine. It was accompanied by a significant increase in motility in the locomotor activity test and climbing behavior in the forced swim test (FST). Neurochemical studies revealed that repeated but not acute administration the a low dose of reserpine triggered opposing adaptive changes in the noradrenergic and serotonin system function analyzed during reserpine withdrawal, i.e. 48 h after the last injection. The tissue concentration of noradrenaline was significantly decreased in the hypothalamus and nucleus accumbens only after repeated drug administration (by about 20% and 35% vs. control; p<0.05, respectively). On the other hand, the concentration of its extraneuronal metabolite, normetanephrine (NM) increased significantly in the VTA during withdrawal both from acute and chronic reserpine. The serotonin concentration was significantly reduced in the VTA after chronic reserpine (by about 40% vs. the control group, p<0.05) as well as its main metabolite, 5-HIAA (by about 30% vs. control; p<0.05) in the VTA and hypothalamus. Dopamine and its metabolites were not changed after acute or chronic reserpine administration. In vivo microdialysis studies clearly evidenced the lack of the effect of a single dose of reserpine, and its distinct effects after chronic treatment on the release of noradrenaline and serotonin in the rat striatum. In fact, the withdrawal from repeated administration of reserpine significantly increased an extraneuronal concentration of noradrenaline in the rat striatum but at the same time produced a distinct fall in the extraneuronal serotonin in this brain structure. On the basis of the presented behavioral and neurochemical experiments, we suggest that chronic administration of reserpine even in such low dose which not yet acted on the release of monoamines but produced an inhibition of VMAT2 caused a long-lasting disadvantageous effect of plasticity in the brain resembling depressive disorders.

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.

1,2,3,4-Tetrahydroisoquinoline (TIQ) is an exo- and endogenous amine naturally present in mammalian brain which displays antidepressant-like effect in various animal models: the forced swim test (FST) and chronic mild stress (CMS) paradigm in rats. To elucidate this action we compared the effects of TIQ with imipramine, a classic antidepressant drug and one of the most clinically effective. Applied behavioral tests showed that TIQ produced an antidepressant-like effect with a potency comparable to that of imipramine. TIQ (25-50mg/kg i.p.), similarly to imipramine (10-30mg/kg i.p.), reduced the immobility time in FST and completely reversed the decrease in sucrose intake caused by CMS in the rat. In addition, in order to avoid the possible psychostimulating effect of TIQ we examined the influence of its administration on locomotor activity in rats. TIQ, like imipramine, produced a reduction in horizontal locomotor activity. This suggested that TIQ did not have psychostimulant properties and that prolonged swimming in the FST was a result of an increased motivation to escape from the stressful situation. The biochemical analyses have shown that TIQ activates monoaminergic systems as a reversible monoamine oxidase (MAO) inhibitor and free radical scavenger. Beyond the activation of noradrenaline and serotonin systems, TIQ also moderately affects the dopamine system. On the basis of the presented behavioral and biochemical studies we suggest that TIQ is a potential new antidepressant which may be effective for the depression therapy in a clinical setting.