The brain mechanism of awakening dysfunction in children with primary nocturnal enuresis based on PVT-NAc neural pathway: a resting-state fMRI study.

Primary nocturnal enuresis (PNE) affects children's physical and mental health with a high rate. However, its neural mechanism is still unclear. Studies have found that the paraventricular thalamus (PVT) is among the key brain regions implicated with awakening regulation and its control of the transition between sleep and wakening is dependent on signaling through the PVT-nucleus accumbens (NAc) pathway. So this study analyzed the function of brain regions and their connectivity of PVT and NAc. A total of twenty-six PNE and typically developing (TD) children were involved in the study and the methods of amplitude of low frequency fluctuation (ALFF), degree centrality (DC) and functional connectivity (FC) based on resting-state functional magnetic resonance imaging (rs-fMRI) were used to analyze the brain functions. Results showed that there was no statistical significant difference in ALFF and DC between PNE and TD children in bilateral PVT and NAc. And there was statistical significant difference of the comparison of the FC of left PVT (lPVT) and left NAc (lNAc) between PNE and TD children. Meanwhile, there was negative correlation between awakening score and the FC of rPVT and lNAc, and no obvious correlation between awakening score and the FC of lPVT and lNAc in PNE children. Meanwhile, there was both negative correlation between awakening score and the FC of lPVT, rPTV and lNAc in TD children. Therefore, the FC between rPVT and lNAc was more reliable in assessing the degree of awakening ability in PNE children. This finding could help establish the evaluation index of PNE.

Stimulating GABAergic Neurons in the Nucleus Accumbens Core Alters the Trigeminal Neuropathic Pain Responses in a Rat Model of Infraorbital Nerve Injury.

The nucleus accumbens core (NAcc) is an important component of brain reward circuitry, but studies have revealed its involvement in pain circuitry also. However, its effect on trigeminal neuralgia (TN) and the mechanism underlying it are yet to be fully understood. Therefore, this study aimed to examine the outcomes of optogenetic stimulation of NAcc GABAergic neurons in an animal model of TN. Animals were allocated into TN, sham, and control groups. TN was generated by infraorbital nerve constriction and the optogenetic virus was injected into the NAcc. In vivo extracellular recordings were acquired from the ventral posteromedial nucleus of the thalamus. Alterations of behavioral responses during stimulation "ON" and "OFF" conditions were evaluated. In vivo microdialysis was performed in the NAcc of TN and sham animals. During optogenetic stimulation, electrophysiological recordings revealed a reduction of both tonic and burst firing activity in TN animals, and significantly improved behavioral responses were observed as well. Microdialysis coupled with liquid chromatography/tandem mass spectrometry analysis revealed significant alterations in extracellular concentration levels of GABA, glutamate, acetylcholine, dopamine, and citrulline in NAcc upon optic stimulation. In fine, our results suggested that NAcc stimulation could modulate the transmission of trigeminal pain signals in the TN animal model.

Characterization of brain functional connectivity in treatment-resistant depression.

OBJECTIVE: To characterize the functional connectivity (FC) of target brain regions for deep brain stimulation (DBS) in patients with treatment-resistant depression (TRD), and to evaluate its gender and brain lateralization dependence. METHODS: Thirty-one TRD patients and twenty-nine healthy control (HC) subjects participated. FC of subcallosal cingulate gyrus (SCG), ventral caudate (VCa), nucleus accumbens (NAc), lateral habenula (LHb), and inferior thalamic peduncle (ITP) were evaluated using resting-state fMRI. FC was characterized by calculating the nodal 'degree', a major feature of the graph theory. RESULTS: The degree measures of the left and right VCa, the left LHb, and the left ITP were significantly greater in the TRD than in the HC group. The degree was greater in females with TRD in all these regions except the right LHb. Finally, the left hemisphere was generally more affected by depression and presented significant degrees in LHb and ITP regions of the patients. CONCLUSION: Our findings demonstrate the ability of degree to characterize brain FC and identify the regions with abnormal activities in TRD patients. This implies that the degree may have the potential to be used as an important graph-theoretical feature to further investigate the mechanisms underlying TRD, and consequently along with other diagnostic markers, to assist in the determination of the appropriate target region for DBS treatment in TRD patients.

Brain Structure and Function of Chronic Low Back Pain Patients on Long-Term Opioid Analgesic Treatment: A Preliminary Study.

Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.

Prior Exposure to Salient Win-Paired Cues in a Rat Gambling Task Increases Sensitivity to Cocaine Self-Administration and Suppresses Dopamine Efflux in Nucleus Accumbens: Support for the Reward Deficiency Hypothesis of Addiction.

Rats trained to perform a version of the rat gambling task (rGT) in which salient audiovisual cues accompany reward delivery, similar to commercial gambling products, show greater preference for risky options. Given previous demonstrations that probabilistic reinforcement schedules can enhance psychostimulant-induced increases in accumbal DA and locomotor activity, we theorized that performing this cued task could perpetuate a proaddiction phenotype. Significantly more rats developed a preference for the risky options in the cued versus uncued rGT at baseline, and this bias was further exacerbated by cocaine self-administration, whereas the choice pattern of optimal decision-makers was unaffected. The addition of reward-paired cues therefore increased the proportion of rats exhibiting a maladaptive cognitive response to cocaine self-administration. Risky choice was not associated with responding for conditioned reinforcement or a marker of goal/sign-tracking, suggesting that reward-concurrent cues precipitate maladaptive choice via a unique mechanism unrelated to simple approach toward, or responding for, conditioned stimuli. Although "protected" from any resulting decision-making impairment, optimal decision-makers trained on the cued rGT nevertheless self-administered more cocaine than those trained on the uncued task. Collectively, these data suggest that repeated engagement with heavily cued probabilistic reward schedules can drive addiction vulnerability through multiple behavioral mechanisms. Rats trained on the cued rGT also exhibited blunted locomotor sensitization and lower basal accumbal DA levels, yet greater cocaine-induced increases in accumbal DA efflux. Gambling in the presence of salient cues may therefore result in an adaptive downregulation of the mesolimbic DA system, rendering individuals more sensitive to the deleterious effects of taking cocaine.SIGNIFICANCE STATEMENT Impaired cost/benefit decision making, exemplified by preference for the risky, disadvantageous options on the Iowa Gambling Task, is associated with greater risk of relapse and treatment failure in substance use disorder. Understanding factors that enhance preference for risk may help elucidate the neurobiological mechanisms underlying maladaptive decision making in addiction, thereby improving treatment outcomes. Problem gambling is also highly comorbid with substance use disorder, and many commercial gambling products incorporate salient win-paired cues. Here we show that adding reward-concurrent cues to a rat analog of the IGT precipitates a hypodopaminergic state, characterized by blunted accumbal DA efflux and attenuated locomotor sensitization, which may contribute to the enhanced responsivity to uncertain rewards or the reinforcing effects of cocaine we observed.

Chronic inflammatory pain decreases the glutamate vesicles in presynaptic terminals of the nucleus accumbens.

Reward system has been proved to be important to nociceptive behavior, and the nucleus accumbens (NAc) is a key node in reward circuitry. It has been further revealed that dopamine system modulates the NAc to influence the pain sensation, whereas the role of glutamatergic projection in the NAc in the modulation of chronic pain is still elusive. In this study, we used a complete Freund's adjuvant-induced chronic inflammatory pain model to explore the changes of the glutamatergic terminals in the NAc, and we found that following the chronic inflammation, the protein level of vesicular glutamate transporter1 (VGLUT1) was significantly decreased in the NAc. Immunofluorescence staining further showed a reduced expression of VGLUT1-positive terminals in the dopamine receptor 2 (D2R) spiny projection neurons of NAc after chronic inflammatory pain. Furthermore, using a whole-cell recording in double transgenic mice, in which dopamine receptor 1- and D2R-expressing neurons can be visualized, we found that the frequency of spontaneous excitatory postsynaptic currents was significantly decreased and paired-pulse ratio of evoked excitatory postsynaptic currents was increased in D2R neurons, but not in dopamine receptor 1 neurons in NAc of complete Freund's adjuvant group. Moreover, the abnormal expression of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex contributed to the reduced formation of glutamate vesicles. Hence, our results demonstrated that decreased glutamate release in the indirect pathway of the NAc may be a critical mechanism for chronic pain and provided a novel evidence for the presynaptic mechanisms in chronic pain regulation.

Frequency-dependent functional connectivity of the nucleus accumbens during continuous transcutaneous vagus nerve stimulation in major depressive disorder.

Transcutaneous vagus nerve stimulation (tVNS) may be a promising treatment for major depressive disorder (MDD). In this exploratory study, fMRI scans were acquired during continuous real or sham tVNS from 41 MDD patients. Then, all patients received real or sham tVNS treatment for four weeks. We investigated the functional connectivity (FC) of the nucleus accumbens (NAc) at different frequency bands during real and sham tVNS and explored their associations with depressive symptom changes after one month of treatment. The results revealed: 1) significant positive FCs between the NAc and surrounding areas including the putamen, caudate, and distinct areas of the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC) during continuous real and sham tVNS; 2) compared with sham tVNS, real tVNS increased the FC between the left NAc and bilateral MPFC/rACC in the slow-5 band (0.008-0.027) and between the right NAc and left insula, occipital gyrus, and right lingual/fusiform gyrum in the typical low band (0.008-0.09); and 3) the FC of the NAc-MPFC/rACC during real tVNS showed a negative association with Hamilton Depression Rating Scale (HAMD) score changes in the real tVNS group after one month of treatment, but not in the sham group. Our findings demonstrate that tVNS can modulate low frequency intrinsic FC among key brain regions involved in reward and motivation processing and provide insights into the brain mechanism underlying tVNS treatment of MDD.

Neural systems mediating the inhibition of cocaine-seeking behaviors.

Over the past decades, research has targeted the neurobiology regulating cocaine-seeking behaviors, largely in the hopes of identifying potential targets for the treatment of cocaine addiction. Although much of this work has focused on those systems driving cocaine seeking, recently, studies examining the inhibition of cocaine-related behaviors have made significant progress in uncovering the neural systems that attenuate cocaine seeking. Such systems include the infralimbic cortex, nucleus accumbens shell, and hypothalamus. Research in this field has focused largely on the infralimbic cortex, as activity in this region appears to attenuate cocaine seeking during reinstatement and contribute to extinction learning. However, an overarching theory of function for this region that includes its role in other types of reward seeking and learning remains to be determined. Furthermore, the precise relationship between other regions involved in attenuating cocaine-seeking behavior and the infralimbic cortex remains unclear. Recent advances in the use of viral vectors combined with optogenetics, chemogenetics, and other approaches have greatly affected our capacity to investigate those systems inhibiting behavior dependent on cocaine-associated memories. This review will present current understanding regarding the neurobiology underlying the inhibition of such behaviors, especially focusing on the extinction of such memories, and explore how viral-vector targeting of specific brain circuits has begun to alter, and will continue to enrich, our knowledge regarding this issue.

The Role of Brain in Energy Balance.

Energy homeostasis is regulated by homeostatic and nonhomeostatic reward circuits which are closely integrated and interrelated. Before, during, and after meals, peripheral nutritional signals, through hormonal and neuronal pathways, are conveyed to selective brain areas, namely the hypothalamic nuclei and the brainstem, the main brain areas for energy balance regulation. These orexigenic and anorexigenic centers are held responsible for the integration of those signals and for an adequate output to peripheral organs involved in metabolism and energy homeostasis.Feeding includes also a hedonic behavior defined as food intake for pleasure independently of energy requirement. This nonhomeostatic regulation of energy balance is based on food reward properties, unrelated to nutritional demands, and involves areas like mesolimbic reward system, such as the ventral tegmental area and the nucleus accumbens, and also opioid, endocannabinoid, and dopamine systems.Herein, focus will be put on the brain circuits of homeostatic and nonhomeostatic regulation of food intake and energy expenditure.

Dual Effects of Limbic Seizures on Psychosis-Relevant Behaviors Shown by Nucleus Accumbens Kindling in Rats.

BACKGROUND: A paradox in epilepsy and psychiatry is that temporal lobe epilepsy is often predisposed to schizophrenic-like psychosis, whereas convulsive therapy can relieve schizophrenic symptoms. We have previously demonstrated that the nucleus accumbens is a key structure in mediating postictal psychosis induced by a hippocampal electrographic seizure. OBJECTIVE/HYPOTHESIS: The purpose of this study is to test a hypothesis that accumbens kindling cumulating in a single (1-time) or repeated (5-times) convulsive seizures have different effects on animal models of psychosis. METHODS: Electrical stimulation at 60 Hz was applied to nucleus accumbens to evoke afterdischarges until one, or five, convulsive seizures that involved the hind limbs (stage 5 seizures) were attained. Behavioral tests, performed at 3 days after the last seizure, included gating of hippocampal auditory evoked potentials (AEP) and prepulse inhibition to an acoustic startle response (PPI), tested without drug injection or after ketamine (3 mg/kg s.c.) injection, as well as locomotion induced by ketamine or methamphetamine (1 mg/kg i.p.). RESULTS: Compared to non-kindled control rats, 1-time, but not 5-times, convulsive seizures induced PPI deficit and decreased gating of hippocampal AEP, without drug injection. Compared to non-kindled rats, 5-times, but not 1-time, convulsive seizures antagonized ketamine-induced hyperlocomotion, ketamine-induced PPI deficit and AEP gating decrease. However, both 1- and 5-times convulsive seizures significantly enhanced methamphetamine-induced locomotion as compared to non-kindled rats. CONCLUSIONS: Accumbens kindling ending with 1 convulsive seizure may induce schizophrenic-like behaviors, while repeated (≥5) convulsive seizures induced by accumbens kindling may have therapeutic effects on dopamine independent psychosis.

Central nervous system regulation of eating: Insights from human brain imaging.

Appetite and body weight regulation are controlled by the central nervous system (CNS) in a rather complicated manner. The human brain plays a central role in integrating internal and external inputs to modulate energy homeostasis. Although homeostatic control by the hypothalamus is currently considered to be primarily responsible for controlling appetite, most of the available evidence derives from experiments in rodents, and the role of this system in regulating appetite in states of hunger/starvation and in the pathogenesis of overeating/obesity remains to be fully elucidated in humans. Further, cognitive and affective processes have been implicated in the dysregulation of eating behavior in humans, but their exact relative contributions as well as the respective underlying mechanisms remain unclear. We briefly review each of these systems here and present the current state of research in an attempt to update clinicians and clinical researchers alike on the status and future directions of obesity research.

Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.

Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were 'odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.

A thalamic input to the nucleus accumbens mediates opiate dependence.

Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.

Sensory Deviancy Detection Measured Directly Within the Human Nucleus Accumbens.

Rapid changes in the environment evoke a comparison between expectancy and actual outcome to inform optimal subsequent behavior. The nucleus accumbens (NAcc), a key interface between the hippocampus and neocortical regions, is a candidate region for mediating this comparison. Here, we report event-related potentials obtained from the NAcc using direct intracranial recordings in 5 human participants while they listened to trains of auditory stimuli differing in their degree of deviation from repetitive background stimuli. NAcc recordings revealed an early mismatch signal (50-220 ms) in response to all deviants. NAcc activity in this time window was also sensitive to the statistics of stimulus deviancy, with larger amplitudes as a function of the level of deviancy. Importantly, this NAcc mismatch signal also predicted generation of longer latency scalp potentials (300-400 ms). The results provide direct human evidence that the NAcc is a key component of a network engaged in encoding statistics of the sensory environmental.

Abnormal striatal resting-state functional connectivity in adolescents with obsessive-compulsive disorder.

Neuroimaging research has implicated abnormalities in cortico-striatal-thalamic-cortical (CSTC) circuitry in pediatric obsessive-compulsive disorder (OCD). In this study, resting-state functional magnetic resonance imaging (R-fMRI) was used to investigate functional connectivity in the CSTC circuitry in adolescents with OCD. Imaging was obtained with the Human Connectome Project (HCP) scanner using newly developed pulse sequences which allow for higher spatial and temporal resolution. Fifteen adolescents with OCD and 13 age- and gender-matched healthy controls (ages 12-19) underwent R-fMRI on the 3T HCP scanner. Twenty-four minutes of resting-state scans (two consecutive 12-min scans) were acquired. We investigated functional connectivity of the striatum using a seed-based, whole brain approach with anatomically-defined seeds placed in the bilateral caudate, putamen, and nucleus accumbens. Adolescents with OCD compared with controls exhibited significantly lower functional connectivity between the left putamen and a single cluster of right-sided cortical areas including parts of the orbitofrontal cortex, inferior frontal gyrus, insula, and operculum. Preliminary findings suggest that impaired striatal connectivity in adolescents with OCD in part falls within the predicted CSTC network, and also involves impaired connections between a key CSTC network region (i.e., putamen) and key regions in the salience network (i.e., insula/operculum). The relevance of impaired putamen-insula/operculum connectivity in OCD is discussed.

Yin and Yang: unsilencing synapses to control cocaine seeking.

In this issue of Neuron, Ma et al. (2014) show that long-term depression of two independent prefrontal cortical inputs to nucleus accumbens modifies behavioral responses controlling incubation of cocaine craving. Intriguingly, one input increases while the other attenuates behavioral responses, hinting that both "prorelapse" and "antirelapse" pathways are strengthened after cocaine self-administration.

Abstinence from cocaine and sucrose self-administration reveals altered mesocorticolimbic circuit connectivity by resting state MRI.

Previous preclinical studies have emphasized that drugs of abuse, through actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of natural rewards. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period. These procedures are known to induce behavioral changes and neuroadaptations. A third group of sedentary animals served as a negative control group for general handling effects. We examined low-frequency spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Decreased rsFC was seen in the cocaine-SA compared with both sucrose-SA and housing control groups between prelimbic (PrL) cortex and entopeduncular nucleus and between nucleus accumbens core (AcbC) and dorsomedial prefrontal cortex (dmPFC). Moreover, individual differences in cocaine SA escalation predicted connectivity strength only in the Acb-dmPFC circuit. These data provide evidence of fronto-striatal plasticity across the addiction trajectory, which are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts, indicating potential circuit level biomarkers that may inform therapeutic interventions. They further suggest that available data from cross-sectional human studies may reflect the consequence of rather a predispositional predecessor to their dependence.

The effects of atomoxetine and methylphenidate on the prepulse inhibition of the acoustic startle response in mice.

Atomoxetine (ATM) and methylphenidate (MPD) have been used for the treatment of attention deficit hyperactivity disorder (ADHD). ATM is a selective norepinephrine reuptake inhibitor, whereas MPD is a psychostimulant and acts as a norepinephrine and dopamine reuptake inhibitor. In the present study, we investigated the effects of ATM (1, 3 or 10mg/kg) and MPD (5, 10 or 20mg/kg) on pharmacological mouse models of sensorimotor gating measured by prepulse inhibition (PPI) using the acoustic startle response test. MK-801, a non-competitive N-methyl-d-aspartate receptor antagonist, or apomorphine, a non-competitive dopamine receptor agonist, was used to induce PPI deficits. ATM (3 or 10mg/kg, s.c.) significantly attenuated the MK-801-, but not apomorphine-, induced PPI deficits. In contrast to ATM, MPD did not reverse the PPI deficits induced by either MK-801 or apomorphine. Immunostaining revealed that the number of c-Fos-immunopositive cells was increased in the nucleus accumbens following MK-801 treatment, and this was reversed by the administration of ATM (3mg/kg), but not MPD (10mg/kg). However, neither ATM nor MPD reversed the increased number of c-Fos-immunopositive cells in the nucleus accumbens following apomorphine treatment. These results suggest that the attenuating effect of ATM on the increased c-Fos immunoreactivity in the nucleus accumbens induced by MK-801 may be attributed to the PPI deficit-ameliorating effects of ATM and that ATM would be useful to treat sensorimotor gating-related disorders by improving the patient's attention span or cognitive function.

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.

Animal models are widely used to study antidepressant-like effect in rodents. However, it should be mentioned that pharmacological models do not always take into account the complexity of the disease process. In the present paper, we demonstrated that repeated but not acute treatment with a low dose of reserpine (0.2 mg/kg i.p.) led to a pharmacological model of depression which was based on its inhibitory effect on the vesicular monoamine transporter 2, and monoamines depleting action in the brain. In fact, we observed that chronic treatment with a low dose of reserpine induced a distinct depressive-like behavior in the forced swim test (FST), and additionally, it produced a significant decrease in the level of dopamine, noradrenaline, and serotonin in the brain structures. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its close methyl derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are exo/endogenous amines present naturally in the mammalian brain which demonstrated a significant antidepressant-like effect in the FST and the reserpine model of depression in the rat. Both compounds, TIQ and 1MeTIQ, administered chronically in a dose of 25 mg/kg (i.p.) together with reserpine completely antagonized reserpine-produced depression as assessed by the immobility time and swimming time. Biochemical data were in agreement with behavioral experiments and demonstrated that chronic treatment with a low dose of reserpine in contrast to acute administration produced a significant depression of monoamines in the brain structures and impaired their metabolism. These neurochemical effects obtained after repeated reserpine (0.2 mg/kg i.p.) in the brain structures were completely antagonized by joint TIQ or 1MeTIQ (25 mg/kg i.p.) administration with chronic reserpine. A possible molecular mechanism of action of TIQ and 1MeTIQ responsible for their antidepressant action is discussed. On the basis of the presented behavioral and biochemical studies, we suggest that both compounds may be effective for the therapy of depression in clinic as new antidepressants which, when administered peripherally easily penetrate the blood-brain barrier, and as endogenous compounds may not have adverse side effects.