Blockade of pre-synaptic and post-synaptic GABAB receptors in the lateral habenula produces different effects on anxiety-like behaviors in 6-hydroxydopamine hemiparkinsonian rats.

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not known how blockade of GABAB receptors in the region affects anxiety-like behaviors, particularly in Parkinson's disease-related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, led to hyperactivity of LHb neurons and decreased the level of extracellular dopamine (DA) in the basolateral amygdala (BLA) compared to sham-lesioned rats. Intra-LHb injection of pre-synaptic GABAB receptor antagonist CGP36216 produced anxiolytic-like effects, while the injection of post-synaptic GABAB receptor antagonist CGP35348 induced anxiety-like responses in both groups. Further, intra-LHb injection of CGP36216 decreased the firing rate of the neurons, and increased the GABA/glutamate ratio in the LHb and release of DA and serotonin (5-HT) in the BLA; conversely, CGP35348 increased the firing rate of the neurons and decreased the GABA/glutamate ratio and release of DA and 5-HT in sham-lesioned and the lesioned rats. However, the doses of the antagonists producing these behavioral effects in the lesioned rats were lower than those in sham-lesioned rats, and the duration of action of the antagonists on the firing rate of the neurons and release of the neurotransmitters was prolonged in the lesioned rats. Collectively, these findings suggest that pre-synaptic and post-synaptic GABAB receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway up-regulates function and/or expression of these receptors.

Kv7.2 subunit-containing M-type potassium channels in the lateral habenula are involved in the regulation of working memory in parkinsonian rats.

Although the lateral habenula (LHb) is involved in the regulation of multiple brain functions and this region expresses abundant M-type potassium channel (M-channel) subunits Kv7.2 and Kv7.3, the role of M-channels in regulating working memory is unclear, particularly in Parkinson's disease (PD). Here we tested the effects of activation and blockade of LHb M-channels on working memory by the T-maze rewarded alternation test in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc). The SNc lesion induced working memory impairment, increased the firing rate of LHb neurons, decreased dopamine (DA) level in the ventral medial prefrontal cortex (vmPFC) and reduced the expression of Kv7.2 subunit in the LHb. Intra-LHb injection of M-channel activator retigabine induced enhancement of working memory in SNc sham-lesioned and SNc-lesioned rats; conversely, the injection of M-channel blocker XE-991 impaired working memory in the two groups of rats. However, doses producing significant effects in SNc-lesioned rats were higher than those in SNc sham-lesioned rats. Further, intra-LHb injection of retigabine decreased the firing rate of LHb neurons and increased release of DA and serotonin (5-HT) in the vmPFC, while XE-991 increased the firing rate and decreased DA and 5-HT release in the two groups of rats. Compared with SNc sham-lesioned rats, the duration of M-channel activation and blockade action on the firing rate of the neurons and release of DA and 5-HT was significantly shortened in SNc-lesioned rats, which was consistent with reduced expression of Kv7.2 subunit in the LHb after lesioning the SNc. Collectively, these findings suggest involvement of LHb Kv7.2 subunit-containing M-channels in working memory impairment in SNc-lesioned rats, and that enhanced or impaired working memory after activation or blockade of M-channels in the LHb is related to the changes in the firing activity of LHb neurons and DA and 5-HT release in the vmPFC.

Activation of calcium-impermeable GluR2-containing AMPA receptors in the lateral habenula produces antidepressant-like effects in a rodent model of Parkinson's disease.

Evidence indicates that depression is closely related to hyperactivity of the lateral habenula (LHb). However, it is not clear how activation and blockade of AMPA receptors (AMPARs) in the LHb affect depressive-like behaviors, particularly in Parkinson's disease-related depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to SNc sham-lesioned rats. Interestingly, intra-LHb injection of AMPAR agonist (S)-AMPA produced antidepressant-like effects in the two groups of rats and antagonist NBQX induced depressive-like behaviors, although (S)-AMPA excited LHb neurons and NBQX inhibited these neurons. We further found that intra-LHb injection of (S)-AMPA excited dopaminergic neurons in the anterior ventral tegmental area (aVTA) and serotonergic neurons in the dorsal raphe nucleus (DRN), which increased release of DA and 5-HT in the medial prefrontal cortex (mPFC), while NBQX induced the opposite effects. Further, lesioning the GABAergic rostromedial tegmental nucleus did not alter the proportions of the responses of these neurons to AMPAR stimulation. Additionally, lesions of the SNc reduced the level of p-GluR2-S880 in the LHb, which can increase the surface expression of calcium-impermeable GluR2-containing AMPARs (CI-AMPARs). This change in SNc-lesioned rats enhanced effects of (S)-AMPA and NBQX on the behaviors, LHb neuronal firing and release of DA and 5-HT. Collectively, antidepressant-like effects produced by (S)-AMPA attribute to activation of LHb neurons expressing CI-AMPAR, which excites aVTA dopaminergic neurons and DRN serotonergic neurons via the direct projection, thereby increasing release of mPFC DA and 5-HT.

Enhanced AMPA receptor-mediated excitatory transmission in the rodent rostromedial tegmental nucleus following lesion of the nigrostriatal pathway.

The GABAergic rostromedial tegmental nucleus (RMTg) has reciprocal connections with the dopaminergic ventral tegmental area and substantia nigra pars compacta (SNc), and is involved in inhibitory control of monoaminergic nuclei. At present, it is not clear whether unilateral 6-hydroxydopamine lesions of the SNc in rats affect AMPA receptor-mediated excitatory transmission in the RMTg. Here we found that lesions of the SNc in rats increased the firing rate of GABAergic neurons and the level of glutamate in the RMTg compared to sham-operated rats. Intra-RMTg injection of AMPA receptor agonist (S)-AMPA increased the firing rate of the GABAergic neurons in both sham-operated and the lesioned rats, while AMPA receptor antagonist NBQX decreased the firing rate of the neurons. Further, intra-RMTg injection of (S)-AMPA decreased the levels of dopamine and serotonin in the medial prefrontal cortex (mPFC) in the two groups of rats; conversely, NBQX increased the levels of dopamine and serotonin. Compared to sham-operated rats, the duration of (S)-AMPA and NBQX action on the firing rate of GABAergic neurons in the RMTg and release of doapmine and serotonin in the mPFC was prolonged in the lesioned rats. In addition, lesions of the SNc in rats increased protein expression of t-GluR1 and p-GluR1-S831 subunits compared to sham-operated rats. Therefore, these changes in the lesioned rats are associated with increased release of glutamate and up-regulated expression of GluR1 subunit-containing AMPA receptors in the RMTg, which suggest that degeneration of the nigrostriatal pathway enhances AMPA receptor-mediated excitatory transmission in the RMTg.

Methylene blue alleviates experimental autoimmune encephalomyelitis by modulating AMPK/SIRT1 signaling pathway and Th17/Treg immune response.

Methylene blue (MB) is an effective neuroprotectant in many neurological disorders. AMP-activated protein kinase (AMPK)/silent mating-type information regulation 2 homolog 1 (SIRT1) plays a crucial role in maintaining inflammatory responses and shows a synergistic effect on cell homeostasis. We investigated the effect of MB on experimental autoimmune encephalomyelitis (EAE), a classical animal model of multiple sclerosis (MS). MB treatment reduced the clinical scores of EAE significantly and attenuated pathological injuries in spinal cords. Furthermore, the protective effects of MB were related to the activation of AMPK/SIRT1 signaling pathway. In addition, MB treatment alleviated T helper type17 (Th17) responses and increased regulatory T cell (Treg) responses. Our findings suggest that MB could be a promising reagent to treat autoimmune diseases and MS.

Treatment with NAD(+) inhibited experimental autoimmune encephalomyelitis by activating AMPK/SIRT1 signaling pathway and modulating Th1/Th17 immune responses in mice.

Nicotinamide adenine dinucleotide (NAD(+)) plays vital roles in mitochondrial functions, cellular energy metabolism and calcium homeostasis. In this study, we investigated the effect of NAD(+) administration for the treatment of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. EAE, a classical animal model of multiple sclerosis (MS), was induced by subcutaneous injection of myelin oligodendrocyteglycoprotein (MOG). The mice were treated with 250mg/kg (body weight) NAD(+) in PBS administered intraperitoneally once daily. We observed that NAD(+) treatment could lessen the severity of EAE. Additionally, NAD(+) treatment attenuated pathological injuries of EAE mice. We also found that the AMP-activated protein kinase (AMPK)/silent mating-type information regulation 2 homolog 1(SIRT1) pathway was activated in the NAD(+)-treated mice and NAD(+) treatment suppressed pro-inflammatory T cell responses. Our findings demonstrated that NAD(+) could be an effective and promising agent to treat multiple sclerosis and its effects on other autoimmune diseases should be explored.