The Dopaminergic System Modulates the Electrophysiological Activity of the Suprachiasmatic Nucleus Dependent on the Circadian Cycle.

The suprachiasmatic nucleus of the hypothalamus (SCN) controls mammalian circadian rhythms. Circadian rhythms influence the dopaminergic system, and dopaminergic tone impresses the physiology and behavior of the circadian clock. However, little is known about the effect of dopamine and dopamine receptors, especially D1-like dopamine receptors (D1Rs), in regulating the circadian rhythm and the SCN neuron's activity. Therefore, the present study aimed to investigate the role of the D1Rs in SCN neural oscillations during the 24-h light-dark cycle using local field potential (LFP) recording. To this end, two groups of rats were given the SKF-38393 (1 mg/kg; i.p.) as a D1-like receptor agonist in the morning or night. LFP recording was performed for ten minutes before and two hours after the SKF-38393 injection. The obtained results showed that diurnal changes affect LFP oscillations so that delta relative power declined substantially, whereas upper-frequency bands and Lempel-Ziv complexity (LZC) index increased at night, which is consistent with rodents' activity cycles. The D1Rs agonist administration in the morning dramatically altered these intrinsic oscillations, decreasing delta and theta relative power, and most of the higher frequency bands and LZC index were promoted. Some of these effects were reversed at the night after the SKF-38393 injection. In conclusion, findings showed that the SCN's neuronal activities are regulated based on the light-dark cycle in terms of population neural oscillatory activity which could be affected by dopaminergic stimulation in a time-dependent way.

The blockade of orexin receptors within the dentate gyrus of the hippocampus attenuated methamphetamine-induced reward learning during conditioning place preference.

Orexins and orexinergic receptors have been shown to play a critical role in reward processing and drug addiction. Previous studies showed that the orexinergic system in the dentate gyrus (DG) region of the hippocampus affects the conditioning (acquisition) and post-conditioning (expression) phases of morphine-induced conditioned place preference (CPP). The action of each orexin receptor within the DG during conditioning and expression phases for methamphetamine (METH)-induced CPP remains unclear. The present study aimed to determine the role of orexin-1 and -2 receptors in the hippocampal DG in METH CPP acquisition and expression. During the 5-day conditioning phase, rats received an intra-DG microinjection of SB334867, a selective orexin-1 receptor (OX1R) antagonist, or TCS OX2-29, a selective orexin-2 receptor (OX2R) antagonist, before injection of METH (1 mg/kg; sc). In different sets of animals on the expression day, rats received each antagonist before the CPP test. The results showed that SB334867 (3, 10, and 30 nmol) and TCS OX2-29 (3, 10, and 30 nmol) significantly decreased the acquisition of METH CPP during the conditioning phase. Furthermore, administration of SB 334867 (10 and 30 nmol) and TCS OX2-29 (3 and 10 nmol) on the post-conditioning day significantly reduced METH-induced CPP expression. The results also indicated that orexin receptors play a more critical role in the conditioning phase than in the expression phase. In summary, the orexin receptors in the DG play a crucial role in drug learning and memory and are essential for METH reward acquisition and expression.

Distinct roles for orexin-1 and orexin-2 receptors in the dentate gyrus of the hippocampus in the methamphetamine-seeking behavior in the rats.

Because of the relapsing properties of psychostimulants such as methamphetamine (Meth), there is no established pharmacotherapy for Meth addiction. The orexinergic system is a promising target for treating psychostimulant use disorders and relapse. However, to the best of our knowledge, no investigation regarding the role of orexin receptors in the dentate gyrus (DG) region of the hippocampus has been conducted in the extinction and reinstatement of Meth-seeking behavior. Two stainless-steel guide cannulae were bilaterally implanted into the DG of the rats' brains. The unbiased conditioned place preference (CPP) procedure was conducted to induce Meth conditioning. Following the five days Meth injections (1 mg/kg; sc), animals received intra-DG microinjection of SB334867 or TCS OX2 29, as orexin 1 (OX1) or orexin 2 (OX2) receptor antagonists, respectively (without Meth administration) during extinction phase to elucidate the role of orexin receptors in the latency of the extinction period in the Meth-conditioned rats. To evaluate the role of orexin receptors in the DG region in the reinstatement of Meth-seeking behavior, the extinguished rats received SB334867 or TCS OX2 29 before injecting a priming dose of Meth (0.25 mg/kg; sc). The results indicated two distinct roles for the OX1 and OX2 receptors in the DG region. TCS OX2 29 attenuated the extinction latency, and SB334867 considerably reduced the reinstatement of Meth-seeking behavior in this region. Therefore, the DG region's orexinergic system might be a potential therapeutic target for psychostimulant use disorders.

Antagonism of the orexin receptors in the ventral tegmental area diminished the stress-induced analgesia in persistent inflammatory pain.

As a part of descending pain inhibitory system, orexin (OXs) in the ventral tegmental area (VTA) are implicated in nociceptive responses. The current study aimed to evaluate the role of OX receptors (OXRs) in the VTA in stress-induced analgesia in persistent inflammatory pain. Ninety-nine adult male Wistar rats underwent forced swim stress (FSS) following intra-VTA infusion of various doses of SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol/0.3 µL) as an OX1R or OX2R antagonist, respectively. The nociceptive threshold was evaluated using the formalin test as an animal model of persistent inflammatory pain. Current results demonstrated FSS as acute stress produced analgesic responses in the persistent inflammatory pain. Moreover, either OX1R or OX2R antagonist infusion in the VTA hindered the FSS-induced analgesia in both early and late phases. The inhibitory effect of SB334768 in the FSS-induced analgesia was stronger than TCS OX2 29 in both early and late phases of the formalin test. Neither SB334768 nor TCS OX2 29 alone affects pain-related behaviors in formalin tests. Intra-VTA microinjection of each treatment could not modify locomotion in rats. The findings suggest that OX1R and OX2R in the VTA are implicated in FSS-induced analgesia mechanisms.

Compensatory Role of Insulin in the Extinction but Not Reinstatement of Morphine-Induced Conditioned Place Preference in the Streptozotocin-Induced Diabetic Rats.

Insulin receptors are distributed in the whole brain, including different parts of the reward circuit that modulate dopamine as the primary neurotransmitter implicated in addiction. The goal of the current study was to illuminate the role of insulin in the extinction period and reinstatement of morphine-induced conditioned place preference (CPP) in the naïve and diabetic rats. One hundred and twelve male rats were randomly divided into two naïve and diabetic groups. Diabetes was induced by one dose administration of streptozotocin (STZ; 60 mg/kg; IP) ten days before the conditioning procedure. To evaluate the insulin's role in the duration of extinction period of morphine-CPP, naïve and diabetic rats received insulin (10 U/kg; IP) before each morphine injection (5 mg/kg; sc) during the 3-day conditioning phase. All rats that passed the conditioning phase and then underwent the extinction period. Morphine priming-induced reinstatement was determined in both naïve and diabetic rats by injection of different ineffective doses of morphine (0.5 and 1 mg/kg; sc) in extinguished rats. In the following experiments, three groups of diabetic rats received insulin during the conditioning, expression, or reinstatement phase to illustrate insulin's effect on the morphine-induced reinstatement and the duration of the extinction period (insulin was only treated during the acquisition phase). The results showed that the extinction period and reinstatement of morphine were potentiated in the STZ-induced diabetic rats. The obtained findings also revealed that insulin replacement shortened the extinction period of morphine-induced CPP in STZ-diabetic rats. However, insulin replacements in conditioning, expression, and reinstatement phases did not affect morphine priming-induced reinstatement in diabetic animals.

Dopamine D1 Receptor-Mediated Regulation of Per1, Per2, CLOCK, and BMAL1 Expression in the Suprachiasmatic Nucleus in Adult Male Rats.

Photic and non-photic inputs are reported to affect clock gene expressions and behavioral activities in the SCN. However, it is not known whether dopaminergic input mediates these regulatory effects on clock genes. The present study examined the molecular effects of dopamine D1 agonist on Per1, Per2, CLOCK, and Bmal1 expressions in the SCN and its effect on behavioral activities to determine the role of dopamine D1 receptor in regulation of these gene expressions and behavioral activities in adult male Wistar rats. To examine the molecular effects of dopamine D1 agonist day and night, we injected 20 mg/kg SKF38393 to the first group of rats at 6 a.m. and the second group at 6 p.m. We also injected saline to the third and fourth groups of rats at 6 a.m. and 6 p.m. as control groups. All rats were sacrificed 2 h following the injections. The real-time PCR technique was used to evaluate the clock gene expression. In addition, to examine the effects of dopamine D1 agonists on behavioral activities, we injected 20 mg/kg SKF38393 to SKF receiving group and saline to control group. The behavioral activities of the rats were monitored on the running wheel for 21 days, 1 week following the injections. SKF injections increased the Per2 and CLOCK expressions in the daytime and significantly decreased the Per1 and Bmal1 expressions. However, at night, SKF injections increased only Per2 expressions significantly and decreased the Per1, CLOCK, and Bmal1 genes expressions. Both saline receiving groups showed that all gene expressions were significantly higher except Per2 during nighttime. SKF injection increased the running wheel activity during nighttime significantly. Based on the obtained result, clock gene expression and behavioral activities in adult male Wistar rats may be altered or monitored by administration of exogenous dopamine.

Bilateral striatal transplantation of human olfactory stem cells ameliorates motor function, prevents necroptosis-induced cell death and improves striatal volume in the rat model of Huntington's disease.

Cellular transplant therapy is one of the most common therapeutic strategies used to mitigate symptoms of neurodegenerative diseases such as Huntington's disease (HD). Briefly, the main goal of the present study was to investigate HD's motor deficits through the olfactory ecto-mesenchymals stem cells (OE-MSC) secretome. OE-MSCs were characterized immunophenotypically by the positive expression of CD73, CD90 and CD105. Also, three specific markers of OE-MSCs were obtained from the nasal cavity of human volunteers. The main features of OE-MSCs are their high proliferation, ease of harvesting and growth factor secretion. All animals were randomly assigned to three groups: control, 3-NP + vehicle treated and 3-NP + Cell groups. In both experimental groups, the subjects received intraperitoneal 3-NP (30 mg/kg) injections once a day for five consecutive days, followed by the bilateral intra-striatal implantation of OE-MSCs in the 3-NP + Cell group. Muscular function was assessed by electromyography and rotarod test, and the locomotor function was evaluated using the open field test. According to our findings, striatal transplants of OE-MSCs reduced microglial inflammatory factor, the tumor necrosis factor (TNFα) in the 3-NP + Cell group, with a significant reduction in RIP3, the markers of necroptosis in striatum. In addition to the remarkable recovery of the striatal volume after engraftment, the motor activities were enhanced in the 3-NP + cell group compared to the 3-NP + vehicle group. Taken together, our results demonstrated the in vivo advantages of OE-MSCs treatment in an HD rat model with numerous positive paracrine effects including behavioral and anatomical recovery.

Neuroprotective effect of exogenous melatonin on the noradrenergic neurons of adult male rats' locus coeruleus nucleus following REM sleep deprivation.

Melatonin is primarily secreted by the pineal gland in dark. In addition to its role as an internal sleep facilitator, melatonin acts as an antioxidant, anti-inflammatory and neuroprotective agents. melatonin has been introduced as a therapeutic strategy for sleep disorders. Hence, in the present study, we studied the neuroprotective effects of pre- and post-treatment of melatonin in locus coeruleus nucleus (LC) of rapid eye movement (REM) sleep deprived (REM-SD) male adult rats. Adult male rats of control, sham and trial groups were used Exogenous melatonin (ExMe) was intraperitoneally injected in two forms of pre and post treatment. The protein level of cleaved caspase-3, the number and density of tyrosine hydroxylase (TH) positive neurons and the microglia population in LC were studied by western blot and immunohistochemistry respectively. Morphological changes of LC nucleus and its neurons were also studied by using stereological analysis. The number of neurons and volume of LC was reserved in animals that had received post-RSD ExMe. Apoptosis significantly was decreased comparing to RSD and Pre-RSD animals. Melatonin post-treatment of RSD rats also decreased cleavage of caspase-3 and increased reduced glutathione content in LC. Moreover, immunohistochemistry analysis showed an increase in the number of TH positive neurons and a decrease in microglia migration. Based on our findings antioxidant properties of exogenous melatonin could play a critical role in certain types of sleep disorders.

Neuro-restorative effect of sertoli cell transplants in a rat model of amyloid beta toxicity.

Alzheimer's disease (AD) is a degenerative nerve disease which adversely affects memory and learning skills. Currently, there is no disease-modifying therapeutic approach for AD. However, a growing body of literature suggests cell based therapies as a promising remedy for neurological disorders. Among the potential cell sources, testis- derived Sertoli cells (SCs) appear to be an attractive choice due to their immune-privileged capacities. Herein, we investigated the neuro-restorative/protective effects of SC transplants in a rat model of amyloid beta toxicity. To this end, GATA-4 and vimentin positive SCs were transplanted into rats with amyloid beta induced hippocampal lesions. According to our in vivo results, implanted SCs survived, exhibited reduction in both apoptosis as well as astrocytic migration. Additionally, transplantation of SCs restored hippocampus dependent memory and learning, along with the recovery of long-term synaptic plasticity. Taken together, these data indicate that SCs are a valuable source for cell-based therapies particularly aimed at AD.