A Review of Binaural Bates and the Brain.

Binaural beat (BB), as a non-invasive auditory beat stimulation type, has found its potential applications in cognitive domains. This review presents a proper summary to deepen our understanding of the soundness of the BB technique by looking into its applications, possible mechanisms of action, effectiveness, limitations, and potential side effects. BB has been claimed to improve cognitive and psychological functions such as memory, attention, stress, anxiety, motivation, and confidence. We have also looked into preclinical and clinical research studies that have been performed using BB and proposed changes in the brain following the application of BB stimulations, including EEG changes. This review also presents applications outside the cognitive domain and evaluates BB as a possible treatment method.

Type-2 Diabetes Alters Hippocampal Neural Oscillations and Disrupts Synchrony between the Hippocampus and Cortex.

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.

Type-2 diabetes alters hippocampal neural oscillations and disrupts synchrony between hippocampus and cortex.

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.

Dopaminergic and nitric oxide systems interact to regulate the electrical activity of neurons in the medial septal nucleus in rats.

Research characterizing the neuronal substrate of anxiety has implicated different brain areas, including the medial septal nucleus (m-SEPT). Previous reports indicated a role of dopamine and nitric oxide (NO) in anxiety-related behaviors. In this study, the extracellular single-unit recording was performed from the m-SEPT in adult male albino Wistar rats. Baseline activity was recorded for 5 min, and the post-injection recording was performed for another 5 min after the microinjection of each drug. The results showed that (1) both D1- and D2-like receptor agonists (SKF-38393 and quinpirole) enhanced the firing rate of m-SEPT neurons; (2) both D1- and D2-like antagonists (SCH-23390 and sulpiride) attenuated the firing rate of m-SEPT neurons; (3) L-arginine (NO precursor) increased the firing rate of m-SEPT neurons, but a non-specific NOS inhibitor, L-NAME, elicited no significant alterations; (4) the non-specific NOS inhibitor reversed the enhanced firing rate produced by SKF-38393 and quinpirole; (5) neither of the dopaminergic antagonists changed the enhanced activity resulted from the application of the NO precursor. These results contribute to our understanding of the complex neurotransmitter interactions in the m-SEPT and showed that both dopaminergic and NO neurotransmission are involved in the modulation of the firing rate of neurons in the m-SEPT.

Reviewing the role of the orexinergic system and stressors in modulating mood and reward-related behaviors.

In this review study, we aimed to introduce the orexinergic system as an important signaling pathway involved in a variety of cognitive functions such as memory, motivation, and reward-related behaviors. This study focused on the role of orexinergic system in modulating reward-related behavior, with or without the presence of stressors. Cross-talk between the reward system and orexinergic signaling was also investigated, especially orexinergic signaling in the ventral tegmental area (VTA), the nucleus accumbens (NAc), and the hippocampus. Furthermore, we discussed the role of the orexinergic system in modulating mood states and mental illnesses such as depression, anxiety, panic, and posttraumatic stress disorder (PTSD). Here, we narrowed down our focus on the orexinergic signaling in three brain regions: the VTA, NAc, and the hippocampus (CA1 region and dentate gyrus) for their prominent role in reward-related behaviors and memory. It was concluded that the orexinergic system is critically involved in reward-related behavior and significantly alters stress responses and stress-related psychiatric and mood disorders.

Similar role of mPFC orexin-1 receptors in the acquisition and expression of morphine- and food-induced conditioned place preference in male rats.

Self-control problems are a typical character of drug addiction and excessive food consumption and it has been shown that natural rewards and drugs of abuse share parts of the same neural substrate and reward processing in the brain. Different brain areas are involved in natural and drug reward processing including the mesolimbic pathway, amygdala, nucleus accumbens (NAc), and prefrontal cortex. Considering the important role of orexins in the addictive behavior and the presence of orexin-1 subtype receptors (Orx1R) in the medial prefrontal cortex (mPFC), this study investigated the role of mPFC in natural- and drug-reward seeking behaviors to deepen our understanding of possible similarities or differences. To induce food- or morphine-conditioned place preference (CPP), adult male Wistar rats underwent CPP testing and received intra-mPFC doses of SB334867 (3, 10, or 30 nM/0.5 µl DMSO 12%), as an Orx1R antagonist, during the acquisition or expression phases of the CPP test. Results indicated that microinjection of Orx1R antagonist into the mPFC had similar effects on both morphine- and food-induced CPP and attenuated CPP scores in the acquisition and expression phases of the CPP test. The data demonstrated that Orx1Rs in the mPFC regulate the reward-related effects of morphine- and food-induced reward.

The cross-talk between dopaminergic and nitric oxide systems in the medial septal nucleus, and their distinct effects on anxiety-like behaviors in male rats.

Anxiety disorders, which have a noticeable global prevalence and may be caused by many factors, include a spectrum of disorders that share features of excessive fear- and anxiety-related behavioral disturbances. Different brain areas and neurotransmitter systems have been under investigation for anxiety-related disorders. In this study, we investigated the possible interaction between the dopaminergic and nitric oxide (NO) neurotransmitter systems in the medial septal nucleus and their roles in anxiety-like behaviors using elevated plus-maze (EPM) test in male rats. Our results showed that: (i) both D1-and D2-like receptor agonists, SKF-38393 and quinpirole, augmented anxiety-like behaviors at their two highest applied doses in the EPM test; (ii) both D1-and D2-like receptor antagonists, SCH- 23390 and sulpiride, reduced anxiety-like behaviors at their two highest applied doses in the EPM test; (iii) L-Arginine, a NO precursor, increased anxiety-like behaviors, but L-NAME, a non-specific nitric oxide synthase (NOS) inhibitor, reduced them in the EPM test; (iv) L-NAME could not reverse the anxiety-like parameters produced by SKF-38393, but it significantly reduced the anxiety-like behaviors induced by quinpirole; (v) Neither SCH- 23390 nor sulpiride changed anxiety-related behaviors induced by L-Arginine. It can be concluded that both dopaminergic and nitric oxide systems in the medial septal nucleus are involved in modulating anxiety-like behaviors. While NO has an involvement in the exerted effects by the D2-like agonist, such effects were not observed at the applied range of the doses for D1-and D2-like antagonists.

Punicalagin effect on total sleep deprivation memory deficit in male Wistar rats.

Sleep deprivation has deteriorating effects on cognitive functions and activation of brain inflammation mechanisms has been reported by some studies following total sleep deprivation. Some studies have reported the health benefits of punicalagin, a main abstract from Punica granatum L., including those for the treatment of Alzheimer's disease. The antioxidant characteristic of punicalagin and the fact that sleep deprivation accelerates mediators of inflammation led us to further explore the possible neuroprotective role of punicalagin in total sleep deprivation memory impairment in a rat model. In this study, male Wistar rats were implanted with a canula in the lateral ventricle to receive intracerebroventricular injections (drug or vehicle). The animals were trained for the passive avoidance test and then received intracerebroventricular injections of different doses of punicalagin (0.001, 0.01, or 0.1 µg/rat). Then, they were placed in the sleep deprivation apparatus for 24 hours and tested afterwards for memory retrieval and locomotion. Our results indicated that 24 hours of total sleep deprivation impaired memory processes. PG microinjection before TSD did not prevent the deteriorating effect of total sleep deprivation on memory, and only showed a tendency of restoring the memory impairment. Comparison of the locomotor activity between the animals in different groups showed a significant increase in the total sleep deprivation sham groups that received two of the highest doses of punicalagin. Considering the reported beneficial actions of PG by other studies, further investigation is needed into the possible effects of PG in memory alterations.

Cannabidiol enhanced the development of sensitization to the expression of methamphetamine-induced conditioned place preference in male rats.

Cannabis and ecstasy are illicit substances, and currently, there are no approved treatments for methamphetamine (METH) use disorder. Some studies have proposed that cannabidiol (CBD) decreases the motivation for METH seeking, but reports indicate that the therapeutic benefits are only for heroin. Here, we studied the interaction between CBD and METH during the sensitization phase on the rewarding effect of METH, using the conditioned place preference (CPP) paradigm to measure possible alterations in sensitivity. Our data showed that i. p. injection of METH created METH-induced CPP at two of the highest applied doses (1 and 2 mg/kg), and injection of METH during the sensitization period caused an establishment of METH-induced CPP at lower doses (0.25 and 0.5 mg/kg). Data also revealed that i. c.v. administration of CBD during the sensitization phase, shifted the establishment of METH-induced CPP toward a lower dose (0.5 mg/kg). Concurrent administration of CBD (10 µg/5 µl, i. c.v.) and METH (0.25 mg/kg, i. p.) during sensitization phase established METH-induced CPP with sub-threshold doses of METH (0.125, 0.25, and 0.5 mg/kg). Our results suggest the involvement of CBD and prior exposure to METH in creating sensitization to METH CPP.

Effects of dopamine D1- and D2-like receptors in the CA1 region of the hippocampus on expression and extinction of morphine-induced conditioned place preference in rats.

Considering the extent of drug use and its relapse rate worldwide, in the present study, we explored the role of intra-CA1 administration of D1-like and D2-like receptor antagonists on the expression and extinction of morphine-induced CPP. To induce morphine CPP, adult male Wistar rats received a daily subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Different doses of SCH23390 (0.25, 1 or 4 µg/0.5 µl saline), as a selective D1-like receptor antagonist, and sulpiride (0.25, 1, or 4 µg/0.5 µl DMSO), as a selective D2-like receptor antagonist, were bilaterally microinjected into the CA1 region in the expression and extinction phases 1 h before CPP evaluation. Conditioning scores and locomotor activities were recorded during the tests. Results indicated that the injection of the antagonists into the CA1 region dose-dependently attenuated the expression of the morphine-induced CPP and sulpiride revealed prominent behavioral results compared to SCH23390 in the expression phases. Furthermore, microinjections of SCH23390 and sulpiride shortened the extinction phase of the morphine-induced CPP without changing the locomotor activity. The results indicated the involvement of D1- and D2-like receptors within the CA1 region in the expression and extinction of rewarding properties of morphine.

D1- but not D2-like dopamine receptor antagonist in the CA1 region of the hippocampus reduced stress-induced reinstatement in extinguished morphine-conditioning place preference in the food-deprived rats.

Relapsing to drugs of abuse is a challenging problem in treatment of addiction and stress is believed to be a major risk factor in relapse to drugs. The hippocampus region and dopamine signaling play a critical role in reward-related behaviors. The purpose of this study is to identify the involvement of D1- and D2-like receptors in the CA1 region of hippocampus in the reinstatement induced by a combination of food deprivation stress and a sub-threshold dose of morphine in extinguished morphine-conditioning place preference in rats. Adult male rats treated with one specific doses of SCH-23390 or sulpiride (0.5, 2 and 4 µg/0.5 µl vehicle/side) as D1- and D2-like receptors antagonists into the CA1 in separate groups, following the conditioning and extinction phase of morphine-conditioning place preference, before initiating the food deprivation stress on the last day of extinction. Then, the food deprived animals examined for reinstatement by injection of the sub-threshold dose of morphine (0.5 mg/kg, s.c.) on reinstatement day. Conditioning place preference scores and locomotor activities were recorded during test. Our results showed that combination of food deprivation stress and a sub-threshold dose of morphine induced the reinstatement of morphine-conditioning place preference. The induced reinstatement was decreased by two higher doses of SCH-23390 (2 and 4 µg/0.5 µl vehicle/side). However, the sulpiride (0.5, 2 and 4 µg/0.5 µl vehicle/side) could not reduce the reinstatement. Results showed that the role of D1-like receptor in the CA1 region was more prominent than D2-like receptor in reinstatement induced by food deprivation stress and re-exposure to morphine. Therefore the D1-like receptor in the CA1 might be a potential therapeutic target for treatment of opiate addiction.

The potential role of the orexin reward system in future treatments for opioid drug abuse.

Despite a history of more than a century of intense research in drug addiction, with currently available medication and behavioral therapy, the rate of relapse to drug use is 40-60 percent within a year after the cessation of treatment. The discovery of the neuropeptide orexin/hypocretin in 1998 and subsequent research during the past 20 years revealed an important role for the lateral hypothalamus (LH) in driving the reward pathway. The present review includes an overview of the orexinergic system and focuses on the role of LH orexin neurons targeting different components of the brain's reward pathway in addictive behaviors. Among major animal models of drug reinforcement and addictive behaviors, we narrowed our focus to include conditioned place preference (CPP) and self-administration methods. In this regard, studies on both orexin-1 receptors (OX1Rs) and orexin-2 receptors (OX2Rs) have shown some positive results, suggesting that single orexin receptor antagonists (SORAs) and dual orexin receptor antagonists (DORAs) may hold promising efficacy in the treatment of addiction compared to the currently used methods. We conclude that since current evidence is still preliminary, development of new SORA and DORA compounds and their evaluation in animal and clinical studies will guide us in our future efforts for developing effective medication.

D1- and D2-like receptors in the dentate gyrus region of the hippocampus are involved in the reinstatement induced by a subthreshold dose of morphine and forced swim stress in extinguished morphine-CPP in rats.

Addiction to opioids is an important global problem. Published research has indicated the powerful rewarding effects of drug use, which in the case of opiates like morphine may lead to drug addiction and maladaptive decision making with negative social consequences. In-depth comprehension of the role of responsible mechanisms in addiction can lead us to better and more effective treatments for drug dependence. Continuing previous work in our laboratory, in this study we aimed to investigate the role of dopamine D1- and D2-like receptors in the dentate gyrus (DG) on the reinstatement of drug-seeking behavior induced by the combination of forced swim stress and a subthreshold dose of morphine on extinguished morphine-conditioned place preference in rats. The rats were bilaterally implanted with 2 separate cannulas into the DG region. After the extinction phase of morphine-conditioned place preference, the animals received different doses (0.5, 2, and 4 µg per 0.5 µL vehicle/side) of SCH-23390 or sulpiride on the reinstatement day and were tested for the combination of forced swim stress and a subthreshold dose of morphine in discrete groups. Our findings indicated that D1- and D2-like receptor antagonists attenuated the reinstatement induced by the combination of FSS and the subthreshold dose of morphine. The reduction was more robust in groups of animals that received sulpiride as compared with SCH-23390. Our results showed a role for DG dopamine receptors in relapse to drugs of abuse, the activity of which may be induced by exposure to a stressor like forced swim stress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Involvement of D1- and D2-like dopamine receptors within the rat nucleus accumbens in the maintenance of morphine rewarding properties in the rats.

Previous studies on drug abuse have shown that response to drug-associated cues exist during prolonged abstinence. In succession to previous investigations in our laboratory on morphine dependence and our research on acquisition and expression phases of morphine-conditioned place preference (CPP), in this study we attempt to determine the effects of intraaccumbal administration of SCH-23390, as a D1-like receptor antagonist, and sulpiride, as a D2-like receptor antagonist, in the maintenance of morphine-induced CPP in rats. Seventy-nine adult male Wistar rats weighing 200-280 g were bilaterally implanted with cannulas into the nucleus accumbens. During the 3-day conditioning phase, the animals received daily subcutaneous administration of morphine (5 mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses (0.25, 1, 4 µg per 0.5 µL vehicle) of D1- and D2-like antagonists were bilateral injected daily after the expression phase and during the extinction phase. Our findings revealed that intraaccumbal administration of D1-like and D2-like antagonists after the CPP test shortened the extinction phase in the rats. The results suggested that the existence of the dopamine receptors in the nucleus accumbens was important for the maintenance of morphine-rewarding properties during the extinction phase. Therefore, dopamine receptors may be considered as a promising therapeutic agent in preventing the maintenance of morphine-rewarding effects in dependent individuals. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Role of orexin-1 and -2 receptors within the nucleus accumbens in the acquisition of sensitization to morphine in rats.

It has been reported that orexins A and B are involved in the mediation of drug reward. In addition, the nucleus accumbens (NAc) has an important role in the development of morphine-conditioned place preference (CPP) and morphine sensitization. In the present study, we aimed to evaluate the role of orexin receptors within the NAc in morphine sensitization using CPP paradigm. Adult male Wistar rats were used and were bilaterally implanted by two cannulae in the NAc. The animals received intra-accumbal administration of OX1 or OX2 receptor antagonists, SB-334867 (0.1, 1, and 10 nM/side) or TCS OX2 29 (2, 10, and 20 nM/side), 10 min before morphine injection during the sensitization period, during which the animals received repeated administration of morphine (5 mg/kg; s.c.) once daily for three days followed by 5 morphine injection-free days. Then the CPP paradigm was conducted for the evaluation of morphine rewarding properties by injecting a sub-threshold dose of morphine (0.5 mg/kg; s.c.). The results showed that bilateral administration of OX1 receptor antagonist into the NAc reduced acquisition of morphine sensitization in a dose-dependent manner, but OX2 receptor antagonist produced similar effect only at its highest dose, indicating that OX1 and OX2 receptors within the NAc are involved in the acquisition of morphine sensitization.

Comparison of the Role of D1- and D2-Like Receptors in the CA1 Region of the Hippocampus in the Reinstatement Induced by a Subthreshold Dose of Morphine and Forced Swim Stress in Extinguished Morphine-CPP in Rats.

Reward-seeking and relapse to drug use are two characteristics of addiction and reports have indicated the role of hippocampal structures in reward learning. To find the best ways of treatment, the understanding of the neurobiological mechanisms of reward and its involved factors is a must. For this reason, in the present study, we aimed to investigate the role of D1- and D2-like dopamine receptors and compared their activities in the CA1 region, focusing on the reinstatement induced by forced swim stress (FSS) or the combination of FSS and a subthreshold dose of morphine in extinguished morphine-CPP in rats. The rats were bilaterally implanted by two separate cannulas into the CA1 region. The animals received different doses of SCH23390 or sulpiride (0.5, 2, and 4 µg/0.5 µl vehicle/side) into the CA1 region on the reinstatement day and were tested for FSS-induced reinstatement or the combination of FSS and a subthreshold dose of morphine in separate groups. Our findings indicated that the D1- and D2-like receptor antagonists attenuated the reinstatement induced by the combination of FSS and the subthreshold dose of morphine. The behavioral results were more prominent in the groups of animals that received SCH23390 as compared to sulpiride. The data may suggest a role for the dopamine receptors in the CA1 region in relapse to drugs of abuse, which may be induced by exposure to a stressor.

The effect of amitriptyline administration on pain-related behaviors in morphine-dependent rats: Hypoalgesia or hyperalgesia?

Pain control in opioid-dependent individuals is a clinical complication. The present study investigated the effects of different doses of amitriptyline in the three stages of the formalin test in morphine-dependent rats (MDRs). Morphine dependency was induced using the oral method, and then, amitriptyline-induced antinociceptive effects were measured at 4 doses (2.5, 5, 10, and 20 mg/kg) and compared with the control group in a formalin-based model of pain. There was no observed antinociceptive effect in the MDRs and morphine-naïve rats (MNRs) in phase I. In the interphase, amitriptyline induced pain suppression at doses of 5 and 20 mg/kg. In phase II, at doses of 5, 10, and 20 mg/kg, the hypoalgesic effect on pain-related behaviors was seen in the MNRs. In MDRs, amitriptyline at doses of 2.5 and 5 mg/kg caused the hyperalgesic effect, whereas at 10 and 20 mg/kg doses, it induced a hypoalgesic effect. A significant attenuation was observed in the latency to fall from the accelerating rotarod at doses of 10 and 20 mg/kg in the MDRs, and at a dose of 20 mg/kg in the MNRs. Data showed that amitriptyline dose-dependently induced paradoxical hypo- and hyper-algesic effects in MDRs.

Involvement of D1- and D2-like dopamine receptors in the dentate gyrus in the acquisition, expression, and extinction of the morphine-induced conditioned place preference in rats.

In the current study, we investigated the role of intra-dentate gyrus (DG) administration of D1 and/or D2 receptor antagonists on the expression, acquisition, and extinction of morphine-CPP. Cannulae were implanted bilaterally into the DG region in male Wistar rats and CPP was induced by the subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Three experimental designs were separately employed in the CPP paradigm during the acquisition, expression and extinction phases, and different doses (0.25, 1, or 4 µg/0.5 µl saline) of SCH23390, as a selective D1-like receptor antagonist, and sulpiride (0.25, 1, or 4 µg/0.5 µl DMSO), as a selective D2-like receptor antagonist, were bilaterally microinjected into the DG region. Conditioning scores and locomotor activities were recorded during the test. Results showed that the injection of the antagonists into the DG region dose-dependently attenuated the acquisition and expression of the morphine-induced CPP and sulpiride revealed prominent behavioral results compared to SCH23390 in both mentioned phases. Moreover, the blockade of D1- and D2-like receptors shortened the extinction phase of the morphine-induced CPP but had no effect on the locomotor activity. We found that the dopamine receptors within the DG region are involved in the acquisition and expression of morphine-CPP and have a critical role in the association between a morphine-paired context and the rewarding proprieties of morphine.

Role of orexin-1 and orexin-2 receptors in the CA1 region of hippocampus in the forced swim stress- and food deprivation-induced reinstatement of morphine seeking behaviors in rats.

Hippocampus (HIP) is an essential brain site to study reward-related learning tasks, such as conditioning place preference (CPP) that can measure the preference for environmental stimuli related to reward. Furthermore, orexin neurons, situated exclusively in the lateral hypothalamus (LH) and link the rewarding effects of drugs of abuse in the LH and the CA1 region of the HIP. Therefore, in this study adult male rats were conditioned with morphine using a CPP paradigm. After the eighth day of the extinction period, on the reinstatement day, orexin-1 and orexin-2 receptor antagonists were administered bilaterally into the CA1 region prior to acute stress. Using two different types of acute stress, forced swim stress (FSS) and food deprivation (FD), the role of orexin-1 and orexin-2 receptors in the CA1 brain region in FSS and FD induced reinstatement was investigated. Our results showed that application of the orexin-1 and orexin-2 antagonists, SB334867 and TCSOX2 29, respectively, reduced the CPP scores in the reinstatement phase. Moreover, it can be concluded that orexin neurons are activated in acute stress states, such as FSS and FD, as blocking the orexin receptors, decreased the effects of acute stress in triggering the reinstatement of morphine-CPP.