Differential Roles of the D1- and D2-Like Dopamine Receptors Within the Ventral Tegmental Area in Modulating the Antinociception Induced by Forced Swim Stress in the Rat.

Several preclinical and clinical studies indicate that exposure to acute stress may decrease pain perception and increases pain tolerance. This phenomenon is called stress-induced analgesia (SIA). A variety of neurotransmitters, including dopamine, is involved in the SIA. Dopaminergic neurons in the mesolimbic circuits, originating from the ventral tegmental area (VTA), play a crucial role in various motivational, rewarding, and pain events. The present study aimed to investigate the modulatory role of VTA dopaminergic receptors in the antinociceptive responses evoked by forced swim stress (FSS) in a model of acute pain. One hundred-five adult male albino Wistar rats were subjected to stereotaxic surgery for implanting a unilateral cannula into the VTA. After one week of recovery, separate groups of animals were given different doses of SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.3 µl) as D1- and D2-like receptor antagonists into the VTA, respectively. Then, the animals were exposed to FSS for a 6-min period, and the pain threshold was measured using the tail-flick test over a 60-min time set intervals. Results indicated that exposure to FSS produces a prominent antinociceptive response, diminishing by blocking both dopamine receptors in the VTA. Nonetheless, the effect of a D1-like dopamine receptor antagonist on FSS-induced analgesia was more prominent than that of a D2-like dopamine receptor antagonist. The results demonstrated that VTA dopaminergic receptors contribute to the pain process in stressful situations, and it might be provided a practical approach to designing new therapeutic agents for pain management.

D2-like dopamine receptors blockade within the dentate gyrus shows a greater effect on stress-induced analgesia in the tail-flick test compared to D1-like dopamine receptors.

INTRODUCTION: Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing of dopamine neurons. Besides, sensitive and advanced research techniques led to the recognition of the mesohippocampal dopaminergic terminals, particularly in the hippocampal dentate gyrus (DG). Moreover, previous studies have shown that dopamine receptors within the hippocampal DG play a critical role in induced antinociceptive responses by forced swim stress (FSS) in the presence of inflammatory pain. Since different pain states can trigger various mechanisms and transmitter systems, the present experiments aimed to investigate whether dopaminergic receptors within the DG have the same role in the presence of acute thermal pain. METHODS: Ninety-seven adult male albino Wistar rats underwent stereotaxic surgery, and a stainless steel guide cannula was unilaterally implanted 1 mm above the DG. Different doses of SCH23390 or sulpiride as D1- and D2-like dopamine receptor antagonists were microinjected into the DG 5-10 min before exposure to FSS, and 5 min after FSS exposure, the tail-flick test evaluated the effect of stress on the nociceptive response at the time-set intervals. RESULTS: The results demonstrated that exposure to FSS could significantly increase the acute pain perception threshold, while intra-DG administration of SCH23390 and sulpiride reduced the antinociceptive effect of FSS in the tail-flick test. DISCUSSION: Additionally, it seems the D2-like dopamine receptor within the DG plays a more prominent role in FSS-induced analgesia in the acute pain model.

The integrative role of orexin-1 and orexin-2 receptors within the hippocampal dentate gyrus in the modulation of the stress-induced antinociception in the formalin pain test in the rat.

The stressful experiences, by triggering a cascade of hormonal and neural changes, can produce antinociception commonly referred to as stress-induced antinociception (SIA). Orexin neuropeptides have an essential role in stress responses and pain modulation. The dentate gyrus receives orexinergic projections and has been shown to be involved in pain processing. The current study investigated the possible role of orexin-1 and orexin-2 receptors (OX1r and OX2r, respectively) within the dentate gyrus in SIA in a rat model of formalin-induced pain behavior in one hind paw. Male Wistar rats weighing 230-250 g underwent stereotaxic surgery and a cannula was implanted in their brains, above the dentate gyrus region. Either SB334867 or TCS OX2 29 (OX1r and OX2r antagonists, respectively) was microinjected into the dentate gyrus region at a range of doses at 1, 3, 10, and 30 nmol (control group received DMSO 12% as vehicle), 5 min before the forced swim stress (FSS) exposure. The formalin test was performed to assess pain-related behaviors. The results indicated that FSS exposure relieves pain-related behavior in the early and late phases of the formalin test. Blockade of intra-dentate gyrus OX1 or OX2 receptors reduced the antinociceptive responses induced by FSS in the formalin test, with more impact during the late phase. Our findings support the potential role of intra-dentate gyrus orexin receptors as target sites of orexin neurons in painful and stressful situations. Therefore, understanding the exact mechanisms of SIA and the role of the orexinergic system in this phenomenon can lead to identifying the strategies to guide future research and offer a new approach to discovering new pain therapeutic agents.

Contribution of the intra-hippocampal orexin system in the regulation of restraint stress response to pain-related behaviors in the formalin test.

Stress-induced antinociception (SIA) is due to the activation of several neural pathways and neurotransmitters that often suppress pain perception. Studies have shown that the orexin neuropeptide system is essential in pain modulation. Therefore, this study aimed to investigate the role of orexinergic receptors in the hippocampal CA1 region in modulating SIA response during the formalin test as an animal model of inflammatory pain. The orexin-1 receptor (OX1r) antagonist, SB334867, at 1, 3, 10, and 30 nmol or TCS OX2 29 as an orexin-2 receptor (OX2r) antagonist at the same doses were microinjected into the CA1 region in rats. Five minutes later, rats were exposed to restraint stress (RS) for 3 h, and pain-related behaviors were monitored in 5-min blocks for the 60-min test period in the formalin test. Results showed that applying RS for 3 h reduced pain responses in the early and late phases of the formalin test. The main findings showed that intra-CA1 injection of orexin receptor antagonists reduced the antinociception caused by stress in both phases of the formalin test. In addition, the contribution of OX2r in mediating the antinociceptive effect of stress was more prominent than that of OX1r in the early phase of the formalin test. However, in the late phase, both receptors worked similarly. Accordingly, the orexin system and its two receptors in the CA1 region of the hippocampus regulate SIA response to this animal model of pain in formalin test.

Intra-accumbal orexinergic system contributes to the stress-induced antinociceptive behaviors in the animal model of acute pain in rats.

Stress and pain are interleaved at numerous levels - influencing each other. Stress can increase the nociception threshold in animals, long-known as stress-induced analgesia (SIA). Orexin is known as a neuropeptide that modulates pain. The effect of stress on the mesolimbic system in the modulation of pain is known. The role of the intra-accumbal orexin receptors in the modulation of acute pain by forced swim stress (FSS) is unclear. In this study, 117 adult male albino Wistar rats (270-300 g) were used. The animals were unilaterally implanted with cannulae above the NAc. The antagonist of the orexin-1 receptor (OX1r), SB334867, and antagonist of the orexin-2 receptor (OX2r), TCS OX2 29, were microinjected into the NAc in different doses (1, 3, 10, and 30 nmol/0.5 µl DMSO) before exposure to FSS for a 6-min period. The tail-flick test was carried out as an assay nociception of acute pain, and the nociceptive threshold [tail-flick latency (TFL)] was measured for 60-minute. The findings demonstrated that exposure to acute stress could remarkably increase the TFLs and antinociceptive responses. Moreover, intra-accumbal microinjection of SB334867 or TCS OX2 29 blocked the antinociceptive effect of stress in the tail-flick test. The contribution of orexin receptors was almost equally modulating SIA. The present study's findings suggest that OX1r and OX2r within the NAc modulate stress-induced antinociceptive responses. The intra-accumbal microinjection of orexin receptors antagonists declares inducing antinociceptive responses by FSS in acute pain. Proposedly, intra-accumbla orexinergic receptors have a role in the development of SIA.

Regulatory Role of PFC Corticotropin-Releasing Factor System in Stress-Associated Depression Disorders: A Systematic Review.

Stress has a substantial role in formation of psychiatric disorders especially depression. Meanwhile, impairment of the prefrontal cortex (PFC) is connected to the executive and cognitive deficits induced by the stress. Given the involvement of the corticotropin-releasing factor (CRF) in stress-related processes and knowing the fact that PFC hosts a lot of CRF receptors and CRF neurotransmissions, it can worth to look at the CRF as a potential treatment for the regulation of depression disorders induced by stress within PFC region. Here, for the first time we aimed to systematically review the effectiveness of intra-PFC CRF system in the modulation of depression dysfunction caused by the stress in clinical and preclinical models/studies. Qualified researches were combined utilizing a comprehensive search of six databases including Scopus, Pubmed, Web of Science, Sciencedirect, APA PsycNet, and Embase in April 2021 and were evaluated through proper methodological quality assessment tools. Results indicate that PFC has a remarkable role in the modulation for stress-induced depression and intra-PFC CRF receptors agonist and antagonist are very considerable for regulating these types of impairments. Specifically, elevation of both CRF immunoreactivity and gene expression were observed in human studies. In the animal studies, mostly immunoreactivity or excitatory/inhibitory currents of CRF within the PFC regulated depression dysfunction. In conclusion, reviewed studies show a positive attitude toward the CRF system in regulation of the stress-induced depression; however, obviously further investigations are required to get closer to the best treatment. Prefrontal cortex corticotropin-releasing factor system regulates stress-induced depression. CRFR1, Corticotropin-releasing factor receptor of type1; PFC, Prefrontal cortex; Minus (-) and Plus (+) signs, dysregulation and upregulation, respectively.

Neuroinflammatory Response in Reward-Associated Psychostimulants and Opioids: A Review.

Substance abuse is one of the significant problems in social and public health worldwide. Vast numbers of evidence illustrate that motivational and reinforcing impacts of addictive drugs are primarily attributed to their ability to change dopamine signaling in the reward circuit. However, the roles of classic neurotransmitters, especially dopamine and neuromodulators, monoamines, and neuropeptides, in reinforcing characteristics of abused drugs have been extensively investigated. It has recently been revealed that central immune signaling includes cascades of chemokines and proinflammatory cytokines released by neurons and glia via downstream intracellular signaling pathways that play a crucial role in mediating rewarding behavioral effects of drugs. More interestingly, inflammatory responses in the central nervous system modulate the mesolimbic dopamine signaling and glutamate-dependent currents induced by addictive drugs. This review summarized researches in the alterations of inflammatory responses accompanied by rewarding and reinforcing properties of addictive drugs, including cocaine, methamphetamine, and opioids that were evaluated by conditioned place preference and self-administration procedures as highly common behavioral tests to investigate the motivational and reinforcing impacts of addictive drugs. The neuroinflammatory responses affect the rewarding properties of psychostimulants and opioids.

A systematic review of the local field potential adaptations during conditioned place preference task in preclinical studies.

Addiction is a global concern with a high relapse rate and without effective therapeutic options. Developing new effective therapeutic strategies is impossible without discovering the disease's neurobiological basis. The present systematic review aimed to comprehensively recognize and discuss the role of local field potentials from brain areas essential in forming and storing context-drug/food associations following the conditioned place preference (CPP) paradigm as a popular animal model of reward and addiction. Qualified studies were incorporated by a broad search of four databases, including Web of Science, Medline/PubMed, Embase, and ScienceDirect, in July 2022, and they were evaluated via appropriate methodological quality assessment tools. The current study found that drug-seeking behavior in different stages of the CPP paradigm is accompanied by alterations in neural oscillatory activity and adaptations in connectivity among various areas such as the hippocampus, nucleus accumbens, basolateral amygdala, and prelimbic area, intensely engaged in reward-related behaviors. These findings need to be extended by more future advanced studies to finally recognize the altered oscillatory activity patterns of large groups of cells in regions involved in reward-context associations to improve clinical strategies such as neuromodulation approaches to modify the abnormal electrical activity of these critical brain regions and their connections for treating addiction and preventing drug/food relapse in abstinent patients. DEFINITIONS: Power is the amount of energy in a frequency band and is the squared amplitude of the oscillation. Cross-frequency coupling refers to a statistical relationship between activities in two different frequency bands. Phase-amplitude coupling is perhaps the most commonly used method of computing cross-frequency coupling. Phase-amplitude coupling involves testing for a relationship between the phase of one frequency band and the power of another, typically relatively higher, frequency band. Thus, within phase-amplitude coupling, you refer to the "frequency for phase" and the "frequency for power." Spectral coherence has been frequently used to detect and quantify coupling between oscillatory signals of two or more brain areas. Spectral coherence estimates the linear phase-consistency between two frequency-decomposed signals over time windows (or trials).

Is Deep Brain Stimulation an Effective Treatment for Psychostimulant Dependency? A Preclinical and Clinical Systematic Review.

Addiction to psychostimulants significantly affects public health. Standard medical therapy is often not curative. Deep brain stimulation (DBS) is a promising treatment that has attracted much attention for addiction treatment in recent years. The present review aimed to systematically identify the positive and adverse effects of DBS in human and animal models to evaluate the feasibility of DBS as a treatment for psychostimulant abuse. The current study also examined the possible mechanisms underlying the therapeutic effects of DBS. In February 2022, a comprehensive search of four databases, including Web of Science, PubMed, Cochrane, and Scopus, was carried out to identify all reports that DBS was a treatment for psychostimulant addiction. The selected studies were extracted, summarized, and evaluated using the appropriate methodological quality assessment tools. The results indicated that DBS could reduce relapse and the desire for the drug in human and animal subjects without any severe side effects. The underlying mechanisms of DBS are complex and likely vary from region to region in terms of stimulation parameters and patterns. DBS seems a promising therapeutic option. However, clinical experiences are currently limited to several uncontrolled case reports. Further studies with controlled, double-blind designs are needed. In addition, more research on animals and humans is required to investigate the precise role of DBS and its mechanisms to achieve optimal stimulation parameters and develop new, less invasive methods.

The Role of Orexin-1 Receptors Within the Hippocampal CA1 Area in the Extinction and Reinstatement of Methamphetamine-Seeking Behaviors.

Psychostimulant addiction is a chronic brain disorder with high relapse rates, requiring new therapeutic strategies. The orexin system is highly implicated in processing reward and addiction through connections with critical areas such as the hippocampus. This study investigated the role of orexin-1 receptors (OX1R) within the CA1 subregion of the hippocampus in the extinction and reinstatement of the methamphetamine-induced conditioned place preference. After cannulae implantation, recovery, and establishing the methamphetamine place preference, 98 male Wistar rats received different doses of bilateral intra-CA1 selective OX1R antagonist, SB334867 (1, 3, 10, and 30 nmol/0.5 µl DMSO per side) during the 10-day extinction period (daily) or after extinction phase, just on the reinstatement day (single dose) in separate experimental and control groups. The findings indicated that bilateral microinjection of SB334867 into the CA1 area during the extinction period could significantly reduce the extinction latency and maintenance of rewarding aspects of methamphetamine dose-dependently (3, 10, and 30 nmol). In another set of experiments, a single dose of bilateral intra-CA1 SB334867 administration on the reinstatement phase prevented the methamphetamine-induced reinstatement of drug-seeking behaviors at the high doses (10, and 30 nmol). The present study provided more evidence for the implication of hippocampal OX1R in the maintenance of rewarding and reinforcing properties of methamphetamine and its role in the relapse of methamphetamine-seeking behavior. Further investigations on the role of the orexin system, including the orexin-2 receptors in treating addiction, are needed to introduce its antagonists as effective therapeutic options for psychostimulant addiction.

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.

Involvement of dopaminergic system in the dentate gyrus of the hippocampus in modulating the orofacial pain-related behaviors in the rats.

Chemical stimulation of the lateral hypothalamus (LH) induces analgesia by forming neural circuitries with multiple brain regions. The involvement of hippocampal dopaminergic receptors in the LH stimulation-induced antinociception in specific pain models in animals has been documented. However, because the neural circuitries involved in the mediation of orofacial pain are not the same as those that mediate the other types of pain, the present study aims to detect the role of dopamine receptors within the dentate gyrus (DG) in the antinociceptive responses induced by LH stimulation in an animal model of orofacial pain. Male Wistar rats (220-250 g) were implanted with two separate cannulae into the LH and DG on the same side. D1- or D2-like dopamine receptor antagonist, SCH23390, or sulpiride (0.25, 1, and 4 µg) were microinjected into the DG, five minutes before intra-LH injection of carbachol (250 nM). The animals were then injected with formalin 1% (50 µL; sc) into the upper lip lateral to the nose and subjected to the orofacial formalin test. Intra-DG administration of SCH23390 or sulpiride attenuated the antinociceptive responses induced by intra-LH microinjection of carbachol during the orofacial formalin test. The findings of the current study suggest that chemical stimulation of the LH modulates orofacial pain, possibly through activation of the DG dopaminergic neurons. Due to the high incidence and prevalence of orofacial pain in the general population, understanding how such neuronal circuitry modulates nociceptive processing will advance the search for novel therapeutics.

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.

The modulatory role of dopamine receptors within the hippocampal cornu ammonis area 1 in stress-induced analgesia in an animal model of persistent inflammatory pain.

The intrinsic pain inhibitory mechanisms can be activated by fear, anxiety, and stress. Stressful experiences produce analgesia, referred to as stress-induced analgesia (SIA). Major components of the limbic system, including the ventral tegmental area, nucleus accumbens, amygdala, and hippocampus, are involved in the SIA. In this study, we tried to understand the role of dopamine receptors in the cornu ammonis area 1 (CA1) of the hippocampus in the forced swim stress (FSS)-induced analgesia. Stereotaxic surgery was unilaterally performed on 129 adult male Wistar rats weighing 220-280 g. SCH23390 (0.25, 1, and 4 µg/0.5 µl saline) or sulpiride (0.25, 1, and 4 µg/0.5 µl DMSO), as D1- and D2-like dopamine receptor antagonists, respectively, were microinjected into the CA1 area, 5 min before exposure to FSS for a 6-min period. The vehicle groups received saline or DMSO instead of SCH23390 or sulpiride, respectively. The formalin test was done using formalin injection (50 µl; 2.5%) into the plantar surface of the rat's hind paw immediately after exposure to FSS. The results demonstrated that FSS produces analgesia during the early and late phases of the formalin test. However, intra-CA1 microinjection of SCH23390 or sulpiride attenuated the FSS-induced analgesia in both phases of the formalin test. This study provides new insight into the role of D1- and D2-like dopamine receptors in the CA1 area in the FSS-induced analgesia during persistent inflammatory pain.

Multigenerational effects of paternal spatial training are lasting in the F1 and F2 male offspring.

Recent studies on intergenerational transmission of learning and memory performances demonstrated that parental spatial training before fertilization could facilitate learning and memory in the offspring, but many questions remain unclarified. Essential issues regarding whether and how long the effects of parental training in a task can last in several generations, and whether learning a task repeated in the successive generations can enhance a load of multigenerational effects. In the present study, the spatial performances of F1 and F2 generations of male offspring of fathers or grandfathers spatially trained in the Morris Water Maze were evaluated and compared with the performance of a control sample matched for age and sex. Further, to investigate the memory process in F1 and F2 male offspring, brain-derived neurotrophic factor (BDNF), p-ERK1/2 and acetylated histone 3 lysine 14 (H3K14) expression levels in the hippocampus were analyzed. The findings showed that paternal training reduced escape latencies and increased time spent in the target quadrant by F1 and F2 male offspring. Besides, paternal spatial training repeated in two generations did not enhance the beneficial effects on offspring's spatial performances. These findings were supported by neurobiologic data showing that paternal training increased BDNF and p-ERK1/2 in the hippocampus of F1 and F2 male offspring. Furthermore, the hippocampal level of acetylated H3K14 increased in the offspring of spatially trained fathers, reinforcing the hypothesis that the augmented histone acetylation might play an essential role in the inheritance of spatial competence.

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.

Adolescent chronic unpredictable stress causes a bias in goal-directed behavior and distinctively changes the expression of NMDA and dopamine receptors in the dorsomedial and dorsolateral striatum in male rats.

The distinct preferences between goal-directed and habit-directed behaviors involve numerous neurodegenerative and psychiatric disorders. Chronic stress during adulthood biases behavior toward habit-oriented strategies. However, it remains to be studied how adolescence, as a stage in which brain regions are still undergoing development, suffering stress will affect this preference. Here, we exposed rats to chronic unpredictable stress (CUS) at PND 21 to PND 33 and PND 34 to PND 47 to examine its effect on sugar pellet-based instrumental behavior in adulthood. We showed that rats exposed to CUS in middle adolescence had a biased goal-directed strategy rather than a habit-oriented strategy in adulthood, whereas CUS exposure in early adolescence did not have this effect. Moreover, middle adolescent CUS caused the downregulation of the N-methyl-d-aspartate receptor subtype 2 B (NR2B) in the dorsolateral striatum (DLS) rather than in the dorsomedial striatum (DMS), whereas no change was observed in NR2A or the dopamine D1 receptor (D1R) or the dopamine D2 receptor (D2R) in the DLS. Together, these findings suggest that CUS in middle adolescence inhibits habitual behavior in adulthood and downregulates the expression of NR2B in DLS, providing new evidence to understand the molecular mechanisms of abnormal habitual behaviors induced by adolescent stress.

Assessment of motor skill accuracy and coordination variability after application of local and remote experimental pain.

Motor learning is a relatively permanent change in motor performance. Also, one of the factors that can affect movement acquisition and movement patterns is pain and injury. The present study aims to investigate the effect of the induced local and remote pain during dart-throwing skill acquisition by examining motor skill accuracy and coordination variability. Three groups of 30 participants with a mean age of 18-25 were randomly assigned to local and remote pain or control groups. Capsaicin gel was applied to the pain groups for measuring the severity of pain using the Visual Analogue Scale (VAS). The results revealed that pain had no impact on dart-throwing skill acquisition, and there was no significant difference (p = 0.732) among the three groups at three stages of retention test. The results also showed that there was a significant difference among the three groups in terms of variability in shoulder-elbow (p = 0.025) and elbow-wrist joints (p = 0.000) in the deceleration and dart-throwing phases. The Central Nervous System seems to make adjustments when the task is associated with pain during the acquisition phase. Also, the groups with or without pain have notably various strategies, so differently, to perceive motor skills.

Thyroid function following radiation therapy in breast cancer patients: risk of radiation-induced hypothyroidism.

Background: Radiation exposure to the thyroid gland seems unavoidable in breast cancer (BC) patients receiving radiation therapy (RT) to the supraclavicular (SC) region. Hence, this study aimed to evaluate the effects of SC region RT on thyroid function and the prevalence of radiation-induced hypothyroidism (RIHT) in BC patients at regular intervals post-treatment. Materials and methods: Twenty-one patients with BC were enrolled in this analytical cross-sectional study by simple and convenient sampling, from March 2019 to March 2020. Thyroid function and the prevalence of RIHT were evaluated and compared by measuring the serum of thyroid-stimulating hormone (TSH) and free thyroxine hormone (fT4) levels before radiation therapy (pre-RT) and 3 and 6 months after radiation therapy (post-RT). The patients underwent 3 dimensional conformal. radiation therapy (3D CRT) of breast/chest wall, axillary, and supraclavicular lymph nodes with 50 Gy/25 fractions/5 weeks. The collected data were analyzed using SPSS software (version 20). Results: Serum levels of TSH increased at 3 and 6 months post-RT, this increase was not statistically significant (p > 0.05). Nevertheless, serum levels of fT4 were significantly elevated at 3 and 6 months post-RT (p < 0.01). A correlation was observed between the follow-up period and the incidence of RIHT, where it was 0% at 3 months and 9.5% at 6 months post-RT. RIHT was not significantly associated with any factors, including patient's age, type of surgery, thyroid gland dose, and thyroid gland volume. Conclusions: It seems that SC region RT does not have a significant adverse effect on the thyroid function among BC patients at 3 and 6 months post-treatment. Hence, a long-term follow-up with a larger sample size is suggested.

Time-Dependent Changes in the Serum Levels of Neurobiochemical Factors After Acute Methadone Overdose in Adolescent Male Rat.

Acute methadone toxicity is a major public health concern which has adverse effects on brain tissue and results in recurrent or delayed respiratory arrest. Our study aimed to investigate the time-dependent changes in several serum biochemical markers of brain damage, spatial working memory, and the brain tissue following acute methadone overdose. Adolescent male rats underwent an intraperitoneal (i.p.) injection of 15 mg/kg methadone. In case of apnea occurrence, resuscitation was performed by a ventilatory pump and administrating naloxone (2 mg/kg; i.p.). The animals were classified into groups of treated rats; methadone and naloxone-Apnea (M/N-Apnea), M/N-Sedate, Methadone, Naloxone, and control (saline) groups. The serum levels of S100B, neuron-specific enolase (NSE), myelin basic protein factors, and (Lactate/Pyruvate) L/P ratio were evaluated at the time-points of 6, 24, and 48 h (h). We found that the alterations of S100B and L/P ratio were considerable in the M/N-Apnea and Methadone groups from the early hours post-methadone overdose, while NSE serum levels elevation was observed only in M/N-Apnea group with a delay at 48 h. Further, we assessed the spatial working memory (Y-maze test), morphological changes, and neuronal loss. The impaired spontaneous alternation behavior was detected in the M/N-Apnea groups on days 5 and 10 post-methadone overdose. The morphological changes of neurons and the neuronal loss were detectable in the CA1, striatum, and cerebellum regions, which were pronounced in both M/N-Apnea and Methadone groups. Together, our findings suggest that alterations in the serum levels of S100B and NSE factors as well as L/P ratio could be induced by methadone overdose with the presence or absence of apnea before the memory impairment and tissue injury in adolescent male rats.