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Understanding the central nervous system (CNS) circuitry and its different neurotransmitters that underlie reward is essential to improve treatment for many common health issues, such as addiction. Here, we concentrate on understanding how the mesolimbic circuitry and neurotransmitters are organized and function, and how drug exposure affects synaptic and structural changes in this circuitry. While the role of some reward circuits, like the cerebral dopamine (DA)/glutamate (Glu)/gamma aminobutyric acid (GABA)ergic pathways, in drug reward, is well known, new research using molecular-based methods has shown functional alterations throughout the reward circuitry that contribute to various aspects of addiction, including craving and relapse. A new understanding of the fundamental connections between brain regions as well as the molecular alterations within these particular microcircuits, such as neurotrophic factor and molecular signaling or distinct receptor function, that underlie synaptic and structural plasticity evoked by drugs of abuse has been made possible by the ability to observe and manipulate neuronal activity within specific cell types and circuits. It is exciting that these discoveries from preclinical animal research are now being applied in the clinic, where therapies for human drug dependence, such as deep brain stimulation and transcranial magnetic stimulation, are being tested. Therefore, this chapter seeks to summarize the current understanding of the important brain regions (especially, mesolimbic circuitry) and neurotransmitters implicated in drug-related behaviors and the molecular mechanisms that contribute to altered connectivity between these areas, with the postulation that increased knowledge of the plasticity within the drug reward circuit will lead to new and improved treatments for addiction.

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BACKGROUND: Autism spectrum disorder (ASD) represents an inheritable neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Numerous studies have underscored the significant roles played by genetic and environmental factors in the etiology of ASD, and these factors are known to perpetuate behavioral impairments across generations. OBJECTIVES: The primary objective of this study was to assess the behavioral and cognitive attributes in the second filial (F2) generation of male and female rats, with a particular focus on those whose parents had been exposed to valproic acid (VPA) during embryonic development. METHODS: In this study, a cohort of 32 male and 32 female rats from the second filial (F2) generation, referred to as Mother.ASD, Father.ASD, or Both.ASD, was examined. These designations indicate whether the mother, father, or both parents had experienced embryonic exposure to valproic acid (600 mg/kg, i.p.). During adolescence, the F2 pups underwent behavioral and cognitive assessments, including open field testing, marble burying, social interaction evaluations, and Morris water maze tasks. RESULTS: Our data revealed that while both the Mother.ASD and Father.ASD groups, regardless of sex, exhibited elevated anxiety-like behavior in the open field test. Only the Mother.ASD group displayed repetitive behaviors and deficits in social memory. Additionally, spatial memory impairments were observed in both sexes. These findings highlight the transmission of autistic-like behaviors in the offspring of Mother.ASD rats from both sexes. Nevertheless, future research endeavors should be more targeted in identifying the specific genes responsible for this transmission. CONCLUSION: In summary, our findings underscore the transmission of autistic-like behaviors, including anxiety-like behavior, repetitive actions, impairments in social interactions, and deficits in memory, to the offspring of the Mother.ASD group, irrespective of their sex.

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including impairment in social communication and restrictive and repetitive behaviors and interests. Music has emerged in the past decade as an intervention therapy for children with ASD. The aim of the present study was to evaluate the effects of music on cognition impairments in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism on embryonic day 12.5 (E12.5) (600 mg/kg). Male and female pups were sub divided into four main groups (Saline.Non-music, VPA.Non-music, Saline.Music, and VPA.Music). The rats in the music groups were exposed to Mozart's piano sonata K.448 for 30 days (4 h/day), from postnatal day (PND) 21 to 50. Autistic-like behaviors were tested using a social interaction, the Morris water maze (MWM), and a passive avoidance tasks at the end of the PND 50. Our results demonstrated that VPA-exposed rat pups had significantly lower sociability and social memory performance compared with the saline-exposed rats in both sexes. VPA-exposed rat pups exhibited learning and memory impairments in the MWM and passive avoidance tasks. Our results demonstrated that music improved sociability in VPA-exposed rats, especially in males. Furthermore, our findings revealed that music improved learning impairments in VPA-exposed male rats in MWM task. In addition, music improved spatial memory impairments in VPA-exposed rats of both sexes. We also found that music improved passive avoidance memory impairments in VPA-exposed rats of both sexes, especially in females. More investigation in future studies are needed.

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INTRODUCTION: The beneficial effects of the administration of selective estrogen receptor modulators (SERMs) and estrogen (E2), alone or in combination with each other, have been reported in postmenopausal diabetic cardiovascular dysfunction. In the present study, we determined the mechanism of action of SERMs and E2 on inflammatory balance, angiotensin II (Ang II) serum levels, and glycemic profile in a postmenopausal diabetic rat model. METHODS: Ovariectomized rats with type 2 diabetes received daily SERMs (tamoxifen and raloxifene) and E2 for one month. After treatment, cardiovascular risk indices, glycemic profile, and serum Ang II, TNF-α and IL-10 levels were measured. RESULTS: Type 2 diabetes caused an abnormal glycemic profile, which was exacerbated by ovariectomy. All treatments inhibited the effects of diabetes and ovariectomy on the glycemic profile, with combined treatments (SERMs + E2) showing stronger effects. Cardiovascular risk indices that became abnormal by diabetes and worsened by ovariectomy were improved in all treatment modalities. Also, combined treatment reduced serum Ang II, TNF-α, and the ratio of TNF-α to IL-10, indicating an improvement in inflammatory balance. CONCLUSION: Our study showed the administration of SERMs and E2, alone or in combination, could be an effective alternative in the treatment of menopausal diabetes, and generally, the beneficial effects of combined treatments were more effective than the effects of E2 or SERMs alone. It appears that E2 or SERMs benefit the cardiovascular system by improving inflammatory balance and reducing Ang II levels.

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OBJECTIVES: The contribution of classic progesterone receptors (PR) in interceding the neuroprotective efficacy of progesterone (P4) on the prevention of brain edema and long-time behavioral disturbances was assessed in traumatic brain injury (TBI). MATERIALS AND METHODS: Female Wistar rats were ovariectomized and apportioned into 6 groups: sham, TBI, oil, P4, vehicle, and RU486. P4 or oil was injected following TBI. The antagonist of PR (RU486) or DMSO was administered before TBI. The brain edema and destruction of the blood-brain barrier (BBB) were determined. Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and beam walk (BW) task were evaluated previously and at various times post-trauma. Long-time locomotor and cognitive consequences were measured one day before and on days 3, 7, 14, and 21 after the trauma. RESULTS: RU486 eliminated the inhibitory effects of P4 on brain edema and BBB leakage (P<0.05, P<0.001, respectively). RU486 inhibited the decremental effect of P4 on ICP as well as the increasing effect of P4 on CPP (P<0.001) after TBI. Also, RU486 inhibited the effect of P4 on the increase in traversal time and reduction in vestibulomotor score in the BW task (P<0.001). TBI induced motor, cognitive, and anxiety-like disorders, which lasted for 3 weeks after TBI; but, P4 prevented these cognitive and behavioral abnormalities (P<0.05), and RU486 opposed this P4 effect (P<0.001). CONCLUSION: The classic progesterone receptors have neuroprotective effects and prevent long-time behavioral and memory deficiency after brain trauma.

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INTRODUCTION: The cardiovascular dysfunctions in postmenopausal diabetic women increase relative to premenopausal women. In this study we evaluated protective effects of selective estrogen receptor modulators (SERMs), alone and in combination with estrogen (E2) in diabetic rats with menopausal model. METHODS: Female rats groups are included: Sham-Control (CTL), Diabetes (DM), and ovariectomized rats divided to DM, DM + Vehicle (Veh), DM + Tamoxifen (TAM), DM + Raloxifene (RLX), DM + Veh + Oil, DM + Oil, DM + E2, DM + E2 + Veh, DM + TAM + E2, DM + RLX + E2. DM was induced by high fat diet and followed by a light dose of streptozotocin. SERMs and E2 were administrated for four weeks after establishment of type 2 diabetes mellitus (T2DM). RESULTS: Our results depicts that, T2DM increased triglyceride, total cholesterol, low-density lipoprotein, and fasting blood glucose. Also it decreased high-density lipoprotein, which had exacerbated by ovariectomy. These changes were reversed by using SERMs, E2 and SERMs+E2, although combinatory treatment is more effective than individual treatment. Additionally the cardiovascular indices were also significantly disrupted in ovariectomized diabetic rats, but all therapeutic groups equally improved these disturbances, whereas in TAM + E2 group, the atherogenic index was more decreased than TAM group. CONCLUSION: We concluded that SERMs treatment, individual or in combination with E2 in menopausal model can be efficient substitute for E2 replacement therapy. This study suggests cellular mechanisms of SERMs in future studies.

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Previous studies have indicated that forced exercise plays a preventive role in synaptic plasticity deficits in the hippocampus and behavioral impairments in sleep-deprived male and female rats. The objective of the present study was to evaluate the effects of voluntary exercise on early long-term potentiation (E-LTP) at the Cornu Ammonis (CA1) area of the hippocampus and behavioral functions by barnes maze and novel location tests in sleep-deprived female rats. Intact female Wistar rats were used in the present study. The exercise protocol was four weeks wheel running and the multiple platform method was applied to induce 72 h Sleep deprivation (SD). We examine the effect of exercise and/or SD on synaptic plasticity using in vivo extracellular recording in the CA1 area of the hippocampus. Spatial learning and memory examined by Barnes maze and recognition memory assessed by novel location test. Field potential recording indicated that the induction and maintenance phase of E-LTP impaired in the sleep deprived animals compared to the other groups. After 72 h SD, LTP impairments were reduced by 4 weeks of voluntary exercise but do not go back to control values. SD impairs learning and memory and exercise could improve these deficits. In conclusion, the synaptic plasticity deficit in sleep-deprived female rats was improved by voluntary exercise. Further studies are suggested to evaluate the possible underlying mechanisms.

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