Dose Of Reserpine Research Articles

Evaluation of reserpine-induced fibromyalgia in mice: A comparative behavioral, neurochemical, and histological assessment of two doses

Fibromyalgia (FM) is a chronic pain disorder characterised by widespread musculoskeletal pain, fatigue, and cognitive disturbances. Due to its complex and poorly understood pathophysiology, reliable animal models are essential for research. Reserpine is commonly used to induce FM in animals, effectively replicating key symptoms such as widespread pain, hypersensitivity, and mood disturbances. However, the varying doses used in studies and the often unclear rationale for dose selection have led to a lack of standardisation for this model. In this study, we investigated the effects of commonly used reserpine doses (0.25 and 0.5mg/kg) to induce FM in mice. Following three consecutive days of subcutaneous reserpine injections, we conducted detailed behavioural assessments and microscopic examinations of tissue changes. We also compared the effects of the two reserpine doses on serotonin, norepinephrine, glutamate, interleukin (IL)-1β, and tumour necrosis factor (TNF)-α levels in the brain and spinal cord. The behavioural assessment demonstrated that both doses of reserpine had nearly the same effect relatively early after administration. Histological examination revealed neurotoxic effects of reserpine, particularly in the hippocampus and thalamus, which was more obvious at day 11 with the 0.5mg/kg dose. Furthermore, this dose significantly altered all neurotransmitter levels compared with the control group. While the effect of the 0.25mg/kg dose on neurotransmitter levels was limited, it altered the IL-1β and TNF-α levels in the brain and spinal cord. Our findings indicate that injecting reserpine at 0.25 or 0.5mg/kg for three consecutive days is effective in inducing FM-like pain in mice, characterised by mechanical and thermal hypersensitivity, along with associated depression and motor deficits. However, the 0.5mg/kg dose is optimal for inducing persistent neurochemical alterations and histopathological changes, lasting up to 10 days following the initial injection.

Population Pharmacokinetic-Pharmacodynamic Analysis of a Reserpine-Induced Myalgia Model in Rats.

(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK-PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10-1 mL/h/kg). A precursor-pool PK-PD model (kin = 6.1 × 10-3 mg/h, kp = 8.6 × 10-4 h-1 and kout = 2.7 × 10-2 h-1) with a parallel transit chain (k0 = 1.9 × 10-1 h-1) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope1 = 1.1 × 10-1 h) and the elimination of MA (Slope2 = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (Cmax), 80% (Cmin), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.

Sleep deprivation induces late deleterious effects in a pharmacological model of Parkinsonism.

Parkinson's disease is a degenerative, chronic and progressive disease, characterized by motor dysfunctions. Patients also exhibit non-motor symptoms, such as affective and sleep disorders. Sleep disorders can potentiate clinical and neuropathological features and lead to worse prognosis. The goal of this study was to evaluate the effects of sleep deprivation (SD) in mice submitted to a progressive pharmacological model of Parkinsonism (chronic administration with a low dose of reserpine). Male Swiss mice received 20 injections of reserpine (0.1mg/kg) or vehicle, on alternate days. SD was applied before or during reserpine treatment and was performed by gentle handling for 6h per day for 10 consecutive days. Animals were submitted to motor and non-motor behavioral assessments and neurochemical evaluations. Locomotion was increased by SD and decreased by reserpine treatment. SD during treatment delayed the onset of catalepsy, but SD prior to treatment potentiated reserpine-induced catalepsy. Thus, although SD induced an apparent beneficial effect on motor parameters, a delayed deleterious effect on alterations induced by reserpine was found. In the object recognition test, both SD and reserpine treatment produced cognitive deficits. In addition, the association between SD and reserpine induced anhedonic-like behavior. Finally, an increase in oxidative stress was found in hippocampus of mice subjected to SD, and tyrosine hydroxylase immunoreactivity was reduced in substantia nigra of reserpine-treated animals. Results point to a possible late effect of SD, aggravating the deficits in mice submitted to the reserpine progressive model of PD.

Repeated reserpine treatment induces depressive-like behaviors accompanied with hippocampal impairment and synapse deficit in mice

Depression remains a significant public health concern, and current animal models of depression are limited in their ability to accurately mimic human depression. However, studying the new development of antidepressants requires the use of progressive animal models. In this study, the mice were exposed to a low dose of reserpine (0.5 mg/kg) once daily for 14 days, followed by a 14-day period to allow for the development of spontaneous depression. We have successfully established a repeated reserpine-induced depressive animal model, which was characterized by emotional symptoms (anhedonia), cognitive symptoms, and psychomotor agitation or retardation. Our study demonstrated that repeated treatment with low-dose reserpine increased immobility time in the TST and FST. It also decreased the sucrose consumption ratio and induced anxiety-like behaviors. These anxiety-like behaviors were evidenced by decreased time spent in the center zone, longer first latency to center zone, and fewer entries into the center zone in the open field test. These findings support the utility of the low-dose reserpine repeated injection animal model for studying the pathogenesis of depression and the development of novel antidepressant treatments. Additionally, this study provides valuable insights into the potential of low-dose reserpine as a tool for modeling chronic depression in animals. Furthermore, our findings suggest that prolonged low-dose reserpine treatment could result in chronic depression. These findings have significant implications for the use of reserpine as a therapeutic agent for various conditions and emphasize the importance of closely monitoring patients' mental health.

Cardamom oil ameliorates behavioral and neuropathological disorders in a rat model of depression induced by reserpine.

Depression is a public health problem. Despite the availability of treatment options, its prevalence is increasing. A high rate of treatment failure is often reported, along with considerable side effects associated with synthetic antidepressants. Therefore, developing effective and safe antidepressants from traditional herbs or natural products as an alternative strategy is warranted to avoid side effects and increase drug efficacy. In traditional medicine, cardamom has traditionally been used to treat conditions like asthma, tooth and gum infections, cataracts, nausea, diarrhea, and even depression and anxiety as well as some problems with the heart, kidneys, and digestive system. The current study aimed to evaluate the antidepressant activity of cardamom oil in a rat model of depression induced by reserpine and compare it with the activity of the antidepressant drug fluoxetine. Depression-like symptoms were induced in male rats by daily i. p. injection of reserpine (0.2mg/kg/d for 15d followed by 0.1mg/kg/d for 21d to maintain the depressive state), and the rats were treated with cardamom oil (oral dose=200mg/kg/d) for 21d along with the maintenance dose of reserpine. We performed behavioral tests (forced swimming test and open-field test) and evaluated biochemical markers of depression. Our findings revealed that cardamom oil attenuated depression-like symptoms in reserpine-injected rats by improving the behavioral changes measured by the forced swimming test and the locomotor activities measured by the open-field test. In reserpine-injected rats, cardamom oil exerted antidepressant-like effects by modulating lower levels of brain monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), GSH, and higher oxido-nitrosative stress parameters (malondialdehyde and nitric oxide). Moreover, cardamom oil alleviated depression-like behaviors by lowering monoamine oxidase activity and raising the activities of Na+/K+-ATPase and acetylcholinesterase and levels of a brain-derived neurotrophic factor in the cortex and hippocampus. We recommend the use of cardamom oil as a safe and reliable treatment or an adjuvant for preventing depression-like symptoms in patients suffering from depression.

Genetic effects in a progressive model of parkinsonism induced by reserpine

We investigated the locomotor, emotional, physiological, and neurobiological effects induced by low-dose reserpine repeated treatment (0.1mg/kg; 14 injections) in males from the Lewis (LEW), Spontaneously Hypertensive Rats (SHR), and SHR.LEW-(D4Rat76-D4Mgh11) (SLA16) isogenic rat strains, which have different genetic backgrounds on chromosome 4. Behavioral responses in the catalepsy, open-field, and oral movements' tests were coupled with blood pressure, body weight, and striatal tyrosine hydroxylase (TH) level assessments to establish neurobiological comparisons between reserpine-induced impairments and genetic backgrounds RESULTS: Results revealed the SHR strain was more sensitive in the catalepsy test and exhibited higher TH immunoreactivity in the dorsal striatum. The SLA16 strain presented more oral movements, suggesting increased susceptibility to develop oral dyskinesia. Our results showed the efficacy of repeated treatment with a low dose of reserpine and demonstrated, for the first time, the genetic influence of a specific region of chromosome 4 on the expression of these effects.

Neuroinflammation in early, late and recovery stages in a progressive parkinsonism model in rats.

Parkinson’s disease (PD) is characterized by motor and non-motor signs, which are accompanied by progressive degeneration of dopaminergic neurons in the substantia nigra. Although the exact causes are unknown, evidence links this neuronal loss with neuroinflammation and oxidative stress. Repeated treatment with a low dose of reserpine—inhibitor of VMAT2—has been proposed as a progressive pharmacological model of PD. The aim of this study was to investigate whether this model replicates the neuroinflammation characteristic of this disease. Six-month-old Wistar rats received repeated subcutaneous injections of reserpine (0.1 mg/kg) or vehicle on alternate days. Animals were euthanized after 5, 10, or 15 injections, or 20 days after the 15th injection. Catalepsy tests (motor assessment) were conducted across treatment. Brains were collected at the end of each treatment period for immunohistochemical and RT-PCR analyzes. Reserpine induced a significant progressive increase in catalepsy duration. We also found decreased immunostaining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc) and increased GFAP + cells in the SNpc and dorsal striatum after 10 and 15 reserpine injections. Phenotyping microglial M1 and M2 markers showed increased number of CD11b + cells and percentage of CD11b + /iNOS + cells in reserpine-treated animals after 15 injections, which is compatible with tissue damage and production of cytotoxic factors. In addition, increased CD11b + /ArgI + cells were found 20 days after the last reserpine injection, together with an increment in IL-10 gene expression in the dorsal striatum, which is indicative of tissue repair or regeneration. Reserpine also induced increases in striatal interleukin TNF-alpha mRNA levels in early stages. In view of these results, we conclude that reserpine-induced progressive parkinsonism model leads to neuroinflammation in regions involved in the pathophysiology of PD, which is reversed 20 days after the last injection. These findings reveal that withdrawal period, together with the shift of microglial phenotypes from the pro-inflammatory to the anti-inflammatory stage, may be important for the study of the mechanisms involved in reversing this condition, with potential clinical applicability.

Female Rats Are Resistant to Cognitive, Motor and Dopaminergic Deficits in the Reserpine-Induced Progressive Model of Parkinson's Disease.

Parkinson’s disease (PD) is the second most common neurodegenerative disease. The main symptoms are motor signs such as resting tremor and difficulty in initializing movements. Non-motor alterations, such as cognitive deficits, can precede the motor symptoms. PD is more frequent in men than women. The mechanisms related to this difference are not completely understood. There is evidence that females present distinct characteristics in dopaminergic function compared to males. While the severity of motor impairments is often compared between sexes, little is known about sex differences in the prodromal stage. Most animal models of PD present acute severe motor impairment, which precludes the study of non-motor symptoms. Our research group have proposed an adaptation of the classic reserpine protocol, using low doses in a chronic treatment. This method allows the observation of progressive motor impairment as well as premotor deficits. Here we investigate possible behavioral and neuronal sex differences in the effects of the repeated treatment with a low dose of reserpine in rats. Male and female Wistar rats received 10–15 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. We followed-up the estrous cycle phases and conducted motor and cognitive assessments (catalepsy, open field, oral movements and object recognition tests). The euthanasia occurred 48 h after the 10th or 15th injections, with the collection of blood for the quantification of sex hormones and brains for tyrosine hydroxylase (TH) immunohistochemistry in the substantia nigra pars compact (SNpc). Reserpine induced progressive catalepsy, involuntary oral movements and cognitive deficits in male rats. The behavioral effects of reserpine were attenuated (motor) or absent (cognitive) in females. Reserpine decreased TH immunoreactivity in males, but not in females. Estrogen levels in females negatively correlated with catalepsy duration. Our findings show that females present a delay and/or a prevention in the reserpine-induced motor alterations in the progressive PD model, compatible with the lower prevalence of this disease in women. Further, females were protected from the deficit in object recognition at the prodromal stage. The absence of reserpine-induce decrease in TH immunoreactivity suggests that differences in dopaminergic function/plasticity are related to this protection in female sex.

Antidepressant and antioxidant effects of transcranial irradiation with 830-nm low-power laser in an animal model of depression.

The present study aimed at investigating the antidepressant and antioxidant actions of near-infrared (NIR) laser at a wavelength of 830nm and power of 100 mW which applied transcranially on an animal model of depression induced by repeated doses of reserpine (0.2mg/kg). Thirty male Wistar adult rats were divided into three groups: rat model of depression; rat model of depression irradiated with laser for 14days after induction of depression; and the control group that was given the drug vehicle and sham-exposed to the laser. Forced swimming test (FST) was used to verify the induction of animal model of depression and to screen the effect of antidepressant effect of low-level laser at the end of the experiment. Monoamine level, oxidative stress markers, and activities of acetylcholinesterase (AchE) and monoamine oxidase (MAO) were determined in the cortex and hippocampus of the rat brain. Reserpine resulted in depletion of monoamines and elevation in the oxidative stress markers and change in the enzymatic activities measured in both brain areas. Laser irradiation has an inhibitory action on the monoamine oxidase (MAO) in the cortex and hippocampus leading to elevation of the monoamine levels and attenuation of the oxidative stress in the studied areas. FST has emphasized the antidepressant effect of the utilized laser irradiation parameters on the behavioral level. The present findings provide evidence for the antidepressant and antioxidant actions of NIR low-power laser in the rat model of depression. Accordingly, low-laser irradiation may be presented as a potential candidate modality for depression treatment.

Changes in the mesocorticolimbic pathway after low dose reserpine-treatment in Wistar and Spontaneously Hypertensive Rats (SHR): Implications for cognitive deficits in a progressive animal model for Parkinson’s disease

Reserpine (RES) is an irreversible inhibitor of VMAT2 used to study Parkinson’s disease (PD) and screening for antiparkinsonian treatments in rodents. Recently, the repeated treatment with a low dose of reserpine was proposed as a model capable of emulating progressive neurochemical, motor and non-motor impairments in PD. Conversely, compared to Wistar rats, Spontaneously Hypertensive Rats (SHR) are resistant to motor changes induced by repeated treatment with a low dose of RES. However, such resistance has not yet been investigated for RES-induced non-motor impairments. We aimed to assess whether SHR would have differential susceptibility to the object recognition deficit induced by repeated low-dose reserpine treatment. We submitted male Wistar and SHR rats to repeated RES treatment (15 s.c. injections of 0.1 mg/kg, every other day) and assessed object memory acquisition and retrieval 48 h after the 6th RES injection (immediately before the appearance of motor impairments). Only RES Wistar rats displayed memory impairment after reserpine treatment. On the other hand, untreated SHR rats displayed object recognition memory deficit, but RES treatment restored such deficits. We also performed immunohistochemistry for tyrosine hydroxylase (TH) and α-synuclein (α-syn) 48 h after the last RES injection. In a different set of animals submitted to the same treatment, we quantified DA, 5-HT and products of lipid peroxidation in the prefrontal cortex (PFC) and hippocampus (HPC). SHR presented increased constitutive levels of DA in the PFC and reduced immunoreactivity to TH in the medial PFC and dorsal HPC. Corroborating the behavioral findings, RES treatment restored those constitutive alterations in SHR. These findings indicate that the neurochemical, molecular and genetic differences in the SHR strain are potentially relevant targets to the study of susceptibility to diseases related to dopaminergic alterations.

A REVIEW ON POTENTIAL BIOACTIVE CHEMICAL FROM RAUWOLFIA SERPENTINA: RESERPINE

The drug Rauwolfia serpentina is known to Indian system of medicine since last many centuries. Because of snake like shape of drug, it has been known as sarpgandha. Although Rauwolfia serpentina contain more than 50 alkaloids but Reserpine is the principal alkaloid of Rauwolfia serpentina. Reserpine has a success application in antihypertensive even at a smaller dose. Rhizomes of Rauwolfia serpentine also have hepatoprotective activity including antihypertensive, hepatoprotective, Rauwolfia serpentina have many other medicinal uses like: Antidiahoerreal, antipsychotic, sedative, anticancer (in breast) etc. Although Rauwolfia serpentina contains major four Indole alkaloids but main object of this context is to provide knowledge about the main active alkaloid Reserpine, having more concentration in the root of plant, play a major role in antihypertensive activity of Rauwolfia serpentina. A much lesser dose of Reserpine is required to provide an antihypertensive effect otherwise it can cause some serious adverse effect like- lethargy, sedation, psychiatric depression, hypotension, nausea, bradycardia, bronchospasm and withdrawal psychosis. Because of its potent activity Reserpine is still used as antihypertensive and sedative agent.

Perturbations in Amino Acid Metabolism in Reserpine-Treated Zebrafish Brain Detected by 1H Nuclear Magnetic Resonance-Based Metabolomics.

Depression is a complex and disabling psychiatric disorder, which is expected to be a leading cause for disability by 2030. According to World Health Organization, about 350 million people are suffering with mental health disorders around the globe, especially depression. However, the mechanisms involved in stress-induced depression have not been fully elucidated. In this study, a stress-like state was pharmacologically induced in zebrafish using reserpine, a drug widely used to mediate depression in experimental animal models. Zebrafish received single intraperitoneal (i.p.) injections of 20, 40, and 80 mg/kg body weight reserpine doses and were subjected to open-field test at 2, 24, 48, 72, and 96 h after the treatment. Along with observed changes in behavior and measurement of cortisol levels, the fish were further examined for perturbations in their brain metabolites by 1H nuclear magnetic resonance (NMR)-based metabolomics. We found a significant increase in freezing duration, whereas total distance travelled was decreased 24 h after single intraperitoneal injection of reserpine. Cortisol level was also found to be higher after 48 h of reserpine treatment. The 1H NMR data showed that the levels of metabolites such as glutamate, glutamine, histamine, valine, leucine and histidine, lactate, l-fucose, betaine and γ-amino butyric acid (GABA), β-hydroxyisovalerate, and glutathione were significantly decreased in the reserpine-treated group. This study provided some insights into the molecular nature of stress that could contribute toward a better understanding of depression disorder.

Antidepressant-like effects of barley (Hordeum vulgare) in a mouse model of reserpine-induced depression

Background: Depression is a mental disorder characterized by low mood and loss of pleasure or interest in usual activities and often results in cognitive dysfunction such as impairment of learning and memory. For most of the synthetic antidepressants, severe defects such as narrow spectrum, adverse reactions, high drug price, and easy recurrence exist. Barley is one of the richest sources of antioxidants; therefore, we examined whether barley has an effect on depression, learning, and memory in a mouse model of reserpine-induced depression. Methods: Mice were individually acclimated for 1 week and then treated with barley (200 mg/kg, p. o.) or/and fluoxetine (20 mg/kg, i. p.) for 4 weeks prior to reserpine treatment. Mice were then injected with a single dose of reserpine (2 mg/kg, i. p.) or vehicle (20 mg/kg, i. p.) and assessed for mouse behaviors 1 h prior to tests. Mouse behavior was examined in the forced swimming test, tail suspension test, hole-board test, novel place/object recognition, social interaction test, spontaneous locomotor movement (SLMA), and stereotype movement following completion of the treatment protocol. Results: There was a significant antidepressant-like effect in the forced swimming test among the barley group than in the reserpine-treated group, and these decreases were significantly attenuated to a similar extent by treatment with fluoxetine. The effect of barley on the mean duration of immobility time was significantly attenuated in comparison with the reserpine group (P

Risk of Developing Hepatocellular Carcinoma following Depressive Disorder Based on the Expression Level of Oatp2a1 and Oatp2b1.

Background Accumulating evidence from prospective epidemiological studies has showed that depression disorder (DD) is a risk factor for cancer. The aim of this study is to explore the association of DD and the overall occurrence risk of hepatocellular carcinoma (HCC) and the mechanism. Methods In this study, 60 mice were randomly divided into four groups: Control group, DD group, HCC group, HCC-DD group. Mice received a chronic dose of reserpine to establish depression model, followed by Diethylnitrosamine and Carbon tetrachloride administration to establish HCC models. Behavioral depression was assessed by sucrose preference test (SPT) and the expression of Serotonin 1A (5-HT1A) receptor in the hippocampal. The expression of Oatp2a1 and Oatp2b1 in the digestive system tissues was detected by PCR and western blotting. Results Reserpine-administrated mice had a reducing sucrose preference at Day 14 compared with blank mice (P<0.05). The expression of 5-HT1A receptor in the hippocampal was decreased in DD mice compared with blank mice. The survival analysis indicated that the HCC mice with DD have poorer survival rate compared with the HCC mice. Compared with HCC mice, the expression of Oatp2a1 and Oatp2b1 was lower in liver and stomach tissue and higher in hepatic carcinoma and colon tissue of HCC-DD mice (P<0.05), and the expression of Oatp2a1 was higher in the spleen tissue of HCC-DD mice while the expression of Oatp2b1 was lower (P<0.05). However, no difference was found in the expression of Oatp2a1 and Oatp2b1 in the small intestine tissue between HCC group and HCC-DD group. Conclusions DD was the adverse factors for the overall occurrence risk of HCC. Mechanistically, be the downregulation of Oatp2a1 and Oatp2b1 in liver tissue induced by DD might be involved.

Sex differences in the progressive model of parkinsonism induced by reserpine in rats

Parkinson's disease (PD) exhibits sexual differences in susceptibility and pathogenesis in humans, with a high incidence in men and a high severity of motor symptoms in male rodents. Furthermore, studies showed that the administration of low dose of reserpine (RES) induces a progressive appearance of motor alterations similar with parkinsonism in male rodents. Here, we investigated sex differences in motor deficits and tyrosine hydroxylase (TH) immunoreactivity induced by a progressive model of parkinsonism. Gonadally intact male and female Wistar rats and ovariectomized female rats received 15 subcutaneous injections (s.c.) every other day of 0.1 mg/kg of RES or vehicle. The repeated administration of low doses of RES (0.1 mg/kg) produces sexually dimorphic impairments on motor performance (catalepsy and open field test). Intact and ovariectomized females were more resistant to the deleterious effect of repeated administration of reserpine in the early, but this resistance in intact female disappears over time. However, intact females showed a reduction of the TH immunoreactivity in substantia nigra pars compacta, but not in ventral tegmental area and dorsal striatum. These results suggest a possible application of this model in the study of sexual dimorphism throughout the progression of PD.

Cognitive and anxiety-like impairments accompanied by serotonergic ultrastructural and immunohistochemical alterations in early stages of parkinsonism

Parkinson’s disease (PD) is mostly known as a dopamine deficiency syndrome due the structural and functional changes in striatal projection neurons. However, studies have considered this pathology as a multi-systemic disease in which the neurodegenerative process extends beyond the dopaminergic system. Therefore, the purpose of the present study was to investigate the morphological and immunohistochemical changes associated with behavioral and cognitive alterations in a model of parkinsonism induced by low dose of reserpine. Animals showed anxiety–like behavior and deficits in short-term recognition memory. Besides, Tyrosine Hydroxylase (TH) immunoreactive cells decreased in reserpine (RES) group in CA1 and serotonin (5-HT) immunoreactive cells decreased in RES group in CA1, CA3 and medial prefrontal cortex (mPFC). Moreover, an increase in the area (μm2) of 5 H T labeled ultrastructure (axon terminal) was observed in RES group only in CA1 and mPFC. The evidence of alterations in 5-HT immunoreactive in the premotor phase of model of parkinsonism highlights the importance of looking beyond the nigrostriatal system to elucidate the underling mechanisms and deficits in other neurotransmitters systems. This provides vital information regarding novel interventions for the management of non-motor symptoms. Additionally, the low-dose reserpine treatment has an early effect on axonal ultrastructure. As the axonopathy in PD has been increasingly recognized, the focus on axonal neurobiology is noteworthy for both neuroprotective and restorative therapeutics, and the progressive reserpine rat model can be a useful tool in this search.

Serotonergic dysfunction in a model of parkinsonism induced by reserpine

Parkinson’s disease (PD) is mainly characterized by a dopamine deficiency accompanied by structural and functional changes in striatal neuronal projections. However, studies have considered PD as a multi-systemic disease in which the neurodegenerative process extends beyond the dopaminergic system. Therefore, the purpose of the present study was to investigate the time-course of serotonergic neuron damage in a progressive model of parkinsonism induced by a low dose of reserpine. Thus, male Wistar rats received 4 (ST, short-treatment of reserpine) or 10 (MT, middle-term treatment of reserpine) subcutaneous injections of vehicle or reserpine (0.1 mg/kg) at a volume of 1 mL/kg body weight, on alternate days. Animals were euthanized 48 h after the last injection for immunohistochemical analysis. After ST, 5-HT immunoreactivity decreased in hippocampal subareas (CA1 and CA3) and medial prefrontal cortex (mPFC) compared to vehicle. Furthermore, animals MT-treated also showed progressive decrease of 5-HT immunoreactivity in CA1 and CA3 subareas. Conversely, a significant increase of 5-HT immunoreactivity was found in mPFC and dorsal raphe nucleus (DRN) in animals submitted to MT when compared to ST exposure. The results showed that, in the repeated low-dose reserpine rat model, variations in the immunoreactivity of 5-HT start early in the course of progressive parkinsonism.

Monoamine system disruption induces functional somatic syndromes associated symptomatology in mice.

Functional somatic syndromes (FSS), a clinical condition manifesting a variety of unexplained somatic symptoms, has been proposed as an inclusive nosology encompassing individual syndromes such as fibromyalgia syndrome and irritable bowel syndrome. Accumulating evidence suggests that disturbance of the endogenous monoamine system could be involved in the aetiology of FSS. Therefore, the purpose of present study was to investigate whether the disturbance of the monoamine system would cause FSS-associated symptomatology in mice. The optimal dose of reserpine, an inducer of endogenous monoamines reduction, was first explored in mice. General body condition (body weight, rectal temperature, and ptosis) and FSS-associated symptomatology (paw withdrawal threshold, small intestinal transit, and locomotor activity) were measured. The concentration of monoamines was measured in central and peripheral tissues. Mice dosed with reserpine (0.25 mg/kg s.c., once daily for 3 consecutive days) exhibited a decrease in paw withdrawal threshold, delay in small intestinal transit, and reduction of locomotor activity without deterioration of general body condition on day 5 after the first reserpine injection. The concentration of monoamines was decreased in the central nervous system and skeletal muscle, but not in the small intestine. A reserpine dose of 0.5 mg/kg or more caused deterioration of general body condition. In conclusion, the optimal protocol of reserpine treatment for inducing pain symptom without deterioration of general physical condition is 0.25 mg/kg s.c., once daily for 3 consecutive days in mice. This protocol causes not only pain but also FSS-associated symptomatology which are associated with disruption of the endogenous monoamine system. The reserpine-treated animal may be useful for the research of not only fibromyalgia syndrome but also FSS, especially for the research focusing on the hypothesis that FSS is associated with the disturbance of endogenous monoamine system.

Antidopaminergic medication in healthy subjects provokes subjective and objective mental impairments tightly correlated with perturbation of biogenic monoamine metabolism and prolactin secretion.

ObjectivesOff-label prescription of antipsychotics to patients without psychotic symptoms has become a routine matter for many psychiatrists and also some general practitioners. Nonetheless, little is known about the possibly detrimental effects of antidopaminergic medications on general psychopathology, subjective mental state, or a possible association with physiological parameters in nonpsychotic individuals.MethodsIn this randomized, single-blinded study, groups of healthy volunteers (n=18) received low doses of reserpine, aripiprazole, haloperidol, or placebo on 7 successive days. Relevant physiological parameters (plasma prolactin, concentrations of catecholamine metabolites in plasma, and 24-hour urine) and each subject’s mental state (Positive and Negative Syndrome Scale, Hamilton Rating Scale for Depression, visual analogue scale, Beck Depression Inventory II) were assessed at the start and end of the trial.ResultsOf the three active treatments, only reserpine caused a significant increase in some plasma- and urine-catecholamine metabolites, but all three medications evoked objective and subjective changes in general psychopathology scores, which correlated with individual increases in plasma homovanillic acid concentrations. Both objective and subjective impairments were significantly more pronounced in the subgroup with greatest increase of plasma prolactin. Subjects experiencing the most pronounced side effects under haloperidol, which compelled them to drop out, showed significantly higher prolactin concentration increases than those who tolerated haloperidol well.ConclusionWe found consistent associations between altered markers of dopamine transmission and several objective and subjective mental impairments in healthy volunteers after 1 week’s treatment with antidopaminergic medications. These findings should draw attention to a more intensive risk–benefit evaluation in cases of off-label prescription of antipsychotic medications.

Antidepressant-like effect of active fraction of Polyrhachisvicina Roger in a rat depression model

OBJECTIVETo investigate the antidepressant-like effect of active fraction of Polyrhachis vicina Roger (AFPR) in a rat depression model, and to elucidate the underlying mechanism. METHODSAFPR was extracted with ethanol followed by petroleum ether. Its antidepressant-like effect was investigated in mice by tail suspension test (TST), forced swimming test (FST) and open field test (OPT). A repeated dose of reserpine (0.5 mg/kg, daily for 14 d) was used to establish a rat depression model. Fluoxetine was used as positive control agent. The effect of AFPR on reserpine-induced ptosis, hypothermia and akinesia, the levels of monoamines and their metabolites, and the activity of monoamine oxidase (MAO) in hippocampus and prefrontal cortex were determined. RESULTSAdministration of AFPR by gavage at 160 and 320 mg/kg significantly reduced the duration of immobility in the FST and TST, and did not affect locomotor activity in the OPT. In the reserpine-induced depression model, AFPR attenuated anhedonia, demonstrated by reversing hypothermia, akinesia and sucrose consumption. AFPR significantly increased the concentration of monoamines, including dopamine, serotonin, noradrenaline and acetylcholine. CONCLUSIONAFPR normalized the metabolism rates of noradrenaline, serotonin and dopamine, and the activity of MAO, which were altered by chronic reserpine exposure. The findings suggest that modulation of the monoaminergic neurotransmitter system likely underlies the antidepressant-like effect of AFPR.