ABSTRACT
Microglial activation has been associated to the physiopathology of neurodegenerative diseases, such as schizophrenia, and can occur during inflammation and oxidative stress. Pharmacological treatment is associated with severe side effects, and studies for use of plant extracts may offer alternatives with lower toxicity. Harpagophytum procumbens (HP) is a plant known for its anti-inflammatory properties. In the present study, we characterized the ethyl acetate fraction of HP (EAF HP) by ESI-ToF-MS and investigated the effects EAF HP in a lipopolysaccharide (LPS) induced inflammation model on microglial cells (BV-2 lineage). MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), DCFH-DA (2',7'-dichlorofluorescein diacetate) and cell cycle flow cytometer analysis were performed. In vivo was investigated the amphetamine-induced psychosis model through behavioral (locomotor and exploratory activities, stereotypies and working memory) and biochemical (DCFH-DA oxidation and protein thiols) parameters in cortex and striatum of mice. EAF HP reduced activation and proliferation of microglial cells in 48 h (300 µg/mL) and in 72 h after treatments (50-500 µg/mL). Reactive oxygen species levels were lower at the concentration of 100 µg/mL EAF HP. We detected a modulatory effect on the cell cycle, with reduction of cells in S and G2/M phases. In mice, the pre-treatment with EAF HP, for 7 days, protected against positive and cognitive symptoms, as well as stereotypies induced by amphetamine. No oxidative stress was observed in this amphetamine-induced model of psychosis. Such findings suggest that EAF HP can modulate the dopaminergic neurotransmission and be a promising adjuvant in the treatment of locomotor alterations, cognitive deficits, and neuropsychiatric disorders.
Subject(s)
Harpagophytum , Animals , Mice , Amphetamine/pharmacology , Harpagophytum/chemistry , Inflammation/drug therapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plant Extracts/chemistry , Oxidative StressABSTRACT
Schizophrenia (SCZ), a multifactorial neuropsychiatric disorder, is treated with inefficient antipsychotics and linked to poor treatment outcomes. This study, therefore, investigated the combined administration of prodigiosin (PDG) and selenium (Na2SeO3) against SCZ induced by amphetamine (AMPH) in rats. Animals were allocated into four groups corresponding to their respective 7-day treatments: control, AMPH (2 mg/kg), PDG (300 mg/kg) + Na2SeO3 (2 mg/kg), and AMPH + PDG + Na2SeO3. The model group exhibited biochemical, molecular, and histopathological changes similar to those of the SCZ group. Contrastingly, co-administration of PDG and Na2SeO3 significantly increased the time for social interaction and decreased AChE and dopamine. It also downregulated the gene expression of NMDAR1 and restored neurotrophin (BDNF and NGF) levels. Further, PDG combined with Na2SeO3 improved the antioxidant defence of the hippocampus by boosting the activities of SOD, CAT, GPx, and GR. These findings were accompanied by an increased GSH, alongside decreased MDA and NO levels. Furthermore, schizophrenic rats having received PDG and Na2SeO3 displayed markedly lower IL-1ß and TNF-α levels compared to the model group. Interestingly, remarkable declines in the Bax (pro-apoptotic) and increases in Bcl-2 (anti-apoptotic) levels were observed in the SCZ group that received PDG and Na2SeO3. The hippocampal histological examination confirmed these changes. Collectively, these findings show that the co-administration of PDG and Na2SeO3 may have a promising therapeutic effect for SCZ. This is mediated by mechanisms related to the modulation of cholinergic, dopaminergic, and glutaric neurotransmission and neurotrophic factors, alongside the suppression of oxidative damage, neuroinflammation, and apoptosis machinery.
Subject(s)
Selenium , Rats , Animals , Selenium/pharmacology , Prodigiosin , Antioxidants/pharmacology , Oxidative Stress , Amphetamine/pharmacology , Dietary SupplementsABSTRACT
RATIONALE: Synthetic phenethylamine (PEA) analogs, such as ß-methylphenethylamine (BMPEA) and N,α-diethylphenethylamine (DEPEA), are often found in dietary supplements, despite regulations prohibiting their sale. PEA analogs are structurally related to amphetamine, and we have shown that BMPEA and DEPEA produce cardiovascular stimulation mimicking the effects of amphetamine. However, few studies have examined behavioral effects of BMPEA, DEPEA, and other PEA analogs. OBJECTIVES: Here, we examined the reinforcing effects of α-ethylphenethylamine (AEPEA, 1 mg/kg/injection), DEPEA (1 mg/kg/injection), and BMPEA (3 mg/kg/injection) as compared to amphetamine (0.1 mg/kg/injection) using a fixed-ratio 1 self-administration paradigm in male rats. METHODS: Male rats were trained in self-administration chambers containing 2 nose-poke holes. A nose-poke response in the active hole delivered drug or saline, whereas a nose-poke response in the inactive hole had no programmed consequence. Four groups of rats were initially trained for 10 days with the doses noted above. Upon acquisition of drug self-administration, a dose-effect function was determined by training rats on 3 additional doses for 3 days each. A separate group of rats was trained with saline. RESULTS: Male rats self-administered each PEA analog and amphetamine, as shown by significant increases in active responses versus inactive responses. Subsequent dose-response testing showed clear differences in potency of the compounds. Amphetamine showed a typical inverted U-shaped dose-effect function, peaking at 0.1 mg/kg/injection. AEPEA and DEPEA also showed inverted dose-effect functions, with each peaking at 0.3 mg/kg/injection. BMPEA did not show an inverted U-shaped dose-effect function, but active responding slowly increased up to a dose of 6 mg/kg/injection. CONCLUSIONS: Taken together, our findings indicate that dietary supplements containing PEA analogs may have significant abuse liability when used recreationally.
Subject(s)
Amphetamine , Phenethylamines , Rats , Male , Animals , Rats, Sprague-Dawley , Amphetamine/pharmacology , Phenethylamines/pharmacology , Self Administration , Dietary Supplements , Dose-Response Relationship, DrugABSTRACT
Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered a prodromal model of SZ, suitable for studying psychotic conversion. We evaluated the preventive effect of chronic N-acetylcysteine (NAC) administration, covering the prenatal era to adulthood, on the reaction following the Amph challenge, which mimics the outbreak or conversion of psychosis, in adult Het Disc1 mice. Biochemical and morphological features were examined in the striatum of NAC-treated mice. Chronic NAC treatment normalized the Amph-induced activity in the Het Disc1 mice. Furthermore, the striatal phenotypes of Het Disc1 mice were rescued by NAC including dopamine receptors, the expression of GSK3s, MSN dendritic impairments, and striatal PV density. The current study demonstrated a potent preventive effect of chronic NAC treatment in Disc1 Het mice on the acute Amph test, which mimics the outbreak of psychosis. Our findings not only support the benefit of NAC as a dietary supplement for SZ prodromes, but also advance our knowledge of striatal dopamine receptors, PV neurons, and GSK3 signaling pathways as therapeutic targets for treating or preventing the pathogenesis of mental disorders.
Subject(s)
Amphetamine , Schizophrenia , Acetylcysteine/pharmacology , Amphetamine/pharmacology , Animals , Disease Models, Animal , Dopamine/metabolism , Female , Glycogen Synthase Kinase 3 , Humans , Mice , Nerve Tissue Proteins , Pregnancy , Receptors, Dopamine , Schizophrenia/drug therapy , Schizophrenia/genetics , Schizophrenia/prevention & controlABSTRACT
The orexin neuropeptides have an important role in the regulation of the sleep/wake cycle and foraging, as well as in reward processing and emotions. Furthermore, recent research implicates the orexin system in different behavioral endophenotypes of neuropsychiatric diseases such as social avoidance and cognitive flexibility. Utilizing orexin-deficient mice, the present study tested the hypothesis that orexin is involved in two further mouse behavioral endophenotypes of neuropsychiatric disorders, i.e., sensorimotor gating and amphetamine sensitivity. The data revealed that orexin-deficient mice expressed a deficit in sensorimotor gating, measured by prepulse inhibition of the startle response. Amphetamine treatment impaired prepulse inhibition in wildtype and heterozygous orexin-deficient mice, but had no effects in homozygous orexin-deficient mice. Furthermore, locomotor activity and center time in the open field was not affected by orexin deficiency but was similarly increased or decreased, respectively, by amphetamine treatment in all genotypes. These data indicate that the orexin system modulates prepulse inhibition and is involved in mediating amphetamine's effect on prepulse inhibition. Future studies should investigate whether pharmacological manipulations of the orexin system can be used to treat neuropsychiatric diseases associated with deficits in sensorimotor gating, such as schizophrenia or attention deficit hyperactivity disorder.
Subject(s)
Amphetamine , Sensory Gating , Acoustic Stimulation , Amphetamine/pharmacology , Animals , Mice , Orexins/genetics , Prepulse Inhibition , Reflex, Startle , Sensory Gating/physiologyABSTRACT
The subthalamic nucleus (STN) is a key node in cortico-basal-ganglia thalamic circuits, guiding behavioral output through its position as an excitatory relay of the striatal indirect pathway and its direct connections with the cortex. There have been conflicting results regarding the role of the STN in addiction-related behavior to psychostimulants, and little is known with respect to the role of STN afferents. To address this, we used viral vectors to express DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in the STN of rats in order to bidirectionally manipulate STN activity during the induction of amphetamine sensitization. In addition, we used a Cre-recombinase dependent Gi/o-coupled DREADD approach to transiently inhibit afferents from ventral pallidum (a subcomponent of the striatal indirect pathway) or the prelimbic cortex (a subcomponent of the cortico-STN hyperdirect pathway). Despite inducing mild hyperactivity in non-drug controls, stimulation of STN neurons with Gq-DREADDs blocked the development and persistence of amphetamine sensitization as well as conditioned responding. In contrast, inhibition of STN neurons with Gi/o-DREADDs enhanced the induction of sensitization without altering its persistence or conditioned responding. Chemogenetic inhibition of afferents from ventral pallidum had no effect on amphetamine sensitization but blocked conditioned responding whereas chemogenetic inhibition of afferents from prelimbic cortex attenuated the persistence of sensitization as well as conditioned responding. These results suggest the STN and its afferents play complex roles in the regulation of amphetamine sensitization and highlight the need for further characterization of how integration of inputs within STN guide behavior.
Subject(s)
Basal Forebrain , Central Nervous System Stimulants , Subthalamic Nucleus , Amphetamine/pharmacology , Animals , Central Nervous System Stimulants/pharmacology , Neural Pathways , Rats , ThalamusABSTRACT
Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.
Subject(s)
Amphetamine/pharmacology , Carbamates/pharmacology , Corpus Striatum/drug effects , Disorders of Excessive Somnolence/drug therapy , Feeding Behavior/drug effects , Locomotion/drug effects , Modafinil/pharmacology , Phenylalanine/analogs & derivatives , Piperidines/pharmacology , Wakefulness-Promoting Agents/pharmacology , 3,4-Dihydroxyphenylacetic Acid/metabolism , Adrenergic Uptake Inhibitors/pharmacology , Animals , Corpus Striatum/metabolism , Disorders of Excessive Somnolence/etiology , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/drug effects , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/pharmacology , Drug Evaluation, Preclinical , Drug Inverse Agonism , Histamine Antagonists/pharmacology , Mice , Narcolepsy/drug therapy , Neostriatum/drug effects , Neostriatum/metabolism , Norepinephrine Plasma Membrane Transport Proteins/drug effects , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Phenylalanine/pharmacology , Receptors, Histamine H3 , Sleep Apnea, Obstructive/complicationsABSTRACT
Schizophrenia modeling by disrupting prepulse inhibition (PPI) is one of the most frequently used psycho-pharmacological methods by administering pharmacological agents to stimulate disruption. However, since PPI is also a biological indicator of schizophrenia, it is possible to classify subjects based on their basal PPI values and group them as "low inhibition" and "high inhibition without taking any pharmacological agent. Therefore this study was conducted to show that rats can be divided into groups in terms of susceptibility to schizophrenia according to basal PPI values. It was also observed that these groups might give different responses to different pharmacological agents (apomorphine, amphetamine, MK-801, scopolamine, nicotine, caffeine). Male Sprague Dawley rats (250-350â¯g) were used in the study. To examine the effects of different pharmacological agents on the groups, apomorphine (0.5â¯mg/kg and 1â¯mg/kg), amphetamine (4â¯mg/kg), MK-801 (0.05â¯mg/kg and 0.15â¯mg/kg), scopolamine (0.4â¯mg/kg), nicotine (1â¯mg/kg) and caffeine (10â¯mg/kg and 30â¯mg/kg) were used. Amphetamine showed a disruptive effect on PPI in both low and high inhibitory groups, while apomorphine, MK-801, scopolamine, and nicotine showed PPI decrease only in the high inhibitory group. Besides, caffeine decreased PPI levels at two doses in the high inhibitory group; however, 10â¯mg/kg dose caffeine was increased only in the low inhibitory group. According to the data obtained from this study, rats can be grouped with baseline inhibition values by using PPI, and response differences of pharmacological agents to groups may vary.
Subject(s)
Central Nervous System Stimulants/pharmacology , Cholinergic Antagonists/pharmacology , Dopamine Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Nicotinic Agonists/pharmacology , Prepulse Inhibition/drug effects , Acoustic Stimulation/methods , Amphetamine/pharmacology , Animals , Apomorphine/pharmacology , Caffeine/pharmacology , Dizocilpine Maleate/pharmacology , Male , Nicotine/pharmacology , Prepulse Inhibition/physiology , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects , Reflex, Startle/physiology , Scopolamine/pharmacologyABSTRACT
Prepulse inhibition (PPI) refers to the modulation of the startle response by the presentation of a weaker stimulus prior to the onset of the startle stimulus. This response is consolidated along the maturation process of the mesocortical system, where the dopamine neurotransmitter plays an important role. In fact, it has been reported that agonist and antagonist dopaminergic drugs are able to change PPI expression. This study was aimed to analyze the relationship between the adult medial prefrontal cortex (mPfc) and dopaminergic involvement in PPI throughout the life span. Specifically, the present experiment analyzed the effect of the administration of dopaminergic agonist amphetamine on PPI in two different age periods in Wistar rats: postnatal day (PND) 28 and PND 70. In this last period, we also explored the relationship between PPI response and amphetamine effects after mPfc lesion. The results showed that PPI was expressed in all groups and periods; however, amphetamine only modulated this effect during adulthood. We also found that the mPfc is essential to modulate PPI after amphetamine consumption. Besides, our results suggest a role for dopamine and mPfc as important modulators of PPI in adulthood. Nevertheless, this neurotransmitter could not be involved in the expression of PPI because the administration of a dopaminergic agonist was ineffective in PND-28 period. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Subject(s)
Amphetamine/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Prepulse Inhibition/drug effects , Acoustic Stimulation , Animals , Dopamine/metabolism , Dopamine Agents/pharmacology , Male , Rats , Rats, Wistar , Reflex, Startle/drug effects , Reflex, Startle/physiologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Kava extract (Piper methysticum) is a phytotherapic mainly used for the treatment of anxiety. Although the reported effects of Kava drinking improving psychotic symptoms of patients when it was introduced to relieve anxiety in aboriginal communities, its effects on models of psychosis-like symptoms are not investigated. AIM OF THE STUDY: To investigate the effects of Kava extract on behavioral changes induced by amphetamine (AMPH) and its possible relation with alterations in monoamine oxidase (MAO) activity. MATERIALS AND METHODS: Mice received vehicle or Kava extract by gavage and, 2 h after vehicle or AMPH intraperitoneally. Twenty-five minutes after AMPH administration, behavioral (elevated plus maze, open field, stereotyped behavior, social interaction and Y maze) and biochemical tests (MAO-A and MAO-B activity in cortex, hippocampus and striatum) were sequentially evaluated. RESULTS: Kava extract exhibited anxiolytic effects in plus maze test, increased the locomotor activity of mice in open field test and decreased MAO-A (in cortex) and MAO-B (in hippocampus) activity of mice. Kava extract prevented the effects of AMPH on stereotyped behavior and, the association between Kava/AMPH increased the number of entries into arms in Y maze test as well as MAO-B activity in striatum. However, Kava extract did not prevent hyperlocomotion induced by AMPH in open field test. The social interaction was not modified by Kava extract and/or AMPH. CONCLUSION: The results showed that Kava extract decreased the stereotyped behavior induced by AMPH at the same dose that promotes anxiolytic effects, which could be useful to minimize the psychotic symptoms in patients.
Subject(s)
Amphetamine/pharmacology , Kava/chemistry , Plant Extracts/pharmacology , Stereotyped Behavior/drug effects , Animals , Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Behavior, Animal/drug effects , Locomotion/drug effects , Male , Maze Learning/drug effects , MiceABSTRACT
In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 µg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.
Subject(s)
Amphetamine/pharmacology , Apomorphine/pharmacology , Arginine/pharmacology , Catalepsy , Dizocilpine Maleate/pharmacology , Dopamine Agents/pharmacology , Enzyme Inhibitors/pharmacology , Haloperidol/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase , Peptide Fragments/pharmacology , Proteins/pharmacology , Schizophrenia , Amphetamine/administration & dosage , Animals , Apomorphine/administration & dosage , Arginine/administration & dosage , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/drug therapy , Catalepsy/physiopathology , Disease Models, Animal , Dizocilpine Maleate/administration & dosage , Dopamine Agents/administration & dosage , Enzyme Inhibitors/administration & dosage , Haloperidol/administration & dosage , Male , NG-Nitroarginine Methyl Ester/administration & dosage , Neuroprotective Agents/administration & dosage , Nitric Oxide Synthase/antagonists & inhibitors , Peptide Fragments/administration & dosage , Proteins/administration & dosage , Rats , Rats, Wistar , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Schizophrenia/physiopathologyABSTRACT
Psychomotor stimulants are prescribed for many medical conditions, including obesity, sleep disorders, and attention-deficit/hyperactivity disorder. However, despite their acknowledged therapeutic utility, these stimulants are frequently abused, and their use can have both short- and long-term negative consequences. Although stimulants such as amphetamines acutely elevate blood pressure, it is unclear whether they cause any long-term effects on cardiovascular function after use has been discontinued. Previous work in our laboratory has demonstrated that physiological and psychosocial stressors will produce sensitization of the hypertensive response, a heightened pressor response to a hypertensinogenic stimulus delivered after stressor exposure. Here, we tested whether pretreatment with amphetamine for 1 wk can sensitize the hypertensive response in rats. We found that repeated amphetamine administration induced and maintained sensitization of the pressor response to angiotensin II following a 7-day delay after amphetamine injections were terminated. We also found that amphetamine pretreatment altered mRNA expression for molecular markers associated with neuroinflammation and renin-angiotensin-aldosterone system (RAAS) activation in the lamina terminalis, a brain region implicated in the control of sympathetic nervous system tone and blood pressure. The results indicated amphetamine upregulated mRNA expression underlying neuroinflammation and, to a lesser degree, message for components of the RAAS in the lamina terminalis. However, we found no changes in mRNA expression in the paraventricular nucleus. These results suggest that a history of stimulant use may predispose individuals to developing hypertension by promoting neuroinflammation and upregulating activity of the RAAS in the lamina terminalis.
Subject(s)
Amphetamine/pharmacology , Central Nervous System Stimulants/pharmacology , Hypertension/physiopathology , Hypothalamus/drug effects , Inflammation/drug therapy , Angiotensin II/pharmacology , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Diet, High-Fat , Disease Models, Animal , Hypertension/chemically induced , Hypothalamus/metabolism , Paraventricular Hypothalamic Nucleus/drug effects , RatsABSTRACT
Amphetamine (AMPH), an appetite suppressant, alters expression levels of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. This study explored the potential role of cJun-N-terminal kinases (JNK) in appetite control, mediated by reactive oxygen species (ROS) and activator protein-1 (AP-1) in AMPH-treated rats. Rats were given AMPH daily for 4 days. Changes in feeding behavior and expression levels of hypothalamic NPY, CART, cFos, cJun, phosphorylated JNK (pJNK), as well as those of anti-oxidative enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GP) and glutathione S-transferase (GST), were examined and compared. Following AMPH treatment, food intake and NPY expression decreased, whereas the other proteins expression and AP-1/DNA binding activity increased. Both cerebral cJun inhibition and ROS inhibition attenuated AMPH anorexia and modified detected protein, revealing a crucial role for AP-1 and ROS in regulating AMPH-induced appetite control. Moreover, both pJNK/CART and SOD/CART activities detected by double immunofluorescent staining increased in hypothalamic arcuate nucleus in AMPH-treated rats. The results suggested that pJNK/AP-1 signaling and endogenous anti-oxidants participated in regulating NPY/CART-mediated appetite control in rats treated with AMPH. These findings advance understanding of the molecular mechanism underlying the role of pJNK/AP-1 and oxidative stress in NPY/CART-mediated appetite suppression in AMPH-treated rats.
Subject(s)
Appetite Regulation/physiology , JNK Mitogen-Activated Protein Kinases/physiology , Neuropeptide Y/physiology , Oxidative Stress/physiology , Reactive Oxygen Species/metabolism , Transcription Factor AP-1/physiology , Amphetamine/pharmacology , Animals , Anthracenes/administration & dosage , Anthracenes/pharmacology , Antioxidants/metabolism , Appetite Regulation/drug effects , Feeding Behavior/drug effects , Fluorescent Antibody Technique , Hypothalamus/metabolism , Hypothalamus/physiology , Infusions, Intraventricular , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Nerve Tissue Proteins/metabolism , Neuropeptide Y/biosynthesis , Rats , Signal Transduction/physiology , Transcription Factor AP-1/metabolismABSTRACT
Motivated behavior is influenced by neural networks that integrate physiological needs. Here, we describe coordinated regulation of hypothalamic feeding and midbrain reward circuits in awake behaving mice. We find that alcohol and other non-nutritive drugs inhibit activity in hypothalamic feeding neurons. Interestingly, nutrients and drugs utilize different pathways for the inhibition of hypothalamic neuron activity, as alcohol signals hypothalamic neurons in a vagal-independent manner, while fat and satiation signals require the vagus nerve. Concomitantly, nutrients, alcohol, and drugs also increase midbrain dopamine signaling. We provide evidence that these changes are interdependent, as modulation of either hypothalamic neurons or midbrain dopamine signaling influences reward-evoked activity changes in the other population. Taken together, our results demonstrate that (1) food and drugs can engage at least two peripheralâcentral pathways to influence hypothalamic neuron activity, and (2) hypothalamic and dopamine circuits interact in response to rewards.
Subject(s)
Central Nervous System Depressants/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Dopaminergic Neurons/drug effects , Ethanol/pharmacology , Feeding Behavior/drug effects , Hypothalamus/drug effects , Nicotinic Agonists/pharmacology , Reward , Agouti-Related Protein/metabolism , Amphetamine/pharmacology , Animals , Cocaine/pharmacology , Dopamine Antagonists/pharmacology , Dopaminergic Neurons/metabolism , Hypothalamus/metabolism , Mice , Neural Pathways/drug effects , Neurons/drug effects , Neurons/metabolism , Nicotine/pharmacology , Pro-Opiomelanocortin/metabolism , Vagotomy , Vagus Nerve/physiologyABSTRACT
Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator responding to hypoxia. Amphetamine (AMPH), however, can activate HIF-1 under normoxic conditions, which is associated with the co-activation of oxidative stress. Hypothalamic neuropeptides and anti-oxidative enzymes have been found to participate in amphetamine (AMPH)-mediated appetite control. The present study examined whether HIF-1 was involved in the oxidative stress and anorectic action of AMPH. Rats were daily treated with AMPH for 4â¯days, and expression levels of HIF-1α, superoxide dismutase (SOD), catalase, neuropeptide Y (NPY), proopiomelanocortin (POMC), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-κB) were assessed and compared. Results revealed that feeding behavior and NPY decreased, whereas HIF-1α/DNA binding activity and SOD, POMC, PI3K, and NF-κB expression levels increased in AMPH-treated rats. Further experiment revealed that intracerebroventricular (i.c.v.) pretreatment with HIF-1α inhibitor modified feeding behavior and expression levels of hypothalamic protein assessed. Another experiment revealed that pretreatment (i.c.v.) with reactive oxygen species scavenger modulated HIF-1α, NPY, POMC, PI3K, and NF-κB expression levels in AMPH-treated rats. It is suggested that HIF-1α plays a functional role in the increase of oxidative stress and the modulation of NFκB/NPY/POMC-mediated appetite control in AMPH-treated rats. These findings advance the knowledge of HIF-1α in the regulation of central dopamine agonist-mediated appetite control.
Subject(s)
Appetite Regulation/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Oxidative Stress/physiology , Amphetamine/pharmacology , Animals , Appetite/drug effects , Appetite Depressants/pharmacology , Catalase/metabolism , Feeding Behavior/drug effects , Hypothalamus/metabolism , Hypothalamus/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Male , NF-kappa B/metabolism , Neuropeptide Y/metabolism , Neuropeptides/metabolism , Neuropeptides/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Pro-Opiomelanocortin/metabolism , Rats , Rats, Wistar , Signal Transduction/drug effects , Superoxide Dismutase/metabolismABSTRACT
Preparations of Ficus platyphylla are used in Nigeria's folk medicine to manage a variety of diseases, including insomnia, psychoses, depression, epilepsy, pain, and inflammation. In this study, we examined the effects of the standardised methanol extract of F. platyphylla stem bark (FP) on two-way active avoidance learning and body core temperature to complement earlier studies on the neuroleptic potential of this medicinal plant, which is already in common use. The extract did not interfere with the acquisition and consolidation of the conditioned avoidance reaction (CAR), but did diminish the retrieval of CAR. The extract dose-dependently reduced body core temperature; this was significantly ameliorated by the use of amphetamine. The results confirmed the neuroleptic-like efficacy of FP, probably via the modulation of dopaminergic neurons.
Subject(s)
Antipsychotic Agents/pharmacology , Avoidance Learning/drug effects , Body Temperature/drug effects , Ficus , Hypothermia/chemically induced , Plant Bark , Plant Extracts/pharmacology , Amphetamine/pharmacology , Animals , Antipsychotic Agents/administration & dosage , Central Nervous System Stimulants/pharmacology , Dose-Response Relationship, Drug , Hypothermia/drug therapy , Male , Memory Consolidation/drug effects , Mental Recall/drug effects , Methanol , Mice , Mice, Inbred C57BL , Plant Extracts/administration & dosage , SolventsABSTRACT
Dysfunction in dopamine (DA) systems is a prominent feature in schizophrenia patients and may result from the abnormal development of mesencephalic (mes)DA systems. Maternal immune activation (MIA) and developmental vitamin D (DVD)-deficiency both induce schizophrenia-relevant dopaminergic abnormalities in adult offspring. In this study, we investigated whether maternal administration of the vitamin D hormone (1,25OHD, VITD) could prevent MIA-induced abnormalities in DA-related behaviors and mesDA development. We administrated the viral mimetic polyriboinosinic-polyribocytidylic (poly (I:C)) simultaneously with 1,25OHD and/or their vehicles, to pregnant mouse dams at gestational day 9. Maternal treatment with VITD prevented MIA-induced hypersensitivity to acute DA stimulation induced by amphetamine, whereas it failed to block prepulse inhibition deficiency in MIA-exposed offspring. MIA and VITD both reduced fetal mesDA progenitor (Lmx1a + Sox2+) cells, while VITD treatment increased the number of mature (Nurr1 + TH+) mesDA neurons. Single-cell quantification of protein expression showed that VITD treatment increased the expression of Lmx1a, Nurr1 and TH in individual mesDA cells and restored normal mesDA positioning. Our data demonstrate that VITD prevents abnormal dopaminergic phenotypes in MIA offspring possibly via its early neuroprotective actions on fetal mesDA neurons. Maternal supplementation with the dietary form of vitamin D, cholecalciferol may become a valuable strategy for the prevention of MIA-induced neurodevelopmental abnormalities.
Subject(s)
Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Vitamin D/pharmacology , Amphetamine/pharmacology , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Female , Gestational Age , Immunohistochemistry , Locomotion/drug effects , Male , Mice , Mice, Inbred C57BL , Poly I-C/pharmacology , PregnancyABSTRACT
High level of positive affectivity acts as a protective factor against adverse effects of stress and decreases vulnerability to mood disorders and drug abuse. Fifty-kHz ultrasonic vocalizations (50-kHz USV) index the level of positive affect in the rat, whereas stable, trait-like inter-individual differences in terms of vocalization activity exist. Previously we have demonstrated that chronic stress can alter the effect of repeated amphetamine administration on 50-kHz vocalizations, and this effect is different in rats with high and low positive affectivity. In the present study it was tested whether the chronic stress effect on amphetamine-induced 50-kHz USV activity is altered by inhibition of serotonin reuptake. Male Wistar high (HC) and low (LC) 50-kHz vocalizing rats were subjected to 43-day chronic variable stress (CVS) regimen. On day 17 of the CVS, the four-week once a day fluoxetine (10â¯mg/kg) treatment was started. After the CVS and fluoxetine treatment, amphetamine (1â¯mg/kg) was daily administered for ten days and again nine days after withdrawal. Chronically stressed rats developed cross-sensitization of 50-kHz USV-s with repeated administration of amphetamine except the stressed LC rats that had not received fluoxetine. Amphetamine treatment decreased serotonin turnover in the fluoxetine-treated HC rats, but increased it in fluoxetine-treated LC rats. The effect of amphetamine on levels of amino acids in frontal cortex and hippocampus also depended on previous experience with chronic stress, repeated treatment with fluoxetine, and positive affectivity. Hence, this study provides further evidence the effects of chronic stress, psychostimulants, and a selective serotonin reuptake inhibitor are influenced by the inherent positive affectivity.
Subject(s)
Affect/drug effects , Amphetamine/pharmacology , Central Nervous System Sensitization/drug effects , Fluoxetine/pharmacology , Stress, Psychological/psychology , Vocalization, Animal/drug effects , Amino Acids/metabolism , Animals , Frontal Lobe/metabolism , Hippocampus/metabolism , Individuality , Male , Rats , Rats, Inbred Strains , Serotonin/metabolism , Time FactorsABSTRACT
Leptin is an adipose tissue hormone which plays an important role in regulating energy homeostasis. Amphetamine (AMPH) is a drug of appetite suppressant, which exerts its effect by decreasing the expression of hypothalamic neuropeptide Y (NPY) and increasing that of cocaine- and amphetamine-regulated transcript (CART). This study investigated whether leptin, the leptin receptor (LepRb) and the signal transducer and activator of transcription-3 (STAT3) were involved in NPY/CART-mediated appetite suppression in AMPH-treated rats. Rats were given AMPH daily for four days, and changes in the levels of blood leptin and hypothalamic NPY, CART, LepRb, Janus kinases 2 (JAK2), and STAT3 were assessed and compared. During the AMPH treatment, blood leptin levels and hypothalamic NPY expression decreased, with the largest reduction observed on Day 2. By contrast, the expression of hypothalamic CART, LepRb, JAK2, and STAT3 increased, with the maximum response on Day 2. Furthermore, the binding activity of pSTAT3/DNA increased and was expressed in similar pattern to that of CART, LepRb, and JAK2. An intracerebroventricular infusion of NPY antisense 60min prior to AMPH treatment increased the levels of leptin, as well as the expression in LepRb, JAK2, and CART, whereas an infusion of STAT3 antisense decreased these levels and the expression of these parameters. The results suggest that blood leptin and hypothalamic LepRb-JAK2-STAT3 signaling involved in NPY-CART-regulated appetite suppression in AMPH-treated rats. The findings may aid understanding the role of leptin-LepRb during the treatment of anorectic drugs.
Subject(s)
Amphetamine/pharmacology , Appetite Regulation/drug effects , Hypothalamus/drug effects , Leptin/metabolism , Nerve Tissue Proteins/metabolism , Neuropeptide Y/metabolism , Receptors, Leptin/metabolism , Animals , Appetite/drug effects , Appetite/physiology , Appetite Depressants/pharmacology , Appetite Regulation/physiology , Hypothalamus/metabolism , Leptin/blood , Male , Rats , Rats, Wistar , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
BACKGROUND AND PURPOSE: Amphetamine is a releaser of dopamine stored in synaptic terminals, which can suppress appetite by changing the expression levels of neuropeptide Y (NPY) and proopiomelanocortin (POMC) in the hypothalamus. This study explored whether ERKs are involved in appetite control mediated by cAMP response element binding protein (CREB), NPY and POMC in amphetamine-treated rats. EXPERIMENTAL APPROACH: Rats were given amphetamine for 4 days, and changes in feeding behaviour and expression levels of phosphorylated-ERK (pERK), pCREB, NPY and melanocortin MC3 receptors were examined and compared. KEY RESULTS: Following amphetamine treatment, food intake, body weight and NPY expression decreased, whereas the expression of pERK, pCREB, MC3 receptors and pCREB/DNA binding activity increased. In amphetamine-treated rats, both cerebral ERK knockdown and pretreatment with a peripheral dopamine receptor antagonist decreased NPY but increased pERK, pCREB and MC3 receptor expression. Moreover, the immunofluorescence of hypothalamic pERK increased following amphetamine treatment. CONCLUSIONS AND IMPLICATIONS: These results suggest that ERK/CREB signalling participates in the effects mediated by dopamine receptor/NPY/POMC on appetite control in rats treated with amphetamine. These findings advance the knowledge on the involvement of ERK/CREB signalling in the reciprocal regulation by NPY and POMC of appetite after amphetamine treatment.