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1.
J Pineal Res ; 76(5): e12984, 2024 Aug.
Article En | MEDLINE | ID: mdl-38874070

The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly prescribed to treat major depressive disorder and is found at high concentrations in the aquatic environment. Concerns have been raised related to the health of aquatic organisms in response to this nontargeted pharmaceutical exposure. For instance, we previously demonstrated that exposure to venlafaxine perturbs neurodevelopment, leading to behavioural alterations in zebrafish (Danio rerio). We also observed disruption in serotonin expression in the pineal and raphe, regions critical in regulating circadian rhythms, leading us to hypothesize that zygotic exposure to venlafaxine disrupts the circadian locomotor rhythm in larval zebrafish. To test this, we microinjected zebrafish embryos with venlafaxine (1 or 10 ng) and recorded the locomotor activity in 5-day-old larvae over a 24-h period. Venlafaxine deposition reduced larval locomotor activity during the light phase, but not during the dark phase of the diurnal cycle. The melatonin levels were higher in the dark compared to during the light photoperiod and this was not affected by embryonic venlafaxine deposition. Venlafaxine exposure also did not affect the transcript abundance of clock genes, including clock1a, bmal2, cry1a and per2, which showed a clear day/night rhythmicity. A notable finding was that exposure to luzindole, a melatonin receptor antagonist, decreased the locomotor activity in the control group in light, whereas the activity was higher in larvae raised from the venlafaxine-deposited embryos. Overall, zygotic exposure to venlafaxine disrupts the locomotor activity of larval zebrafish fish during the day, demonstrating the capacity of antidepressants to disrupt the circadian rhythms in behaviour. Our results suggest that disruption in melatonin signalling may be playing a role in the venlafaxine impact on circadian behaviour, but further investigation is required to elucidate the possible mechanisms in larval zebrafish.


Circadian Rhythm , Larva , Locomotion , Venlafaxine Hydrochloride , Zebrafish , Animals , Zebrafish/embryology , Venlafaxine Hydrochloride/pharmacology , Venlafaxine Hydrochloride/toxicity , Larva/drug effects , Locomotion/drug effects , Circadian Rhythm/drug effects , Zebrafish Proteins/metabolism , Zebrafish Proteins/genetics , Zygote/drug effects , Zygote/metabolism , Motor Activity/drug effects , Melatonin/pharmacology
2.
Mol Brain ; 17(1): 36, 2024 Jun 11.
Article En | MEDLINE | ID: mdl-38858755

Chronic perturbations of neuronal activity can evoke homeostatic and new setpoints for neurotransmission. Using chemogenetics to probe the relationship between neuronal cell types and behavior, we recently found reversible decreases in dopamine (DA) transmission, basal behavior, and amphetamine (AMPH) response following repeated stimulation of DA neurons in adult mice. It is unclear, however, whether altering DA neuronal activity via chemogenetics early in development leads to behavioral phenotypes that are reversible, as alterations of neuronal activity during developmentally sensitive periods might be expected to induce persistent effects on behavior. To examine the impact of developmental perturbation of DA neuron activity on basal and AMPH behavior, we expressed excitatory hM3D(Gq) in postnatal DA neurons in TH-Cre and WT mice. Basal and CNO- or AMPH-induced locomotion and stereotypy was evaluated in a longitudinal design, with clozapine N-oxide (CNO, 1.0 mg/kg) administered across adolescence (postnatal days 15-47). Repeated CNO administration did not impact basal behavior and only minimally reduced AMPH-induced hyperlocomotor response in adolescent TH-CrehM3Dq mice relative to WThM3Dq littermate controls. Following repeated CNO administration, however, AMPH-induced stereotypic behavior robustly decreased in adolescent TH-CrehM3Dq mice relative to controls. A two-month CNO washout period rescued the diminished AMPH-induced stereotypic behavior. Our findings indicate that the homeostatic compensations that take place in response to chronic hM3D(Gq) stimulation during adolescence are temporary and are dependent on ongoing chemogenetic stimulation.


Amphetamine , Dopaminergic Neurons , Stereotyped Behavior , Animals , Amphetamine/pharmacology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Stereotyped Behavior/drug effects , Clozapine/pharmacology , Clozapine/analogs & derivatives , Locomotion/drug effects , Mice , Male , Motor Activity/drug effects , Mice, Transgenic , Tyrosine 3-Monooxygenase/metabolism , Tyrosine 3-Monooxygenase/genetics , Behavior, Animal/drug effects , Integrases
3.
Addict Biol ; 29(6): e13420, 2024 06.
Article En | MEDLINE | ID: mdl-38898729

Alcohol consumption occurring in a social or solitary setting often yields different behavioural responses in human subjects. For example, social drinking is associated with positive effects while solitary drinking is linked to negative effects. However, the neurobiological mechanism by which the social environment during alcohol intake impacts on behavioural responses remains poorly understood. We investigated whether distinct social environments affect behavioural responses to ethanol and the role of the dopamine system in this phenomenon in the fruit fly Drosophila melanogaster. The wild-type Canton-S (CS) flies showed higher locomotor response when exposed to ethanol in a group setting than a solitary setting, and there was no difference in females and males. Dopamine signalling is crucial for the locomotor stimulating effect of ethanol. When subjected to ethanol exposure alone, the dopamine transport mutant flies fumin (fmn) with hyper dopamine displayed the locomotor response similar to CS. When subjected to ethanol in a group setting, however, the fmn's response to the locomotor stimulating effect was substantially augmented compared with CS, indicating synergistic interaction of dopamine signalling and social setting. To identify the dopamine signalling pathway important for the social effect, we examined the flies defective in individual dopamine receptors and found that the D1 receptor dDA1/Dop1R1 is the major receptor mediating the social effect. Taken together, this study underscores the influence of social context on the neural and behavioural responses to ethanol.


Dopamine , Drosophila Proteins , Drosophila melanogaster , Ethanol , Animals , Ethanol/pharmacology , Dopamine/metabolism , Drosophila melanogaster/drug effects , Male , Female , Drosophila Proteins/genetics , Receptors, Dopamine D1/drug effects , Social Environment , Signal Transduction/drug effects , Locomotion/drug effects , Receptors, Dopamine/drug effects , Receptors, Dopamine/metabolism , Behavior, Animal/drug effects , Central Nervous System Depressants/pharmacology , Social Behavior , Dopamine Plasma Membrane Transport Proteins/drug effects , Dopamine Plasma Membrane Transport Proteins/genetics , Motor Activity/drug effects
4.
PLoS One ; 19(6): e0305868, 2024.
Article En | MEDLINE | ID: mdl-38913661

The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the therapeutic potential of CB1R by direct activation is limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating the CB1R by utilizing positive allosteric modulators (PAMs). Studies have shown that CB1R PAMs (ZCZ011 and GAT211) are effective in mouse models of Huntington's disease and neuropathic pain, and hence, we assess the therapeutic potential of ZCZ011 in a well-established mouse model of neuroHIV. The current study investigates the effect of chronic ZCZ011 treatment (14 days) on various behavioral paradigms and the endocannabinoid system in HIV-1 Tat transgenic female and male mice. Chronic ZCZ011 treatment (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless of sex or genotype. However, differential effects were noted in hot plate latency, motor coordination, and recognition memory in female mice only, with ZCZ011 treatment increasing hot plate latency and improving motor coordination and recognition memory. Only minor effects or no alterations were seen in the endocannabinoid system and related lipids except in the cerebellum, where the effect of ZCZ011 was more pronounced in female mice. Moreover, AEA and PEA levels in the cerebellum were positively correlated with improved motor coordination in female mice. In summary, these findings indicate that chronic ZCZ011 treatment has differential effects on antinociception, motor coordination, and memory, based on sex and HIV-1 Tat expression, making CB1R PAMs potential treatment options for HAND without the psychoactive side effects.


Endocannabinoids , Mice, Transgenic , Receptor, Cannabinoid, CB1 , tat Gene Products, Human Immunodeficiency Virus , Animals , Female , Male , Endocannabinoids/metabolism , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB1/genetics , Mice , tat Gene Products, Human Immunodeficiency Virus/genetics , tat Gene Products, Human Immunodeficiency Virus/metabolism , HIV-1/drug effects , Allosteric Regulation/drug effects , Behavior, Animal/drug effects , Motor Activity/drug effects , Disease Models, Animal
5.
Brain Behav ; 14(6): e3539, 2024 Jun.
Article En | MEDLINE | ID: mdl-38849974

BACKGROUND AND OBJECTIVES: Maternal hypoxia disrupts neural development and subsequently leads to cerebral palsy and epilepsy in newborns. Hypoxia plays a role in neurodegeneration by increasing oxidative stress. Pistacia atlantica is known as an important antioxidant, and its anti-inflammatory and antioxidant effects have been shown in various studies. This study aims to investigate the effects of methanolic extract of P. atlantica leaves (MEPaLs) on the oxidative parameters in the serum of rats affected by maternal hypoxia. MATERIAL AND METHODS: In this study, eight pregnant rats were used. The newborns were divided into four groups, including the control and the hypoxia groups, which are affected by maternal hypoxia, hypoxia + MEPaL 100 mg/kg, and hypoxia + MEPaL 150 mg/kg. MEPaL was injected (i.p) for 21 days into the neonatal rats after the lactation period. Hypoxia was induced by keeping pregnant rats in a hypoxic chamber with 7% oxygen and 93% nitrogen intensity for 3 h on the 20th day of pregnancy. Behavioral changes were measured using open-field and rotarod tests. Finally, biomarkers of oxidative stress, nitric oxide (NO), glutathione (GSH), GSSG, TAS, TOS, and oxidative stress index (OSI) were measured in the experimental groups. RESULTS: Behavioral results showed that the anxiety behavior in the hypoxia group increased, but the motor activity (moved distance and movement speed) decreased. Moreover, the amount of time spent maintaining balance on the rotarod rod was significantly decreased in the hypoxia group. The concentration of NO in the group of hypoxia + MEPaL 100 mg/kg showed a significant decrease, and MEPaL 100, and 150 mg/kg + hypoxia also increased the concentration of GSH and decreased GSSG. In addition, MEPaL100 and 150 mg/kg caused a significant increase in the ratio of GSH to GSSG and decreased OSI and total oxidant capacity. CONCLUSIONS: Oxidative stress increased in the rats affected by maternal hypoxia and may be the main mechanism for motor activity impairment and balance disturbance, whereas MELaL improved motor performance by decreasing oxidative stress.


Antioxidants , Oxidative Stress , Plant Extracts , Animals , Oxidative Stress/drug effects , Female , Pregnancy , Rats , Antioxidants/pharmacology , Plant Extracts/pharmacology , Plant Extracts/administration & dosage , Hypoxia/physiopathology , Rats, Wistar , Animals, Newborn , Prenatal Exposure Delayed Effects/physiopathology , Prenatal Exposure Delayed Effects/metabolism , Motor Activity/drug effects , Motor Activity/physiology , Glutathione/metabolism , Glutathione/blood , Male , Behavior, Animal/drug effects , Behavior, Animal/physiology , Nitric Oxide/metabolism , Nitric Oxide/blood
6.
PLoS One ; 19(6): e0305173, 2024.
Article En | MEDLINE | ID: mdl-38875300

Chlorpyrifos is an organophosphate pesticide associated with numerous health effects including motor performance decrements. While many studies have focused on the health effects following acute chlorpyrifos poisonings, almost no studies have examined the effects on motoneurons following occupational-like exposures. The main objective of this study was to examine the broad effects of repeated occupational-like chlorpyrifos exposures on spinal motoneuron soma size relative to motor activity. To execute our objective, adult rats were exposed to chlorpyrifos via oral gavage once a day, five days a week for two weeks. Chlorpyrifos exposure effects were assessed either three days or two months following the last exposure. Three days following the last repeated chlorpyrifos exposure, there were transient effects in open-field motor activity and plasma cholinesterase activity levels. Two months following the chlorpyrifos exposures, there were delayed effects in sensorimotor gating, pro-inflammatory cytokines and spinal lumbar motoneuron soma morphology. Overall, these results offer support that subacute repeated occupational-like chlorpyrifos exposures have both short-term and longer-term effects in motor activity, inflammation, and central nervous system mechanisms.


Chlorpyrifos , Motor Activity , Motor Neurons , Animals , Chlorpyrifos/toxicity , Motor Neurons/drug effects , Motor Neurons/pathology , Rats , Male , Motor Activity/drug effects , Insecticides/toxicity , Spinal Cord/drug effects , Spinal Cord/pathology , Rats, Sprague-Dawley , Lumbosacral Region , Cholinesterases/metabolism , Cholinesterases/blood , Cholinesterase Inhibitors/toxicity
7.
Behav Brain Res ; 468: 115035, 2024 Jun 25.
Article En | MEDLINE | ID: mdl-38703793

Parkinson's Disease is a progressive neurodegenerative disorder characterized by motor symptoms resulting from the loss of nigrostriatal dopaminergic neurons. Kisspeptins (KPs) are a family of neuropeptides that are encoded by the Kiss-1 gene, which exert their physiological effects through interaction with the GPR54 receptor. In the current investigation, we investigated the prospective protective effects of central KP-54 treatments on nigrostriatal dopaminergic neurons and consequent motor performance correlates in 6-hydroxydopamine (6-OHDA)-lesioned rats. Male adult Sprague Dawley rats underwent stereotaxic injection of 6-OHDA into the right medial forebrain bundle to induce hemiparkinsonism. Following surgery, rats received chronic central treatments of nasal or intracerebroventricular KP-54 (logarithmically increasing doses) for seven consecutive days. Motor performance was evaluated seven days post-surgery utilizing the open field test and catalepsy test. The levels of dopamine in the striatum were determined with mass spectrometry. Immunohistochemical analysis was conducted to assess the immunoreactivities of tyrosine hydroxylase (TH) and the GPR54 in the substantia nigra. The dose-response curve revealed a median effective dose value of ≈3 nmol/kg for both central injections. Due to its non-invasive and effective nature, nasal administration was utilized in the second phase of our study. Chronic administration of KP-54 (3nmol/kg, nasally) significantly protected 6-OHDA-induced motor deficits. Nasal KP-54 attenuated the loss of nigrostriatal dopaminergic neurons induced by 6-OHDA. Additionally, significant correlations were observed between motor performance and nigrostriatal dopamine levels. Immunohistochemical analysis demonstrated the localization of the GPR54 within TH-positive nigral cells. These findings suggest the potential efficacy of central KP-54 on motor impairments in hemiparkinsonism.


Administration, Intranasal , Corpus Striatum , Dopamine , Dopaminergic Neurons , Kisspeptins , Oxidopamine , Parkinsonian Disorders , Rats, Sprague-Dawley , Substantia Nigra , Animals , Male , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Dopamine/metabolism , Oxidopamine/pharmacology , Rats , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Kisspeptins/administration & dosage , Kisspeptins/pharmacology , Kisspeptins/metabolism , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/metabolism , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Disease Models, Animal , Motor Activity/drug effects , Tyrosine 3-Monooxygenase/metabolism
8.
Epilepsy Behav ; 156: 109832, 2024 Jul.
Article En | MEDLINE | ID: mdl-38761450

Crack cocaine is a highly addictive and potent stimulant drug. Animal studies have shown that the cholinergic system plays a role in neurotoxicity induced by cocaine or its active metabolites inhalation. Behavioral alterations associated with crack cocaine use include hyperactivity, depressed mood, and decreased seizure threshold. Here we evaluate the acetylcholinesterase (AChE) and reactive oxygen species (ROS) activity, behavioral profile, and the threshold for epileptic seizures in rats that received intrahippocampal pilocarpine (H-PILO) followed by exposure to crack cocaine (H-PILO + CRACK). Animals exposed to H-PILO + CRACK demonstrated increased severity and frequency of limbic seizures. The AChE activity was reduced in the groups exposed to crack cocaine alone (CRACK) and H-PILO + CRACK, whereas levels of ROS remained unchanged. In addition, crack cocaine exposure increased vertical locomotor activity, without changing water and sucrose intake. Short-term memory consolidation remained unchanged after H-PILO, H-PILO + CRACK, and CRACK administration. Overall, our data suggest that crack cocaine inhalation reduced the threshold for epileptic seizures in rats submitted to low doses of pilocarpine through the inhibition of AChE. Taken together, our findings can be useful in the development of effective strategies for preventing and treating the harmful effects of cocaine and crack cocaine on the central nervous system.


Acetylcholinesterase , Crack Cocaine , Pilocarpine , Rats, Wistar , Seizures , Animals , Male , Acetylcholinesterase/metabolism , Rats , Pilocarpine/toxicity , Seizures/chemically induced , Administration, Inhalation , Disease Models, Animal , Reactive Oxygen Species/metabolism , Motor Activity/drug effects , Hippocampus/drug effects , Hippocampus/metabolism
9.
Behav Brain Res ; 469: 115051, 2024 Jul 09.
Article En | MEDLINE | ID: mdl-38777263

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.


Dopamine Plasma Membrane Transport Proteins , Exploratory Behavior , Recognition, Psychology , Animals , Dopamine Plasma Membrane Transport Proteins/metabolism , Male , Recognition, Psychology/drug effects , Recognition, Psychology/physiology , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/drug effects , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2A/drug effects , Motor Activity/drug effects , Motor Activity/physiology , Brain/metabolism , Brain/drug effects , Emotions/drug effects , Emotions/physiology , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT2 Receptor Agonists/pharmacology , Rats, Wistar
10.
Biomed Pharmacother ; 176: 116792, 2024 Jul.
Article En | MEDLINE | ID: mdl-38795645

BACKGROUND: Mounting experimental evidence has underscored the remarkable role played by the Wnt family of proteins in the spinal cord functioning and therapeutic potential in spinal cord injury (SCI). We aim to provide a therapeutic prospect associated with the modulation of canonical Wnt signaling, examining the spatio-temporal expression pattern of Dickkopf-1 (Dkk1) and its neutralization after SCI. We employ an intraparenchymal injection of the clinically validated Dkk1-blocking antibody, BHQ880, to elucidate its effects in SCI. METHODS: A rat model of contusion SCI was used. Histological analyses were performed, wherein Dkk1 protein was sought, and ELISA analyses were employed for Dkk1 detection in cerebrospinal fluid and serum. To ascertain the BHQ880 therapeutic effect, rats were subjected to SCI and then injected with the antibody in the lesion epicenter 24 hours post-injury (hpi). Subsequent evaluation of motor functional recovery extended up to 56 days post-injury (dpi). qRT-PCR and histological analyses were conducted. RESULTS: We demonstrate the presence of Dkk1 in the healthy rat spinal cord, with pronounced alterations observed following injury, primarily concentrated in the epicenter regions. Notably, a significative upregulation of Dkk1 was detected at 24 hpi, peaking at 3 dpi and remaining elevated until 42 dpi. Moreover, we revealed that early administration of BHQ880 considerably improved motor functional recovery, promoted preservation of myelinated tissue, and reduced astroglial and microglia/macrophage reactivity. Furthermore, there was a decrease in the acute expression of different inflammatory genes. CONCLUSIONS: Collectively, our findings highlight the therapeutic potential of BHQ880 treatment in the context of SCI.


Intercellular Signaling Peptides and Proteins , Recovery of Function , Spinal Cord Injuries , Animals , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Recovery of Function/drug effects , Intercellular Signaling Peptides and Proteins/metabolism , Rats , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Cord/pathology , Male , Rats, Sprague-Dawley , Disease Models, Animal , Motor Activity/drug effects
11.
Eur J Pharmacol ; 975: 176635, 2024 Jul 15.
Article En | MEDLINE | ID: mdl-38734296

BACKGROUND: Degeneration of the nigrostriatal dopaminergic pathway has been seen as a significant cause of movement disability in Parkinson's disease (PD) patients. However, the exact reason for these degenerative changes has remained obscure. In recent years, incretins have been neuroprotective in various pathologies. In the current study, we have investigated the neuroprotective potential of alogliptin (Alo), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, in a lipopolysaccharide (LPS) induced experimental model of PD. EXPERIMENTAL APPROACH: LPS (5µg/5 µl) was infused intranigrally to induce PD in experimental rats. Post-LPS infusion, these animals were treated with Alo for 21 days in three successive dosages of 10, 20, and 40 mg/kg/day/per oral. The study is well supported with the determinations of motor functions biochemical, neurochemical, and histological analysis. KEY RESULTS: Intranigral infusion of LPS in rats produced motor deficit. It was accompanied by oxidative stress, elevation in neuroinflammatory cytokines, altered neurochemistry, and degenerative changes in the striatal brain region. While Alo abrogated LPS-induced biochemical/neurochemical alterations, improved motor functions, and preserved neuronal morphology in LPS-infused rats. CONCLUSION: The observed neuroprotective potential of Alo may be due to its antioxidant and anti-inflammatory actions and its ability to modulate monoaminergic signals. Nonetheless, current findings suggest that improving the availability of incretins through DPP-IV inhibition is a promising strategy for treating Parkinson's disease.


Dipeptidyl-Peptidase IV Inhibitors , Lipopolysaccharides , Neuroprotective Agents , Oxidative Stress , Piperidines , Uracil , Animals , Uracil/analogs & derivatives , Uracil/pharmacology , Uracil/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Male , Rats , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Oxidative Stress/drug effects , Rats, Wistar , Disease Models, Animal , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/pathology , Cytokines/metabolism , Motor Activity/drug effects , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/pathology
12.
Schizophr Res ; 267: 432-440, 2024 May.
Article En | MEDLINE | ID: mdl-38642484

Maternal immune activation (MIA) during pregnancy is known to increase the risk of development of schizophrenia in the offspring. Sex steroid hormone analogues have been proposed as potential antipsychotic treatments but the mechanisms of action involved remain unclear. Estrogen has been shown to alter N-methyl-d-aspartate (NMDA) receptor binding in the brain. We therefore studied the effect of chronic treatment with 17ß-estradiol, its isomer, 17α-estradiol, and the selective estrogen receptor modulator, raloxifene, on MIA-induced psychosis-like behaviour and the effect of the NMDA receptor antagonist, MK-801. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15. Adult female offspring were tested for changes in baseline prepulse inhibition (PPI) and the effects of acute treatment with MK-801 on PPI and locomotor activity. Poly(I:C) offspring had significantly lower baseline PPI compared to control offspring, and this effect was prevented by 17ß-estradiol and raloxifene, but not 17α-estradiol. MK-801 reduced PPI in control offspring but had no effect in poly(I:C) offspring treated with vehicle. Chronic treatment with 17ß-estradiol and raloxifene restored the effect of MK-801 on PPI. There were no effects of MIA or estrogenic treatment on MK-801 induced locomotor hyperactivity. These results show that MIA affects baseline PPI as well as NMDA receptor-mediated regulation of PPI in female rats, and strengthen the view that estrogenic treatment may have antipsychotic effects.


Disease Models, Animal , Dizocilpine Maleate , Estradiol , Poly I-C , Prenatal Exposure Delayed Effects , Prepulse Inhibition , Raloxifene Hydrochloride , Receptors, N-Methyl-D-Aspartate , Schizophrenia , Animals , Female , Estradiol/pharmacology , Raloxifene Hydrochloride/pharmacology , Schizophrenia/drug therapy , Schizophrenia/chemically induced , Pregnancy , Prepulse Inhibition/drug effects , Dizocilpine Maleate/pharmacology , Poly I-C/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/drug effects , Prenatal Exposure Delayed Effects/chemically induced , Rats , Excitatory Amino Acid Antagonists/pharmacology , Male , Selective Estrogen Receptor Modulators/pharmacology , Estrogens/pharmacology , Motor Activity/drug effects
13.
Drug Alcohol Depend ; 259: 111301, 2024 Jun 01.
Article En | MEDLINE | ID: mdl-38640863

BACKGROUND: The incidence of combination methamphetamine (METH)-opioid overdose has substantially increased in recent years. While agitation is uncommon after the naloxone (NLX) reversal of opioids, it is a major clinical concern in acute METH intoxication and can be physiologically antagonized by opioid-induced sedation. This study aimed to perform initial preclinical analysis of the safety and efficacy of dexmedetomidine (DEXMED) co-administered with NLX to attenuate METH-induced locomotor activity, as a rat model of agitation, after the reversal of fentanyl (FENT)-induced sedation. METHODS: Male Sprague Dawley rats were administered subcutaneous (SC) 0.1mg/kg FENT ± 1mg/kg METH. Fifteen min later, SC 0.1mg/kg NLX ± an increasing (0, 0.032, 0.056, and 0.1mg/kg) DEXMED dose was administered prior to the measurement of locomotor activity. After a washout period, the FENT ± METH and NLX ± DEXMED administration with the highest dose of DEXMED was administered for measurement of blood oxygen saturation and heart rate. RESULTS: After the NLX reversal of FENT-induced sedation, adjunct DEXMED substantially and significantly reduced METH-induced locomotor activity (p<0.05) at all doses tested. While the addition of DEXMED did not significantly reduce blood oxygenation in METH treated rats, it did so in the absence of METH. Also, DEXMED significantly reduced heart rate compared to non-DEXMED treated groups and resulted in further significant reductions in the animals not exposed to METH (p<0.05). CONCLUSIONS: These data provide preclinical evidence that DEXMED may be a safe and effective chemical restraint for METH-induced agitation after NLX opioid reversal.


Dexmedetomidine , Fentanyl , Methamphetamine , Naloxone , Rats, Sprague-Dawley , Animals , Dexmedetomidine/pharmacology , Dexmedetomidine/administration & dosage , Male , Methamphetamine/administration & dosage , Fentanyl/pharmacology , Fentanyl/administration & dosage , Rats , Naloxone/pharmacology , Naloxone/administration & dosage , Narcotic Antagonists/pharmacology , Narcotic Antagonists/administration & dosage , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacology , Motor Activity/drug effects , Hypnotics and Sedatives/pharmacology , Hypnotics and Sedatives/administration & dosage , Heart Rate/drug effects , Dose-Response Relationship, Drug
14.
Behav Neurosci ; 138(2): 108-124, 2024 Apr.
Article En | MEDLINE | ID: mdl-38661670

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase inhibition while also inhibiting transient receptor potential vanilloid Type 1 channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor Type 1 agonist arachidonoyl-2'-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with seven daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA decreased rearing and decreased phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference, then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a conditioned place preference or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct cannabinoid receptor Type 1 agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Cannabinoid Receptor Agonists , Dopamine , Mice, Inbred C57BL , Animals , Dopamine/metabolism , Male , Mice , Cannabinoid Receptor Agonists/pharmacology , Serotonin/metabolism , Locomotion/drug effects , Behavior, Animal/drug effects , Arachidonic Acids/pharmacology , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Cocaine/pharmacology , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Motor Activity/drug effects
15.
Physiol Behav ; 281: 114552, 2024 Jul 01.
Article En | MEDLINE | ID: mdl-38614419

BACKGROUND: Recent research has highlighted the potential role of Helicobacter pylori in the pathogenesis of psychiatric disorders. This study aimed to evaluate the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in a mouse model. METHODS: Male C57BL/6 mice were divided into four groups: control, H. pylori infection, antidepressant treatment, and combined treatment. H. pylori infection was induced by oral gavage with a clinically relevant strain, and the antidepressant drug was administered via intraperitoneal injections. Behavioral tests including the forced swim test, sucrose preference test, and open field test were conducted to assess depressive-like behaviors and locomotor activity. RESULTS: The study demonstrated that H. pylori infection induced depressive-like behaviors in mice, as evidenced by increased immobility time in the forced swim test and reduced sucrose preference. Antidepressant treatment alone partially ameliorated these behavioral changes. Strikingly, the combined treatment of the antidepressant drug and H. pylori eradication therapy led to a significantly greater reduction in depressive-like behaviors compared to either treatment alone. Furthermore, the combined treatment group exhibited increased locomotor activity in the open field test, suggesting a potential improvement in overall psychomotor functioning. ELISA assays revealed alterations in inflammatory cytokines in the H. pylori-infected mice, which were partially attenuated by the combined treatment. CONCLUSION: The study provides novel evidence for the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in alleviating depressive-like behaviors in a mouse model.


Amitriptyline , Cytokines , Disease Models, Animal , Helicobacter Infections , Helicobacter pylori , Mice, Inbred C57BL , Animals , Male , Helicobacter Infections/drug therapy , Amitriptyline/pharmacology , Amitriptyline/administration & dosage , Cytokines/metabolism , Helicobacter pylori/drug effects , Depression/drug therapy , Mice , Antidepressive Agents/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Synergism , Motor Activity/drug effects , Swimming
16.
Brain Res ; 1834: 148904, 2024 Jul 01.
Article En | MEDLINE | ID: mdl-38561086

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective ß receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and ß1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.


Antidepressive Agents , Dopamine , Monoamine Oxidase , Organoselenium Compounds , Animals , Male , Mice , Antidepressive Agents/pharmacology , Organoselenium Compounds/pharmacology , Monoamine Oxidase/metabolism , Monoamine Oxidase/drug effects , Dopamine/metabolism , Dopamine Antagonists/pharmacology , Swimming , Norepinephrine/metabolism , Receptors, Dopamine/metabolism , Receptors, Dopamine/drug effects , Depression/drug therapy , Depression/metabolism , Motor Activity/drug effects
17.
Physiol Behav ; 280: 114548, 2024 Jun 01.
Article En | MEDLINE | ID: mdl-38615729

Corn and soybean oils are among the most frequently used vehicles for water-insoluble compounds in toxicological studies. These two vegetable oils are nutrients and may induce some biological effects on animals that might interfere with the experimental results. However, their chronic effects on a developing brain have not been reported. This study aims to evaluate the neurobehavioral and brain biochemical effects of both oils on male and female Swiss albino mice. Pregnant female mice were exposed to 1 µl/g/d of either tap water, corn oil (CO), or soybean oil (SO) from early gestation (GD1) until weaning then offspring mice were exposed to the same treatment regimen until adulthood (PND70). Our results showed that developmental exposure to both oils induced body weight changes in offspring mice. In addition, we detected some behavioral abnormalities where both oil-treated groups showed a significant decrease in locomotor activity and greater levels of anxiety behavior. Moreover, our results suggest that continuous exposure to these oils may alter motor coordination, spatial memory and induce depression-like behavior in adult mice. These alterations were accompanied by increased malondialdehyde, superoxide dismutase, and glutathione peroxidase activities in specific brain regions. Together, these data suggest that exposure to CO and SO as vehicles in developmental studies may interfere with the behavioral response and brain redox homeostasis in offspring mice.


Brain , Corn Oil , Oxidative Stress , Prenatal Exposure Delayed Effects , Soybean Oil , Animals , Female , Corn Oil/administration & dosage , Oxidative Stress/drug effects , Mice , Pregnancy , Male , Prenatal Exposure Delayed Effects/chemically induced , Brain/drug effects , Brain/metabolism , Brain/growth & development , Glutathione Peroxidase/metabolism , Body Weight/drug effects , Malondialdehyde/metabolism , Superoxide Dismutase/metabolism , Motor Activity/drug effects , Behavior, Animal/drug effects , Anxiety/chemically induced , Maze Learning/drug effects , Pharmaceutical Vehicles
18.
Behav Pharmacol ; 35(4): 156-160, 2024 Jun 01.
Article En | MEDLINE | ID: mdl-38651975

Exposure to chronic caffeine during adolescence has been shown to produce decreased anxiety-like behaviors in rats as well as decreased immobility in the forced swim test (FST) suggesting an antidepressant-like effect. The effects of chronic caffeine on anxiety, however, have been found to be test-dependent and sexually dimorphic. In addition, decreased immobility in the FST has been argued to reflect a shift toward active coping behavior as opposed to an antidepressant-like effect. In order to further characterize the effects of adolescent caffeine exposure, the present experiment assessed the effects of caffeine on marble burying behavior in a two-zone marble burying task. There was no difference in the amount of time rats spent in the two zones failing to support a shift in coping strategy. Caffeine-exposed rats spent less time engaged in marble burying activity and buried slightly fewer marbles, suggesting an anxiolytic effect of caffeine. In addition, caffeine treated rats spent less time engaged in nondirected burying and slightly more time actively engaging with the marbles; however, these effects appeared to be sexually dimorphic as they were driven by larger changes in the females. Overall, these results support an anxiolytic effect of adolescent caffeine, with female behavior appearing to be more affected by caffeine than males.


Anxiety , Behavior, Animal , Caffeine , Animals , Caffeine/pharmacology , Caffeine/administration & dosage , Male , Anxiety/drug therapy , Female , Rats , Behavior, Animal/drug effects , Central Nervous System Stimulants/pharmacology , Anti-Anxiety Agents/pharmacology , Rats, Sprague-Dawley , Motor Activity/drug effects
19.
Biomed Pharmacother ; 174: 116526, 2024 May.
Article En | MEDLINE | ID: mdl-38574621

Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder of the cerebellum and brainstem. Memantine has been proposed as a potential treatment for SCA1. It blocks N-methyl-D-aspartate (NMDA) receptors on neurons, reduces excitotoxicity and decreases neurodegeneration in Alzheimer models. However, in cerebellar neurodegenerative diseases, the potential value of memantine is still unclear. We investigated the effects of memantine on motor performance and synaptic transmission in the cerebellum in a mouse model where mutant ataxin 1 is specifically targeted to glia. Lentiviral vectors (LVV) were used to express mutant ataxin 1 selectively in Bergmann glia (BG). In mice transduced with the mutant ataxin 1, chronic treatment with memantine improved motor activity during initial tests, presumably due to preserved BG and Purkinje cell (PC) morphology and numbers. However, mice were unable to improve their rota rod scores during next days of training. Memantine also compromised improvement in the rota rod scores in control mice upon repetitive training. These effects may be due to the effects of memantine on plasticity (LTD suppression) and NMDA receptor modulation. Some effects of chronically administered memantine persisted even after its wash-out from brain slices. Chronic memantine reduced morphological signs of neurodegeneration in the cerebellum of SCA1 model mice. This resulted in an apparent initial reduction of ataxic phenotype, but memantine also affected cerebellar plasticity and ultimately compromised motor learning. We speculate that that clinical application of memantine in SCA1 might be hampered by its ability to suppress NMDA-dependent plasticity in cerebellar cortex.


Disease Models, Animal , Memantine , Phenotype , Spinocerebellar Ataxias , Animals , Memantine/pharmacology , Spinocerebellar Ataxias/drug therapy , Spinocerebellar Ataxias/pathology , Mice , Ataxin-1/metabolism , Ataxin-1/genetics , Motor Activity/drug effects , Cerebellum/drug effects , Cerebellum/pathology , Cerebellum/metabolism , Purkinje Cells/drug effects , Purkinje Cells/pathology , Purkinje Cells/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Mice, Transgenic , Mice, Inbred C57BL , Neuroglia/drug effects , Neuroglia/pathology , Neuroglia/metabolism , Male , Neuronal Plasticity/drug effects
20.
Neurosci Lett ; 832: 137801, 2024 May 29.
Article En | MEDLINE | ID: mdl-38685377

The continuous high intake of caffeinated products may harm CNS. Sodium benzoate (SB), broadly used for food preservation, may also have an impact. The current research studied the influence of caffeine and two doses of SB during adolescence period on behavior and brain alterations. Adolescent rats (90-120 gm) were exposed to vehicle, SB 100 and 400 mg/kg, p.o, caffeine (30 mg/kg, i.p), SB 100 or 400 + caffeine for 28 days. Locomotor performances were assessed by the open field, learning and memory were considered with novel object and y-maze, while anxiety was evaluated by light and dark as well as successive allays tests. The results showed that the motor activity of adolescent rats increased with each single treatment. Recognition memory was improved by SB100 and its combination with caffeine while working memory was reduced by SB (100 or 400) combination with caffeine compared with caffeine group. The anxiolytic effect of caffeine was reduced by SB co-treatment in either dose. Concerning biochemical study in the frontal cortex and hippocampus, oxidative biomarkers as well as Cholinesterase content were elevated due to SB400 + caffeine. Dopamine content was almost elevated by all treatments in both regions while GABA content was increased in the frontal cortex only. The obtained results pointed to histopathological changes as a result of brain oxidative stress and undesirable working memory consequences due to caffeine administration with SB, mostly the large dose. The outcomes propose new recommendations to evade the consolidation between processed nourishment and caffeinated beverages during adolescence.


Caffeine , Rats, Wistar , Sodium Benzoate , Animals , Sodium Benzoate/pharmacology , Caffeine/pharmacology , Male , Rats , Behavior, Animal/drug effects , Oxidative Stress/drug effects , Maze Learning/drug effects , Anxiety/chemically induced , Anxiety/psychology , Central Nervous System Stimulants/pharmacology , Motor Activity/drug effects , Brain/drug effects , Brain/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Dopamine/metabolism
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