Behavioural Pharmacology最新文献

The prototype endocannabinoid, anandamide activates both CB 1 and transient receptor potential vanilloid type 1 channels (TRPV1) receptor at different concentrations. At high concentrations, anandamide-mediated TRPV1 effects are opposite to its effects at low concentrations via CB 1 receptor. Thus, synaptic concentrations of anandamide govern the neuronal activity and consequently might affect the response of a drug. This study was undertaken to investigate the influence of high and low doses of anandamide on the anticonvulsant action of diazepam on the subcutaneous dose of pentylenetetrazole (PTZ) in Swiss mice weighing 20-25 g. Results revealed that intracerebroventricular administration of capsazepine (a TRPV1 antagonist: 1, 10, or 100 µg/mouse) and the low doses (10 µg/mouse) of anandamide, AM404 (anandamide transport inhibitor), or URB597 (fatty acid amide hydrolase inhibitor) augmented the anticonvulsant effect of diazepam. Conversely, higher dose of anandamide, AM404, URB597 (100 µg/mouse) as well as capsaicin (a TRPV1 agonist: 1, 10, or 100 µg/mouse) attenuated the protective effect of diazepam against PTZ-induced seizures. Thus, this study demonstrates that the effects of diazepam may be augmented by activating CB 1 receptors or dampened via TRPV1 receptors. The findings of the present study can be extrapolated to understand the use of TRPV1 blockers alone or in combination of benzodiazepines in the treatment of benzodiazepines-refractory status epilepticus, a condition associated with maladaptive trafficking of synaptic gamma-aminobutyric acid and glutamate receptors. However, potential clinical applications are needed to further support such preclinical studies.

Pain is a major problem that burdens the health and economy of societies worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are over-the-counter medications that are widely indicated for mild to moderate pain conditions. Clinically, the selection of a medication among this class is mainly based according to both patient's and doctor's previous experiences. Herein, we studied differences in therapeutic efficacies among the most commonly prescribed NSAIDs and acetaminophen in inflammatory pain rat model. Body stretching and food consumption behaviors were assessed after intraperitoneal administration of lactic acid. Initially, different concentrations of lactic acid were evaluated in adult male rats in both behavioral models. Acid concentrations of 1.8 and 3.2% were selected to assess the effects of ibuprofen, diclofenac, naproxen, and acetaminophen in body stretching and feeding behaviors, respectively. In the feeding study, food restriction for 1-24 h prior to feeding studies was assessed at first, and 24 h was selected for further tests. Acetaminophen (100 mg/kg), diclofenac (10 mg/kg), ibuprofen (10-32 mg/kg), and naproxen (3.2-10 mg/kg) significantly decreased acid-stimulated body stretching. Likewise, acetaminophen (100 mg/kg), diclofenac (10 mg/kg), and ibuprofen (32 mg/kg) increased food consumption significantly after 3.2% lactic acid. There were no significant differences between different test drugs efficacies in both stretching and feeding behaviors. In conclusion, feeding behavior provides a good appraisal for pain and analgesic drugs in preclinical studies. There were comparable efficacies between all tested medications in both lactic acid-stimulated body stretching and -depressed feeding behaviors.

The insufficiency of human aldehyde dehydrogenase 2 (ALDH2) has been consistently associated with high blood acetaldehyde levels and impaired locomotor function during acute alcohol intoxication. The ALDH2-associated change in peripheral glutamic acid (Glu) and gamma-aminobutyric acid (GABA) levels and its correlation with pharmacokinetics and psychomotor function remain unclear. In this study, ALDH2*2 mice were used to build an acute alcohol intoxication model after intraperitoneal administration. The blood ethanol and acetaldehyde concentrations were analyzed to generate concentration-time curves at two doses of alcohol (2.0 and 4.0 g/kg). The dose of 4.0 g/kg was selected in accordance with the preliminary behavioral evaluation result to perform the following behavioral tests (e.g. the rotarod test, the open field test, and the Y-maze test), so as to assess locomotor activity, anxiety and cognitive ability. Plasma Glu and GABA levels were determined through enzyme-linked immunosorbent assays. The results suggested that the ALDH2*2 mice had highly accumulated acetaldehyde levels, impaired locomotor activity and anxiety-like emotion but unimpaired cognitive function, compared to the wild type (WT) mice. The plasma Glu level and the ratio of Glu/GABA in the alcohol-treated WT and ALDH2*2 groups decreased from 2 to 5 h after intraperitoneal administration, whereas the GABA level did not change significantly. The blood alcohol concentration in the WT and ALDH2*2 mice was positively correlated with plasma Glu level, whereas the blood acetaldehyde level was found as the opposite. We speculate that the decline degree of Glu/GABA ratio could be associated with psychomotor retardation and needs to be further investigated.

During pregnancy, women are prone to depression, for which selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are usually the first-line treatment. However, fluoxetine can cross the placental barrier and affect fetuses, causing changes in serotonin levels early in life. Long-term effects in the brain circuits that control cognitive and emotional behavior are related to early fluoxetine exposure during development. In this study, we aimed to investigate whether fluoxetine exposure (10 mg/kg/day) from the 13th gestational day (GD13) to GD21 may lead to behavioral emotional-cognitive changes in male and female rat offspring approximately 90 days postnatally (~PN90). We have analyzed the performance of individuals in the open field and in the plus-maze discriminative avoidance task, which assesses anxiety and learning/memory processing behaviors. We have found that prenatal (GD13-GD21) exposure to fluoxetine strengthened aversive memory and induced higher anxiety levels in males, and quick extinction of aversive memory in females. Taken together, these results suggest that early exposure to fluoxetine impairs the basal state of anxiety and the cognitive functions of rats during adulthood, which may be in a sex-specific manner because males appear more susceptible than females.

Parkinson's disease is a neurodegenerative disease, the etiology of which remains unknown, but some likely causes include oxidative stress, mitochondrial dysfunction and neuroinflammation. Peroxisome-proliferator-activated receptor (PPAR) agonists have been studied in animal models of Parkinson's disease and have shown neuroprotective effects. In this study, we aimed to (1) confirm the neuroprotective effects of PPAR-alpha agonist fenofibrate. To this end, male rats received fenofibrate (100 mg/kg) orally for 15 days, 5 days before the intraperitoneal injections of rotenone (2.5 mg/kg for 10 days). After finishing the treatment with rotenone and fenofibrate, animals were subjected to the open field, the forced swim test and the two-way active avoidance task. Subsequently, rats were euthanized for measurement of dopamine and metabolites levels in the striatum and quantification of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (SNpc). In addition, we aimed to (2) evaluate the neuroprotective effects of fenofibrate on the accumulation of α-synuclein aggregates. Here, rats were treated for 5 days with fenofibrate continuing for over 28 days with rotenone. Then, animals were perfused for immunohistochemistry analysis of α-synuclein. The results showed that fenofibrate reduced depressive-like behavior and memory impairment induced by rotenone. Moreover, fenofibrate diminished the depletion of striatal dopamine and protected against dopaminergic neuronal death in the SNpc. Likewise, the administration of fenofibrate attenuated the aggregation of α-synuclein in the SNpc and striatum in the rotenone-lesioned rats. Our study confirmed that fenofibrate exerted neuroprotective effects because parkinsonian rats exhibited reduced behavioral, neurochemical and immunohistochemical changes, and importantly, a lower number of α-synuclein aggregates.

Age is known to be the major risk factor for both pain sensation and sporadic Alzheimer's disease (sAD). Pain management in AD is a critical health condition. However, assessing pain in sAD patients is challenging. The intracerebroventricularly injected streptozotocin (icv-STZ) rat model of sAD has been brought to the fore as a hopefully suitable model that could mimic some features of sAD. However, the exact mechanism by which this agent may induce AD-like pathology is largely unknown. In some studies, analgesic drugs have been suggested as possible prevention of AD and icv-STZ-induced AD-like pathology. Therefore, this study used formalin and tail-flick tests to investigate whether different doses of icv-STZ injections could affect acute and inflammatory pain sensation and edema volume over time. Behavioral responses were observed at four testing time points (1, 2.5, 3.5, and 6 months postinjection). The results indicate that icv-STZ was able to significantly decrease the animals' formalin pain threshold in both a time- and dose-dependent manner. Formalin-induced acute and chronic pain scores of animals treated with streptozotocin 3 mg/kg (STZ3) increased dramatically 2.5 months after injection and persisted thereafter. The augmentation in pain score induced by streptozotocin 1 mg/kg (STZ1) was observed from 3.5 months after STZ injection. However, the effect of streptozotocin 0.5 mg/kg (STZ0.5) was NS until 6 months after injection. However, formalin-induced paw edema occurred with a longer delay and was not detectable in STZ0.5-treated animals. In addition, only STZ3-treated animals significantly reduced the thermal pain threshold of animals 6 months after injection. These observations indicate that icv-STZ can sensitize central and/or peripheral receptors to pain. The effect of STZ is dose- and time-dependent. AD-like pathology induced by icv-STZ could be partially activated via pain processing pathways. Therefore, anti-inflammatory agents could alleviate AD-like symptoms via pain treatments.

Sleep deprivation may induce anxiety. On the other hand, anxiety disorders elicit main changes in the quality of sleep. Moreover, orexin and citalopram play a role in the modulation of insomnia and mood diseases. Thus, we planned preclinical research to evaluate the effect of combinations of orexin agents and citalopram on anxiety behavior in rapid eye movement (REM) sleep-deprived mice. For drug intracerebroventricular (i.c.v.) infusion, the guide cannula was surgically implanted in the left lateral ventricle of mice. REM sleep deprivation was conducted via water tank apparatus for 24 h. The anxiety behavior of mice was evaluated using the elevated plus maze (EPM). Our results revealed that REM sleep deprivation reduced the percentage of open arm time (%OAT) and the percentage of the open arm entries (%OAE) but not closed arm entries (locomotor activity) in the EPM test, presenting an anxiogenic response ( P  < 0.05). We found a sub-threshold dose of SB-334867, orexin-1 receptor antagonist, and orexin-1 which did not alter anxiety reaction in the REM sleep-deprived mice ( P  > 0.05). Intraperitoneal (i.p.) injections of citalopram (5 and 10 mg/kg) increased both %OAT and %OAE ( P  < 0.001) representing an anxiolytic effect, but not locomotor activity in the REM sleep-deprived mice. Interestingly, co-treatment of citalopram (1, 5 and 10 mg/kg; i.p.) and SB-334867 (0.1 µg/mouse; i.c.v.) potentiated the anxiolytic effect in the REM sleep-deprived mice. On the other hand, co-treatment of different dosages of citalopram along with a sub-threshold dose of orexin-1 did not alter %OAT, %OAE, and locomotor activity in the REM sleep-deprived mice. We found a synergistic anxiolytic effect of citalopram and SB-334867 in the REM sleep-deprived mice. These results suggested an interaction between citalopram and SB-334867 to prevent anxiogenic behavior in the REM sleep-deprived mice.

The lateral habenula (LHb) is a critical brain structure involved in the aversive response to drug abuse. It has been determined that the gamma-aminobutyric acid (GABA)-ergic system plays the main role in morphine dependency. The role of GABA type A receptors (GABAARs) in LHb on morphine-induced conditioned place preference (CPP) remains unknown. In this study, the effect of bilateral intra-LHb microinjection of GABAAR agonist and antagonist on the acquisition and expression phases of CPP, utilizing a 5-day CPP paradigm in male rats, was evaluated. Subcutaneous administration of different doses of morphine caused a dose-dependent CPP. Intra-LHb microinjection of the GABAAR agonist, muscimol, in combination with morphine (5 mg/kg; subcutaneously) enhanced CPP scores in the acquisition phase of morphine CPP, whereas the GABAAR antagonist, bicuculline, significantly reduced the conditioning scores in the acquisition phase. Furthermore, pretreatment with a high dose of bicuculline reversed the additive effect of muscimol during the acquisition phase, yet the low dose of antagonist had no significant effect on agonist-induced CPP scores. On the other hand, muscimol (3 µg/rat) significantly increased CPP scores in the expression phase but bicuculline did not induce a significant effect on CPP scores. Bicuculline and muscimol microinjections did not affect locomotor activity in the testing sessions. Our results confirm that GABAARs in LHb play an active role in morphine reward. In addition, microinjections of bicuculline/muscimol may alter the morphine response through the GABAergic system.

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

The effect of curcumin (Cur) on cognitive impairment and the possible role of brain tissue oxidative stress, nitric oxide (NO) levels, and brain-derived neurotrophic factor (BDNF) were investigated in juvenile hypothyroid rats. The juvenile rats (21 days old) were allocated into the following groups: (1) control; (2) hypothyroid (0.05% propylthiouracil (PTU) in drinking water); (3-5) hypothyroid-Cur 50, 100, and 150, which in these groups 50, 100, or 150 mg/kg, Cur was orally administered by gavage during 6 weeks. In the hypothyroid rats, the time elapsed and the traveled distance to locate the hidden platform in the learning trials of Morris water maze (MWM) increased, and on the probe day, the amount of time spent in the target quadrant and the distance traveled in there was decreased. Hypothyroidism also decreased the latency and increased the time spent in the darkroom of the passive avoidance (PA) test. Compared with the hypothyroid group, Cur enhanced the performance of the rats in both MWM and PA tests. In addition, Cur reduced malondialdehyde concentration and NO metabolites; however, it increased thiol content as well as the activity of catalase (CAT) and superoxide dismutase enzymes in both the cortex and hippocampus. Cur also increased hippocampal synthesis of BDNF in hypothyroid rats. The beneficial effects of Cur cognitive function in juvenile hypothyroid rats might be attributed to its protective effect against oxidative stress and potentiation of BDNF production.