Behavioural Pharmacology最新文献

Increasing evidence indicates that neuroinflammation, oxidative stress, and neurotrophic factors play a key role in the pathophysiology of major depressive disorder (MDD). In addition, the attenuation of inflammatory response has been considered a putative mechanism for MDD treatment. PT-31 is an imidazolidine derivative and a putative α₂-adrenoceptor agonist that has previously demonstrated antinociceptive activity. The present study aimed to investigate the effect of PT-31 on depressive-like behavior and lipopolysaccharide-induced neurochemical changes. To this end, mice received intraperitoneally saline or lipopolysaccharide (600 µg/kg), and 5 h postinjection animals were orally treated with saline, PT-31 (3, 10, and 30 mg/kg), or fluoxetine (30 mg/kg). Mice were subjected to the open field test (OFT) 6 and 24 h after lipopolysaccharide administration and to the tail suspension test (TST) 24 h postlipopolysaccharide. Subsequently, animals were euthanized, and brains were dissected for neurochemical analyses. The administration of lipopolysaccharide-induced sickness- and depressive-like behaviors, besides promoting an increase in myeloperoxidase activity and a reduction in brain-derived neurotrophic factor (BDNF) levels. Noteworthy, PT-31 3 mg/kg attenuated lipopolysaccharide-induced decreased locomotor activity 6 h after lipopolysaccharide in the OFT. All tested doses of PT-31 significantly reduced the immobility time of animals in the TST and attenuated lipopolysaccharide-induced increased myeloperoxidase activity in the cortex of mice. Our results demonstrate that PT-31 ameliorates behavioral changes promoted by lipopolysaccharide in OFT and TST, which is possibly mediated by attenuation of the inflammatory response.

Riparin A is a synthetic form of natural riparins. Acute scale studies that take into consideration the structure-activity relationship have shown preliminary evidence of antidepressant and anxiolytic effects of riparin A, similar to that already known for other riparins. However, for better pharmacological characterization of this new compound, further studies are required. The aim of this work was to evaluate the effect of chronic treatment with riparin A (10 mg/kg; intraperitoneally) on depressive-like behavior in the forced swimming test and tail suspension test, as well as the reduction of anhedonia in the sucrose preference test, and on anxiety-like behavior in the open field and elevated plus maze apparatus, triggered in rats previously subjected to unpredictable chronic mild stress by 4 weeks. In addition, a pentobarbital-induced sleep time test was also used. Riparin A reduced the duration of immobility in both the forced swimming test and tail suspension test, as well as attenuated the anhedonia in the sucrose preference test. Furthermore, riparin A appears to produce anxiolytic effects in rats exposed to an open field and elevated plus maze, while increasing the alertness/vigilance in rats submitted to pentobarbital-induced sleep time test, without altering their locomotor integrity. Our results suggest that chronic riparin A appears to be a potential pharmacological target for new studies on the control of depression- and anxiety-like behaviors in stressed rats.

This study determined whether consumption of a highly palatable liquid is a reliable measure of inflammatory pain and antinociception in male and female rats. After a 10-day acquisition period, the impact of intraplantar oil vs. complete Freund adjuvant (CFA) on consumption of vanilla-flavored Ensure was assessed, with a sipper tube height 12 or 19 cm above the floor. CFA significantly decreased Ensure consumption, which completely recovered within 4-7 days to levels in oil-treated controls; neither sex nor sipper tube height significantly influenced Ensure consumption. CFA also significantly suppressed Ensure consumption in rats not exposed to the 10-day acquisition period, but only in males. To test the predictive validity of Ensure consumption as a measure of pain, separate rats were pretreated with a vehicle, an opioid, a nonsteroidal anti-inflammatory drug, or a cannabinoid the day after CFA treatment. Morphine and ibuprofen significantly attenuated CFA-suppressed drinking in at least one sex, and tetrahydrocannabinol did not. Neither ibuprofen nor tetrahydrocannabinol significantly altered drinking in oil-injected, 'pain-free' controls, but morphine increased drinking. These results demonstrate that CFA decreases consumption of a highly palatable liquid regardless of previous exposure (training) to the consumption procedure, but only in males. Although standard analgesics attenuate CFA-suppressed drinking, nonspecific hyperphagic effects can confound the interpretation of results. Thus, consumption of a highly palatable liquid is not an optimal measure for candidate analgesic screening.

Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2 mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10 mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72 h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.

Excessive prescribing and misuse of prescription opioids, such as oxycodone, significantly contributed to the current opioid crisis. Although oxycodone is typically consumed orally by humans, parenteral routes of administration have primarily been used in preclinical models of oxycodone dependence. To address this issue, more recent studies have used oral self-administration procedures to study oxycodone seeking and withdrawal in rodents. Behavioral differences, however, following oral oxycodone intake versus parenteral oxycodone administration remain unclear. Thus, the goal of the current studies was to compare anxiety- and withdrawal-like behaviors using established opioid dependence models of either home cage oral intake of oxycodone (0.5 mg/ml) or repeated subcutaneous (s.c.) injections of oxycodone (10 mg/kg) in male and female mice. Here, mice received 10 days of oral or s.c. oxycodone administration, and following 72 h of forced abstinence, anxiety- and withdrawal-like behaviors were measured using elevated zero maze, open field, and naloxone-induced precipitated withdrawal procedures. Global withdrawal scores were increased to a similar degree following oral and s.c. oxycodone use, while both routes of oxycodone administration had minimal effects on anxiety-like behaviors. When examining individual withdrawal-like behaviors, mice receiving s.c. oxycodone exhibited more paw tremors and jumps during naloxone-induced precipitated withdrawal compared with oral oxycodone mice. These results indicate that both models of oxycodone administration are sufficient to elevate global withdrawal scores, but, when compared with oral consumption, s.c. oxycodone injections yielded more pronounced effects on some withdrawal-like behaviors.

Drug dependence is a chronic brain disease characterized by craving and recurrent episodes of relapse. Tramadol HCl is a promising agent for withdrawal symptoms management, considering its relatively low abuse potential and safety. Oral administration, however, is not preferred in abstinence maintenance programs. Introducing an implantable, long-lasting formula is suggested to help outpatient abstinence programs achieve higher rates of treatment continuation. Tramadol implants (T350 and T650) were prepared on polycaprolactone polymer ribbons by the wet method. Male Wistar rats were adapted to heroin-conditioned place preference (CPP) at escalating doses (3-30 mg/kg, intraperitoneally, for 14 days). Implants were surgically implanted in the back skin of rats. After 14 days, the CPP score was recorded. Naloxone (1 mg/kg, intraperitoneally) was used to induce withdrawal on day 15, and symptoms were scored. Elevated plus maze and open field tests were performed for anxiety-related symptoms. Striata were analyzed for neurochemical changes reflected in dopamine, 3,4-dihydroxyphenyl acetic acid, gamma-aminobutyric acid, and serotonin levels. Brain oxidative changes including glutathione and lipid peroxides were assessed. The tramadol implants (T350 and T650) reduced heroin CPP and limited naloxone-induced withdrawal symptoms. The striata showed increased levels of 3,4-dihydroxyphenyl acetic acid, and serotonin and decreased levels of gamma-aminobutyric acid and dopamine after heroin withdrawal induction, which were reversed after implanting T350 and T650. Implants restore the brain oxidative state. Nonsignificant low naloxone-induced withdrawal score after the implant was used in naive subjects indicating low abuse potential of the implants. The presented tramadol implants were effective at diminishing heroin CPP and withdrawal in rats, suggesting further investigations for application in the management of opioid withdrawal.

Introduction: Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing of dopamine neurons. Besides, sensitive and advanced research techniques led to the recognition of the mesohippocampal dopaminergic terminals, particularly in the hippocampal dentate gyrus (DG). Moreover, previous studies have shown that dopamine receptors within the hippocampal DG play a critical role in induced antinociceptive responses by forced swim stress (FSS) in the presence of inflammatory pain. Since different pain states can trigger various mechanisms and transmitter systems, the present experiments aimed to investigate whether dopaminergic receptors within the DG have the same role in the presence of acute thermal pain.

Methods: Ninety-seven adult male albino Wistar rats underwent stereotaxic surgery, and a stainless steel guide cannula was unilaterally implanted 1 mm above the DG. Different doses of SCH23390 or sulpiride as D1- and D2-like dopamine receptor antagonists were microinjected into the DG 5-10 min before exposure to FSS, and 5 min after FSS exposure, the tail-flick test evaluated the effect of stress on the nociceptive response at the time-set intervals.

Results: The results demonstrated that exposure to FSS could significantly increase the acute pain perception threshold, while intra-DG administration of SCH23390 and sulpiride reduced the antinociceptive effect of FSS in the tail-flick test.

Discussion: Additionally, it seems the D2-like dopamine receptor within the DG plays a more prominent role in FSS-induced analgesia in the acute pain model.

Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28 days. From 15th to the 22nd day, the animals received RIP I or RIP II (50 mg/kg) or fluoxetine (FLU, 10 mg/kg) or vehicle, by gavage. On the 29th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 - Iba-1) and astrocyte (glial fibrillary acidic protein - GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1β) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1β levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression.

LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P  < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P  < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.

Rapid-eye movement (REM) sleep deprivation (SD) can induce manic-like behaviors including hyperlocomotion. On the other hand, crocin (one of the main compounds of Crocus sativus L. or Saffron) may be beneficial in the improvement of mental and cognitive dysfunctions. Also, crocin can restore the deleterious effects of SD on mental and cognitive processes. In this study, we investigated the effect of REM SD on female rats' behaviors including depression- and anxiety-like behaviors, locomotion, pain perception, and obsessive-compulsive-like behavior, and also, the potential effect of crocin on REM SD effects. We used female rats because evidence on the role of REM SD in modulating psychological and behavioral functions of female (but not male) rats is limited. REM SD was induced for 14 days (6h/day), and crocin (25, 50, and 75 mg/kg) was injected intraperitoneally. Open field test, forced swim test, hot plate test, and marble burying test were used to assess rats' behaviors. The results showed REM SD-induced manic-like behavior (hyperlocomotion). Also, REM SD rats showed decreased anxiety- and depression-like behavior, pain subthreshold (the duration it takes for the rat to feel pain), and showed obsessive compulsive-like behavior. However, crocin at all doses partially or fully reversed REM SD-induced behavioral changes. In conclusion, our results suggested the possible comorbidity of OCD and REM SD-induced manic-like behavior in female rats or the potential role of REM SD in the etiology of OCD, although more studies are needed. In contrast, crocin can be a possible therapeutic choice for decreasing manic-like behaviors.