OBJECTIVES: The present study was performed to investigate the discriminative stimulus effects of MG in rats. The pharmacological mechanism of MG action and its derivative, 7-hydroxymitragynine (7-HMG) with a specific focus on opioid receptor involvement was examined in rats trained to discriminate morphine from vehicle. In order to study the dual actions of MG, the effect of cocaine substitution to the MG discriminative stimulus was also performed in MG-trained rats.
METHODS: Male Sprague Dawley rats were trained to discriminate MG from vehicle in a two-lever drug discrimination procedure under a tandem variable-interval (VI 60') fixed-ratio (FR 10) schedule of food reinforcement.
RESULTS: Rats acquired the MG discrimination (15.0 mg/kg, i.p.) which was similar to the acquisition of morphine discrimination (5.0 mg/kg, i.p.) in another group of rats. MG substituted fully to the morphine discriminative stimulus in a dose-dependent manner, suggesting pharmacological similarities between the two drugs. The administration of 7-HMG derivative in 3.0 mg/kg (i.p.) dose engendered full generalisation to the morphine discriminative stimulus. In addition, the MG stimulus also partially generalised to cocaine (10.0 mg/kg, i.p.) stimulus.
CONCLUSION: The present study demonstrates that the discriminative stimulus effect of MG possesses both opioid- and psychostimulant-like subjective effects.
OBJECTIVES: This study investigated the effects of fish oil supplementation on cognitive function in elderly person with MCI.
METHODS: This was a 12-month, randomised, double-blind, placebo-controlled study using fish oil supplementation with concentrated docosahexaenoic acid (DHA). Thirty six low-socioeconomic-status elderly subjects with MCI were randomly assigned to receive either concentrated DHA fish oil (n = 18) or placebo (n = 18) capsules. The changes of memory, psychomotor speed, executive function and attention, and visual-constructive skills were assessed using cognitive tests. Secondary outcomes were safety and tolerability of the DHA concentrate.
RESULTS: The fish oil group showed significant improvement in short-term and working memory (F = 9.890; ηp (2) = 0.254; p
OBJECTIVES: The present study investigates the effect of a novel 5-HT3 receptor antagonist 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on several pathogenic markers of depression associated with obesity such as plasma insulin resistance, hippocampal cyclic adenosine monophosphate (cAMP), brain-derived neurotrophic factor (BDNF), serotonin (5-HT) concentrations, hippocampal neuronal damage, and p53 protein expression in high-fat-diet (HFD)-fed mice.
METHODS: Obesity was experimentally induced in mice by feeding with HFD for 14 weeks followed by administration of QCM-4 (1 and 2 mg/kg, p.o.)/standard escitalopram (ESC) (10 mg/kg, p.o.)/vehicle (10 ml/kg, p.o.) for 28 days. Behavioral assays such as sucrose preference test (SPT); forced swim test (FST); elevated plus maze (EPM); biochemical assays including oral glucose tolerance tests (OGTT), insulin, cAMP, BDNF, and 5-HT concentrations; and molecular assays mainly histology and immunohistochemistry (IHC) of p53 protein in the dentate gyrus (DG), CA1, and CA3 regions of hippocampus in HFD fed mice were performed.
RESULTS: Chronic treatment with QCM-4 in HFD-fed mice reversed the behavioral alterations in SPT, FST, and EPM. QCM-4 showed poor sensitivity for plasma glucose, improved insulin sensitivity, increased hippocampal cAMP, BDNF, and 5-HT concentrations. In the hippocampal DG, CA1, and CA3 regions, QCM-4 treatment improved the neuronal morphology in the histopathology and inhibited p53 protein expression in IHC assay in HFD-fed mice.
CONCLUSION: QCM-4 attenuated the depressive-like phenotype in HFD-fed mice by improving behavioral, biochemical, and molecular alterations through serotonergic neuromodulation.
OBJECTIVES: This study examined the dependence-producing effects of MG using operant-scheduled behaviour in rats and investigated the potential therapeutic effect of MG by comparing effects to buprenorphine in morphine-dependent rats using the same schedule-controlled behavioural task.
METHODS: The effects of acutely administered MG and morphine were determined in rats trained to respond under fixed-ratio (FR) 10 schedule of food reinforcement. Next, the rats were administered MG and morphine twice daily for 14 consecutive days to determine if physiological dependence would develop by examining cessation of drug treatment and following antagonist-precipitated withdrawal. The study then examined the effects of MG substitution to suppress naloxone-precipitated morphine withdrawal effects on scheduled responding.
RESULTS: Acute doses of MG did not produce dose-related decreases on FR schedules of responding compared to morphine. Unlike morphine, MG-treated rats showed no suppression of response rates following cessation of MG treatment. However, withdrawal effects were evident for MG after precipitation by either naloxone or SR141716A (rimonabant), similar to morphine-treated rats. MG in higher doses (10 and 30 mg/kg) attenuated the naloxone-precipitated morphine withdrawal effects while smaller doses of buprenorphine (0.3 and 1.0 mg/kg) were necessary to alleviate these effects.
CONCLUSION: The findings suggest that MG does not induce physiological dependence but can alleviate the physical symptoms associated with morphine withdrawal which represent the desired characteristics of novel pharmacotherapeutic interventions for managing opioid use disorder (OUD).
OBJECTIVES: The present study examines the cellular mechanisms by which scopolamine produces antidepressant-like effects through its action in the ventrolateral midbrain periaqueductal gray (vlPAG).
METHODS: We used a well-established mouse model of depression induced by chronic restraint stress (CRS) exposure for 14 days. Behaviors were tested using the forced swim test (FST), tail suspension test (TST), female urine sniffing test (FUST), novelty-suppressed feeding test (NSFT), and locomotor activity (LMA). Synaptic transmission in the vlPAG was measured by whole-cell patch-clamp recordings. IntravlPAG microinjection was used to pharmacologically verify the signaling cascades of scopolamine in the vlPAG.
RESULTS: The results demonstrated that intraperitoneal injection of scopolamine produced antidepressant-like effects in a dose-dependent manner without affecting locomotor activity. CRS elicited depression-like behaviors, whereas intraperitoneal injection of scopolamine alleviated CRS-induced depression-like behaviors. CRS diminished glutamatergic transmission in the vlPAG, while scopolamine reversed the above effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist CNQX prevented scopolamine-induced antidepressant-like effects.
CONCLUSIONS: Scopolamine ameliorated CRS-elicited depression-like behavior required activation of VDCC, resulting in activity-dependent release of brain-derived neurotrophic factor (BDNF), engaging the TrkB receptor and downstream mTORC1 signaling in the vlPAG.
OBJECTIVES: Using the pentylenetetrazol (PTZ) discrimination assay, this study aims to investigate the effects of MG in responding to the PTZ stimulus and to assess the generalisation effects of withdrawal from MG to the PTZ stimulus.
METHODS: Rats (n = 20) were trained on a tandem (FR-10, VI-15) schedule of food reinforcement to press one lever after administration of the anxiogenic compound PTZ (16 mg/kg, i.p.) and an alternate lever after vehicle. Following acute tests, training was suspended, and rats were chronically treated with MG or morphine at 8-h intervals for 9 days and withdrawal was precipitated on the tenth day using naloxone (1 mg/kg, i.p.). The rats were tested for generalisation to PTZ at 2, 8 and 24 h after the last dose of MG or morphine administration.
RESULTS: Unlike morphine that produced dose-related PTZ-like stimulus, MG at 3, 10, 30 and 45 mg/kg doses showed no substitution to the PTZ discriminative stimulus. In contrast to morphine which produced a time-dependent generalisation to the PTZ stimulus, naloxone did not precipitate withdrawal effects in MG-treated rats as they selected the vehicle lever at three withdrawal time points.
CONCLUSION: These results demonstrate that MG produces a very different response to morphine withdrawal that is not associated with anxiogenic-like subjective symptoms. These characteristics of MG may provide further support for use as a novel pharmacotherapeutic intervention for managing opioid use disorder.
OBJECTIVES: The investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms.
METHODS: Male C57BL/6 J mice and Sprague-Dawley rats were examined in five independent experiments. We assessed APH199 (0.1-5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light-dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats.
RESULTS: APH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats.
CONCLUSIONS: Our data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.
OBJECTIVES: We aimed to examine the cognitive effects of mitragynine substitution in morphine-withdrawn rats. Furthermore, we asked whether neuronal addiction markers like the brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent kinase II alpha (αCaMKII) might mediate the observed effects.
METHODS: Male Sprague-Dawley rats were given morphine at escalating doses before treatment was discontinued to induce a spontaneous morphine withdrawal. Then, vehicle or mitragynine (5 mg/kg, 15 mg/kg, or 30 mg/kg) substitution was given for 3 days. A vehicle-treated group was used as a control. Withdrawal signs were scored after 24 h, 48 h, and 72 h, while novel object recognition (NOR) and attentional set-shifting (ASST) were tested during the substitution period.
RESULTS: Discontinuation of morphine significantly induced morphine withdrawal signs and cognitive deficit in the ASST. The substitution with mitragynine was able to alleviate the withdrawal signs. Mitragynine did not affect the recognition memory in the NOR but significantly improved the reversal learning deficit in the morphine-withdrawn rats.
CONCLUSIONS: These data support the idea that mitragynine could be used as safe medication therapy to treat opiate addiction with beneficial effects on cognitive deficits.