Wheel running during chronic nicotine exposure is protective against mecamylamine‐precipitated withdrawal and up‐regulates hippocampal α7 nACh receptors in mice

Background and purpose Evidence suggests that exercise decreases nicotine withdrawal symptoms in humans; however, the mechanisms mediating this effect are unclear. We investigate, in a mouse model, the effect of exercise intensity during chronic nicotine exposure on nicotine withdrawal severity, binding of α4β2*, α7 nicotinic acetylcholine (nAChR), μ-opioid (μ receptors) and D2 dopamine receptors, and on brain-derived neurotrophic factor (BDNF) and plasma corticosterone levels. Experimental approach Male C57Bl/6J mice treated with nicotine (minipump, 24 mg kg-1 day-1) or saline for 14 days underwent one of three concurrent exercise regimes: 24, 2 or 0 hrs day-1 voluntary wheel running. Mecamylamine-precipitated withdrawal symptoms were assessed on day 14. Quantitative autoradiography of α4β2*, α7 nAChRs, μ receptors and D2 receptor binding was performed in brain sections of these mice. Plasma corticosterone and brain BDNF levels were also measured. Key results Nicotine-treated mice undertaking 2 or 24 hrs day-1 wheel running displayed a significant reduction of withdrawal symptom severity compared with the sedentary group. Wheel-running induced a significant upregulation of α7 nAChR binding in the CA2/3 area of the hippocampus of nicotine-treated mice. Neither exercise nor nicotine treatment affected μ or D2 receptor binding or BDNF levels. Nicotine withdrawal increased plasma corticosterone levels and α4β2* nAChR binding, irrespective of exercise regimen. Conclusions and implications We demonstrate for the first time a profound effect of exercise on α7 nAChRs of nicotine-dependent animals, irrespective of exercise intensity. These findings shed light onto the mechanism underlining the protective effect of exercise in the development of nicotine dependence

Anxiety-like behavior profile in morphine dependent rats exposed to acute and chronic stress

Background: Previous studies indicate that morphine dependent and withdrawal from chronic opiates enhanced anxiety-related behaviours in novel and stressful conditions in rats. Recent studies have shown that exposure to a stressor generates a wide variety of adaptive responses, while enhancing abilities to adopt with the stressor. Therefore, the aim of this study was to examine the effect of chronic restraint stress and acute water immersion (WI) stress on the anxiety profile in morphine-dependent rats.Methods: Thirty two rats were injected with twice daily doses (10 mg/kg, subcutaneous, at 12 hour intervals) of morphine over a period of 10 days in the presence or absence chronic restraint stress (1 hour/day). On day 11, two hour after morphine injection, anxiety-like behaviours were tested in the elevated plus-maze model in the presence or absence acute water immersion stress. Rats were divided into four groups: dependent- No restraint stress (D/NRS), dependent- restraint stress (D/RS), dependent- restraint stress+ water immersion stress (D/RS+WI), dependent- water immersion stress (D/WI).Results: Finding have shown that D/RS+WI rats exhibited an increase in the elevated plus-maze open arm entries and time as compared with the control groups (P=0.018 and P=0.037, respectively). Also, this measure was significantly lower in the WI rats than the D/RS+WI rats (P=0.049 and P=0.031, respectively).Conclusion: Our findings indicate that chronic restraint stress followed by acute water immersion stress decreases the severity of the anxiogenic-like behaviours in morphine dependent rats; thus it may have a therapeutic application in the treatment of the asso-ciated disorders in addiction

Anxiety Assessment in Methamphetamine - Sensitized and Withdrawn Rats: Immediate and Delayed Effects

   Objective: The anxiety profile in the stimulant-sensitized animals is not clear. Thus, this study was conducted to elucidate the effects of acute and chronic administration of methamphetamine (METH) on the anxiety profile. The aim of this study was to examine whether METH-sensitized rats would show an increase in the expression of anxiogenic-like behaviors and to determine whether a low dose of METH elicits behavioral sensitization. Methods:Rats were repeatedly given METH (2 mg/kg, s.c., once a day for 14 days), and the immediate and delayed effects of METH on the anxiety profile was compared considering 30 minutes (min) and 120 min after injections in METH-sensitized, withdrawn and intact rats using the elevated plus-maze (EPM), also, to re-challenge with a low dose of METH (0.5 mg/kg) in withdrawn groups . Results:Results have shown that METH-sensitized rats exhibited an increase in the open arm time and entries 120 min after injection compared to the control group. We found a reduction in the time spent in open arms for the immediate effects of METH (30 min after injection) in METH-sensitized rats as compared to the control group. In withdrawn rats, METH/METH groups exhibited an increase in the open arm time and entries than METH/Sal and Sal/METH groups. Conclusion:It was found that unlike delayed effects, an immediate effect of METH exhibited anxiogenic-like behaviors in METH-sensitized rats using the EPM. Also, results indicated that a low dose of METH is a potent stimulus for reinstatement of methamphetamine behavioral sensitization in a long withdrawn period

Environmental Enrichment Prevents Methamphetamine-Induced Spatial Memory Deficits and Obsessive-Compulsive Behavior in Rats

Objective: This study was designed to examine the effect of environmental enrichment during methamphetamine (METH) dependency and withdrawal on methamphetamine-induced spatial learning and memory deficits and obsessive-compulsive behavior. Method: Adult male Wistar rats (200 ± 10 g) chronically received bi-daily doses of METH (2 mg/kg, sc, with 12 hours intervals) for 14 days. Rats reared in standard (SE) or enriched environment (EE) during the development of dependence on METH and withdrawal. Then, they were tested for spatial learning and memory (the water maze), and obsessive-compulsive behavior as grooming behavior in METH-withdrawn rats. Results: The results revealed that the Sal/EE and METH/EE rats reared in EE spent more time in the target zone on the water maze and displayed significantly increased proximity to the platform compared to their control groups. METH withdrawn rats reared in EE displayed less grooming behavior than METH/SE group. Conclusion: Our findings revealed EE ameliorates METH-induced spatial memory deficits and obsessive-compulsive behavior in rats

Voluntary and forced exercises prevent the development of tolerance to analgesic effects of morphine in rats

Objective(s):Morphine is widely used to treat chronic pain. However, its utility is hindered by the development of tolerance to its analgesic effects. Despite the renowned beneficial effects of physical exercise on cognitive functions and signs of morphine withdrawal in morphine-dependent rats, little is known about the roles of voluntary and forced exercises in tolerance to analgesic effect of morphine in rats. Materials and Methods: In this study, rats were injected with 10 mg/kg of morphine, once daily, SC over a period of 8 days of either voluntary or treadmill exercise. Following these injections, the percent of maximum possible effect (%MPE) of morphine was measured on the 1st, 4th, and 8th days by hot plate test. Results: Both voluntary and forced exercises significantly increased pain threshold compared to the sedentary group (

Environmental Enrichment Attenuates Morphine-Induced Conditioned Place Preference and Locomotor Sensitization in Maternally Separated Rat Pups

Introduction: This study investigated the effect of the environmental enrichment during adolescence on morphine-induced Conditioned Place Preference (CPP) and locomotor sensitization in maternally separated male and female rat pups. Methods: Male Wistar rats were allowed to mate with female virgin Wistar rats. Pups were separated from them 3 hours per day during 2–14 days postnatal. All pups were weaned at 21 Postnatal Day (PND) and reared in standard environment or enriched environment from 21 to 50 PND with litter-mates of the same sex. The CPP and behavioral sensitization to morphine were assessed by an unbiased place conditioning paradigm and open filed method. Results: The results showed that the maternal separation enhanced morphine-induced CPP in both sexes, locomotor sensitization in male pups and tolerance to morphine-induced motor activity in female pups during adolescence. While, male and female pups reared in an EE exhibited a decrease in morphine-induced CPP, locomotor sensitization and tolerance induced by maternal separation compared to their control pups. Conclusion: Access to enriched environment during adolescence may have a protective effect against morphine-induced reward, locomotor sensitization and tolerance in adolescent male and female rats following maternal separation

Swimming exercise attenuates psychological dependence and voluntary methamphetamine consumption in methamphet- amine withdrawn rats

Objective(s): This study evaluated the effect of swimming exercise during spontaneous methamphetamine (METH) withdrawal on the anxiety, depression, obsessive-compulsive disorder (OCD) and voluntary METH consumption in METH-dependent rats.  Materials and Methods: Male Wistar rats were repeatedly administered with bi-daily doses of METH (2 mg/kg, subcutaneous) over a period of 14 days. Exercised rats were submitted to swimming sessions (45 min/day, five days per week, for 14 days) during spontaneous METH-withdrawal. Then, all animals were tested for the assessment of anxiety by using the elevated plus-maze (EPM), the grooming behaviors (OCD), and depression using forced swimming test (FST) and voluntary METH consumption using a two-bottle choice (TBC) paradigm for the assessment of craving. Results: The results showed that the swimmer METH-withdrawn rats exhibited an increase in EPM open arm time and entries and a reduction of immobility and grooming behaviors compared with the sedentary METH groups. Also, voluntary METH consumption was less in the swimmer METH-withdrawn rats than the sedentary METH groups throughout 5–8 days. Conclusion: This study showed that regular swimming exercise reduced voluntary METH consumption in animal models of craving by reducing anxiety, OCD, and depression in the METH-withdrawn rats. Thus, physical training may be ameliorating some of the withdrawal behavioral consequences of METH

Effects of forced treadmill exercise during the induction of morphine dependence on the severity of physical and psychological dependence in morphine-dependent rats

Introduction: Previous studies have indicated that the voluntary and swimming exercise decreases the severity of the physical and psychological dependence on morphine in morphine-dependent and withdrawn rats. The aim of the present study was to investigate the effects of the forced treadmill exercise during the induction of morphine dependence on naloxone-precipitated morphine withdrawal signs and anxiety like behavior. Materials and Methods: Rats were injected with increasing doses of morphine (8, 16, 26, 36, 46, 56 and 64 mg/kg, daily, s.c.) over a period of 7 days in which they were also trained at mild intensity on a treadmill for 30 min of daily. The anxiety-like behaviors were tested 2h after receiving morphine injection (56 mg/kg) using the elevated plus-maze (EPM) on day 8. Then, the severity of morphine dependence was measured after an acute injection of naloxone (0.4mg/kg, IP), 2h after receiving morphine injection (56 mg/kg) according to a modified version of the Gellert–Holtzman scale on day 9. Results: The results showed that the withdrawal graded signs including abdominal contractions, weight loss, and overall Gellert–Holtzman score and among the checked signs; consisted of diarrhea, irritability and teach chattering were decreased in treadmill runner morphine-dependent rats than the sedentary rats. Also, the results showed that the treadmill runner morphine-dependent rats exhibited an increase in time spent in, and entries into, the EPM open arms than the sedentary morphine-dependent groups. Conclusion: Our findings indicated that the forced treadmill exercise during the induction of morphine dependence diminished the severity of dependence on morphine and anxiety like behavior. Thus, forced treadmill exercise may decrease some of the behavioral consequences of physical and psychological dependence on morphine

Environmental Enrichment Ameliorates Psychological Dependence Symptoms and Voluntary Morphine Consumption in Morphine Withdrawn Rats Under Methadone Maintenance Treatment

Introduction: Previous studies have shown that physical and psychological dependence and the vulnerability to relapse are still present during MMT. Thus, this study examined whether Enriched Environment (EE) would attenuate anxiety, depressive, and obsessive-compulsive-like behaviors, as well as voluntary morphine consumption following Methadone Maintenance Treatment (MMT) in morphine withdrawn rats. Methods: The rats were injected bi-daily doses (10 mg/kg, 12-h interval) of morphine for 14 days. Then, the rats were reared in a Standard Environment (SE) or EE for 30 more days during morphine withdrawal, simultaneous with receiving MMT. The rats were tested for anxiety (the Elevated Plus Maze [EPM]) and depression (Sucrose Preference Test [SPT]), Obsessive-Compulsive Disorder (OCD) as grooming behavior, and voluntary morphine consumption using a Two-Bottle Choice (TBC) paradigm. Results: The findings revealed that EE experience in morphine withdrawn rats under MMT significantly increased the EPM open-arm time and higher sucrose preference than SE rats. Also, we found that the EE decreased the self-grooming behavior and morphine preference ratio in morphine withdrawn rats receiving MMT compared to the SE group. Conclusion: We conclude that exposure to EE decreased methadone-induced anxiety, depressive and OCD-like behaviors, and voluntary morphine consumption in morphine withdrawn rats under MMT. Thus, the EE seems to be one of the strategies for reducing MMT-induced behavioral dysfunction and the risk of relapse induced by morphine withdrawal

Effects of Valeriane Officinalis, Satureja Hortensis, and Mentha Piperita extracts on the withdrawal syndrome signs in mice

Introduction: Several studies have demonstrated the antinociceptive, anti-inflammatory, sedative and smooth muscle relaxant activities of the Valeriane Officinalis (VO), Satureja Hortensis (SH), and Mentha Piperita (MP). The aim of this study was to determine the effects of the aqueous or hydroalcoholic extracts from these plants on morphine withdrawal syndrome signs in mice. Materials and Methods: 112 male albino mice (25-30 g) were used. Morphine was used to produce drug dependency by Marshall method. Different doses of the aqueous extracts of VO (25, 50, 100 mg/kg) and SH (25, 50, 100, 200 mg/kg IP) and the hydroalcoholic extract of MP (50, 100, 200, 500 mg/kg IP) were injected to morphine-dependent mice 30 min before the naloxone injection (2mg/kg). Control mice received saline. The severity of the morphine withdrawal responses was estimated by recordeing the number of jumping and the amount of weight feces during 3o min after naloxone injection. Results: The results showed that the extracts of VO (25 mg/kg), SH (200 mg/kg), and MP (all doses) significantly (P<0.05) decreased the number of jumping. Also, the VO (50 and 100 mg/kg), SH and MP (all tested doses) significantly decreased the weight of stool Conclusion: Our findings indicate that the extracts of VO, SH, and MP may diminish the morphine withdrawal syndrome signs