Results showed that non-stressed withdrawn mice did not exhibit alcohol-place preference or alteration of plasma corticosterone concentrations relative to water controls. After stress, however, withdrawn mice exhibited a significant alcohol-place preference and higher circulating corticosterone concentrations as compared to stressed water controls.
Interestingly, repeated administration during the withdrawal phase of baclofen but not diazepam suppressed both the alcohol-place preference and normalized corticosterone levels in stressed withdrawn animals.
In conclusion, this study evidences that a pre-treatment with baclofen but not with diazepam during the withdrawal phase normalized, even after a long period of abstinence, the HPA axis response to stress, which contributes to the long-term preventing effects of this compound on alcohol-seeking behavior. There is substantial evidence that cognitive and neurobiological alterations are either dramatically enhanced or gradually developed after alcohol withdrawal 1 — 4.
One of the main disturbances associated with alcohol withdrawal involves a dysregulation of the hypothalamic—pituitary—adrenal HPA axis, which accounts for excessive glucocorticoid GC release 5. Thus, evidence in humans 6 — 8 and rodents 9 — 11 has shown that alcohol withdrawal markedly affects plasma GC levels.
Moreover, studies in rodents have evidenced brain regional GC disturbances after long alcohol withdrawal periods 12 , which account for protracted cognitive dysfunction 13 , The relationships between the HPA axis activity, craving, and alcohol intake during early abstinence have been well documented 15 , Clinical and experimental studies pointed out how corticosterone and stress interact with the brain reward system and contribute to alcohol reinforcing effects 17 , 18 and relapse to alcohol-seeking behavior Therefore, reducing or suppressing GC dysregulations in alcohol-withdrawn mice can prevent relapse to alcohol-seeking behavior.
Indeed, baclofen an agonist of GABA B receptors and diazepam a benzodiazepine having an agonist action on GABA A receptors have been found to reduce the HPA axis activity in withdrawn alcoholics 7 , 21 — 24 and addiction to alcohol in both humans and animals 25 — Main issues remain, however, i to determine the beneficial effects of these compounds after a long abstinence, since most of the existing studies have been mainly carried out after short withdrawal periods 31 , 32 , and ii since stress is a main factor of alcohol-seeking behavior and relapse 33 , 34 , if the long-term beneficial effects of these compounds are still observed in the stress condition.
We previously developed a mouse model of alcohol withdrawal inducing protracted cognitive deficits and persistent brain regional GC alterations up to 6 weeks after the cessation of alcohol intake 13 , 14 , As yet, however, we did not investigate if withdrawn mice exhibit persistent altered motivation for alcohol. To that aim, we first determined the emotional profile anxiety and depression-like behaviors of withdrawn animals after short 1 week or long 4 weeks withdrawal periods.
Then, in Experiment 2, we studied alcohol-seeking behavior in an odor recognition task and measured the circulating corticosterone concentrations in non-stressed or stressed mice after the 1-week or 4-week alcohol-withdrawal periods. Finally, in Experiment 3, we compared the effects of repeated injections of diazepam or baclofen delivered during the withdrawal phase on the stress-induced alcohol-seeking behavior and HPA axis dysfunction found in Experiment 2, more particularly in 4-week withdrawn animals.
They were provided with food and water or alcohol ad libitum. All procedures were carried out during the light phase of the cycle. All experimental procedures were performed between and a. The procedure has been described in full previously Alcohol consumption was measured during the 6-month alcohol consumption period, by scoring each week the decrease of liquid consumption on graduated bottles.
The mean daily alcohol intake per mouse was then calculated for each group of alcohol-withdrawn mice used in the study. At the end of that period, all mice were housed in individual cages and alcohol-treated mice were progressively withdrawn from alcohol. Behavioral testing began either after 1 week withdrawn 1W or 4 weeks withdrawn 4W of water supply. To avoid potential negative effects of isolation in individual cages, wooden marbles were added in the cages that were constructed of transparent Plexiglas, allowing us to visualize congeners.
In the present study, alcohol-withdrawn mice were attributed to 13 different independent groups over the three experiments of the study. Each task and experiment was performed with independent cohorts of mice. Thus, withdrawn 1W and withdrawn 4W mice belong to independent groups. A total of mice were used as control mice, also attributed to independent groups. They were housed similarly as the alcohol-withdrawn groups, but permanently received water control 1W and control 4W.
Animals were submitted to behavioral testing either 1 week or 4 weeks after the end of the withdrawal periods and were therefore 9 to 10 months old at the time of behavioral testing. Experiments 1, 2, and 3 were run using different cohorts of mice.
Figure 1 depicts the general procedure used for alcohol administration and withdrawal, followed by behavioral testing of Experiments 1, 2, and 3. Figure 1 Schematic overview of the alcohol exposure, withdrawal, and behavioral experiments.
Control groups were exposed to the same general schedule except that they received permanently water as the sole source of fluid. Either 1 week or 4 weeks after the end of the withdrawal phase, independent groups of mice were used to test alcohol withdrawal anxiety-like reactivity Experiment 1 in elevated plus maze EPM , open-field, and Porsolt tasks; similarly, independent groups of 1-week or 4-week withdrawn mice were submitted to the odor recognition task and blood sampling in stress or non-stress conditions Experiment 2 and Experiment 3: withdrawn 4-week mice only.
The acute stress was constituted by electric footshocks delivered 45 min before behavioral testing. This task is classically used to evaluate anxiety-like reactivity in rodents The elevated plus maze was made of gray Plexiglas with four arms arranged in the shape of a plus sign. Each arm was 30 cm long, 7 cm wide, and elevated 40 cm above the ground. The four arms were joined at the center by a 7-cm square platform.
Mice were allowed to freely explore all arms for 5 min. The open-field task allows the evaluation of anxiety-like locomotor reactivity in an open space, known to be an anxious situation in rodents The open-field chamber was constructed of white Plexiglas in the shape of a circle measuring cm in diameter and surrounded by a wall that is 15 cm high.
The floor was made in white Plexiglas. A bright illumination was provided by two lamps positioned 2 m above the apparatus and providing a lux illumination equally distributed over the whole surface of the apparatus.
At the start of each trial, animals were placed in the periphery of the apparatus and the subjects were allowed to freely explore for 10 min. Two parameters were recorded: first, the latency to move from the periphery to the center; secondly, the total number of virtual crossed zones.
The forced-swim test is commonly used to evaluate depressive-like behaviors in mice An animal presenting a depressive-like behavior will spend more immobility time than a non-depressive control mouse. The odor of alcohol is used as a cue for inducing a place preference. In this task, mice were allowed to discriminate between an area humidified with water neutral odor and another one with the alcohol solution previously drunk during the 6-month alcohol exposure. The rationale is that the time spent in the alcohol area would be an index of a place preference and therefore of alcohol-seeking behavior.
The floor was covered with sawdust. Figure 2 The odor recognition task. The apparatus is a rectangular chamber made of transparent Plexiglas. To enhance exploration, two identical familiar empty gray Plexiglas boxes were placed in the water and alcohol zones empty boxes, black squares.
During the recognition session, animals were placed in the central neutral zone and allowed to explore the apparatus for 6 min. The times spent exploring the alcohol and water zones were scored.
Mice received electric footshocks 45 min before the recognition test, according to previous studies that have shown high plasma and brain corticosterone concentrations at this post-stress delay 40 , The floor consisted of 35 stainless steel rods 3 mm diameter , spaced 5 mm apart and wired to a shock generator for the delivery of three successive footshocks 0.
Non-stressed mice were also placed in the chamber except that they did not receive footshocks. Sampling occurred between a. All procedures were similar to those described in Experiment 2. This experiment was conducted in withdrawn 4W mice, which exhibited higher recognition scores in the odor recognition task. The pharmacological administration procedure is depicted in Figure 3.
Figure 3 Pharmacological study Experiment 3. All mice received on the first 12 days of treatment either vehicles or diazepam at 0. Water groups were submitted to the same pharmacological procedures as those used in withdrawn groups.
Behavioral testing occurred 4 weeks after the last injection. Diazepam and baclofen were given during the 15 days preceding the end of the withdrawal phase Day 0 Figure 3. The doses were progressively decreased from Day 15 to Day 1, to avoid potential negative effects of an abrupt cessation of drug administrations. Diazepam was first delivered at a dose of 0. Similarly, baclofen was first delivered at a dose of 1.
Behavioral testing began 4 weeks after the last injection. This study was designed to discard any acute effects of diazepam and baclofen on the alcohol-place preference scores.
For that purpose, samples were sent to the Laboratory of Pharmacology and Toxicology Bordeaux, France for analyses. Statistical analyses were performed using the Statview 5. Behavioral performance and corticosterone assays were analyzed using one- or two-way analyses of variance ANOVAs. These analyses have been conducted using the R statistical software v3. Among the withdrawn mice, the mean daily alcohol consumption mL was 4. Thus, it can be assumed that the different withdrawn groups used in the present study received equivalent exposure to alcohol.
In comparison, the mean daily water consumption was measured in two groups of water controls; the mean daily water consumption was 2. Thus, it can be assumed that alcohol-treated mice were not dehydrated during alcohol exposure and at the time of experiments. Post hoc analyses showed a significant decrease of entry ratio in withdrawn 1W mice A decrease of entry ratio was also observed in the withdrawn 4W group A non-significant decrease of time ratio Figure 4B was observed in withdrawn 1W mice A small significant decrease of time ratio was observed in the withdrawn 4W group Figure 4 Emotional reactivity.
B In contrast, the decrease of time ratios observed in withdrawn groups was not statistically different from respective water control groups. No significant between-group difference was observed on latency to reach the periphery of the arena to the center zone.
C 1W withdrawn mice showed a significant mild reduction of activity in the center zone D. No significant difference was observed on the immobility time E.
More precisely, 1W withdrawn mice Similarly, the 4W withdrawn group More precisely, withdrawn 1W mice exhibited a lower number of crossed zones as compared to control 1W mice [6.
In contrast, withdrawn 4W mice 7. More precisely, withdrawn 1W mice exhibited a non-significant higher immobility time as compared to control 1W mice [ This experiment was performed with independent cohorts of mice not used in Experiment 1. Data are depicted in Figure 5. Figure 5 The odor recognition task. In non-stressed animals, no significant between-group difference was observed [control 1W: In the non-stress condition, no significant between-group difference was observed [control 1W: In the stress condition, a significant between-group difference was observed [control 1W: In the non-stress condition, no significant between-group difference was observed [control 1W: 1.
More precisely, the withdrawn 1W group exhibited a higher discrimination ratio as compared to the control 1W group [1. More specifically, the stressed control 4W group In the non-stress condition, no significant difference was observed between 1W Data are summarized in Table 1. Although there appears to be insufficient data on metaxalone and methocarbamol, these may be useful in patients who cannot tolerate the sedative properties of cyclobenzaprine or tizanidine.
Of note, methocarbamol costs substantially less than metaxalone. Carisoprodol is metabolized to meprobamate a class III controlled substance and has been shown to produce psychological and physical dependence.
Although all skeletal muscle relaxants should be used with caution in older patients, diazepam especially should be avoided in older patients or in patients with significant cognitive or hepatic impairment. Already a member or subscriber? Log in. Interested in AAFP membership? Learn more. She received her doctor of pharmacy degree from Rutgers University College of Pharmacy in New Brunswick, NJ, and completed an inpatient family medicine pharmacy specialty residency at Deaconess Hospital and the St.
Louis College of Pharmacy in St. Louis, Mo. She received her doctor of pharmacy degree from St. Reprints are not available from the authors. Carisoprodol carisoprodol tablet [package insert]. Philadelphia, Pa. Accessed January 14, Chlorzoxazone chlorzoxazone tablet [package insert].
Sellersville, Pa. Cyclobenzaprine hydrochloride cyclobenzaprine hydrochloride tablet [package insert]. Corona, Calif. Diazepam diazepam tablet [package insert]. Miami, Fla. Skelaxin metaxalone [package insert]. Briston, Tenn. Methocarbamol methocarbamol tablet [package insert]. January 14, Orphenadrine citrate extended-release orphenadrine citrate tablet [package insert]. Princeton, NJ: Sandoz, Inc. Tizanidine hydrochloride tizanidine hydrochloride tablet [package insert].
Pomona, NY: Barr Laboratories. United States Food and Drug Administration. Zanaflex tizanidine hydrochloride tablets and capsules. Top brand-name drugs by units in Top generic drugs by units in Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society [published correction appears in Ann Intern Med.
Ann Intern Med. National Headache Foundation. National Headache Foundation standards of care for headache diagnosis and treatment. Chicago, Ill. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis.
Prescription of nonsteroidal anti-inflammatory drugs and muscle relaxants for back pain in the United States. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. Diamond S. Double-blind study of metaxalone; use as a skeletal-muscle relaxant.
Chou R, Huffman LH. Activity of tetrazepam in low back pain. Clin Trials J. Treatment of chronic low-back syndrome with tetrazepam in a placebo controlled double-blind trial. J Drug Dev. Scheiner JJ. Cyclobenzaprine in the treatment of local muscle spasm. Minneapolis, Minn. Aiken DW. A comparative study of the effects of cyclobenzaprine, diazepam, and placebo on acute skeletal muscle spasm of local origin.
Brown BR jr, Womble J. Cyclobenzaprine in intractable pain syndrome with muscle spasms. Basmajian JV. Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar region and neck: two double-blind controlled clinical laboratory studies.
Arch Phys Med Rehabil. Cyclobenzaprine and back pain: a meta-analysis. Arch Intern Med. Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin Ther. Show detailed description. Hide detailed description. Detailed Description:. Drug Information available for: Diazepam Baclofen. FDA Resources. Arms and Interventions. Vaginal suppository placed once daily, patients will record pelvic pain daily on a VAS scale, sexual satisfaction and quality of life on a standardized questionnaire weekly.
Vaginal suppository placed once daily, patient will record pelvic pain daily on a VAS scale, sexual satisfaction and quality of life on a standardized questionnaire weeky. Outcome Measures. Ranks patients overall feeling about health from 1 very much better to 7 very much worse. Standardized self assessment tool to measure overall health status. Eligibility Criteria.
Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Inclusion Criteria: Patients with significant pelvic floor dyssynergia and pain during sexual activity. Exclusion Criteria: Decide you do not wish to participate Are pregnant Have active pelvic inflammatory disease Have an active sexually transmitted infection STI Have a known or suspected cancer of the genital tract Have untreated or unevaluated changes in your Pap smear Are not currently sexually active Have an allergy to either baclofen or valium Are unable to complete the necessary study questionnaires.
Contacts and Locations. More Information. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Pelvic Floor Dyssynergia. Not Applicable. Study Type :. Interventional Clinical Trial.
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