Behavioral Symptoms Of Withdrawal Research Articles

Oxycodone self-administration and withdrawal behaviors in male and female Wistar rats.

Over the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans. We assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats. Both male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed. The present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.

Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal

Excessive alcohol consumption in humans induces deficits in decision making and emotional processing, which indicates a dysfunction of the prefrontal cortex (PFC). The present study aimed to determine the impact of chronic intermittent ethanol (CIE) inhalation on mouse medial PFC pyramidal neurons. Data were collected 6–8 days into withdrawal from 7 weeks of CIE exposure, a time point when mice exhibit behavioral symptoms of withdrawal. We found that spine maturity in prelimbic (PL) layer 2/3 neurons was increased, while dendritic spines in PL layer 5 neurons or infralimbic (IL) neurons were not affected. Corroborating these morphological observations, CIE enhanced glutamatergic transmission in PL layer 2/3 pyramidal neurons, but not IL layer 2/3 neurons. Contrary to our predictions, these cellular alterations were associated with improved, rather than impaired, performance in reversal learning and strategy switching tasks in the Barnes maze at an earlier stage of chronic ethanol exposure (5–7 days withdrawal from 3 to 4 weeks of CIE), which could result from the anxiety-like behavior associated with ethanol withdrawal. Altogether, this study adds to a growing body of literature indicating that glutamatergic activity in the PFC is upregulated following chronic ethanol exposure, and identifies PL layer 2/3 pyramidal neurons as a sensitive target of synaptic remodeling. It also indicates that the Barnes maze is not suitable to detect deficits in cognitive flexibility in CIE-withdrawn mice.

Effects of environmental enrichment during induction of methamphetamine dependence on the behavioral withdrawal symptoms in rats

This study was designed to examine the effect of environmental enrichment during METH administration on the behavioral withdrawal symptoms after drug abstinence in rats. Rats reared in standard (SE) or enriched environment (EE) during induction of METH dependence with bi-daily injections of METH (2mg/kg, at 12-h. intervals) for 14 days. Then, rats were evaluated for behavioral withdrawal symptoms, and also for anxiety (elevated plus maze-EPM) and depression (Forced swim test-FST) over a ten day period of abstinence. The results showed that stereotypic behaviors score and the number of rearing were significantly lower in METH/EE rats compared to the SE group during 1–4 days. Also, The METH/EE group exhibited more weight gain during 6–10 days of abstinence. The METH/EE rats exhibited lower levels of immobility after METH abstinence than control group in the FST. EE had no effect on anxiety-like behavior. This study showed that exposure to EE diminished the severity of withdrawal symptoms and depressive-like behavior during spontaneous withdrawal from METH.

Mice from lines selectively bred for high voluntary wheel running exhibit lower blood pressure during withdrawal from wheel access

Exercise is known to be rewarding and have positive effects on mental and physical health. Excessive exercise, however, can be the result of an underlying behavioral/physiological addiction. Both humans who exercise regularly and rodent models of exercise addiction sometimes display behavioral withdrawal symptoms, including depression and anxiety, when exercise is denied. However, few studies have examined the physiological state that occurs during this withdrawal period. Alterations in blood pressure (BP) are common physiological indicators of withdrawal in a variety of addictions. In this study, we examined exercise withdrawal in four replicate lines of mice selectively bred for high voluntary wheel running (HR lines). Mice from the HR lines run almost 3-fold greater distances on wheels than those from non-selected control lines, and have altered brain activity as well as increased behavioral despair when wheel access is removed. We tested the hypothesis that male HR mice have an altered cardiovascular response (heart rate, systolic, diastolic, and mean arterial pressure [MAP]) during exercise withdrawal. Measurements using an occlusion tail-cuff system were taken during 8days of baseline, 6days of wheel access, and 2days of withdrawal (wheel access blocked). During withdrawal, HR mice had significantly lower systolic BP, diastolic BP, and MAP than controls, potentially indicating a differential dependence on voluntary wheel running in HR mice. This is the first characterization of a cardiovascular withdrawal response in an animal model of high voluntary exercise.

Smokers’ expectancies for abstinence: Preliminary results from focus groups.

Smokers' expectancies regarding the effects of cigarette use are powerful predictors of smoking motivation and behavior. However, studies have not investigated the consequences that smokers expect when they attempt to quit smoking: abstinence-related expectancies. The primary goal of this qualitative study was to gain initial insight into smokers' expectancies for abstinence. Eight focus groups were conducted with 30 smokers diverse with respect to age, gender, and ethnoracial background. Content analyses indicated that smokers anticipate a variety of outcomes from abstinence. The most frequently reported expectancies included pharmacologic withdrawal symptoms, behavioral withdrawal symptoms, decreased monetary expense, and immediate improvement of certain aspects of physical functioning and health. Additional expectancies concerned weight gain, improved attractiveness, enhanced social functioning/self-esteem, long-term health outcomes, and loss of relationships. Finally, a number of relatively unheralded expectancies were revealed. These involved nicotine replacement therapy effectiveness, alcohol and other drug use, cue reactivity, cessation-related social support, aversion to smoking, and "political process" implications. This study provides a preliminary step in understanding smokers' expectancies for abstinence from cigarettes.

Behavioral effects of nicotine withdrawal in adult male and female rats

Nicotine withdrawal may differ between men and women but clinical reports are inconsistent. Two experiments were conducted to examine behavioral effects of nicotine withdrawal in male and female adult rats in dimly-lit and brightly-lit environments. Ninety-six Sprague–Dawley male and female rats received 7 days continuous subcutaneous infusion via ALZET osmotic minipumps filled with saline or 3.16 mg/kg/day nicotine hydrogen tartrate expressed as base. Behavioral observations were made before, during, and after drug administration. During observations, occurrences of empty-mouth-chewing, whole-body-shakes, abnormal grooming, abnormal posture/movement, diarrhea, ptosis, eyeblinks, and any other abnormal behaviors were counted. Cessation of nicotine administration upon pump removal caused a significant increase in withdrawal behaviors in males and females in both environments. In the dimly-lit environment, females showed more withdrawal behavior than males; there was no sex difference in the brightly-lit environment. Males that had received nicotine displayed more withdrawal behavior in the brightly-lit environment than in the dimly-lit environment, while females that had received nicotine displayed similar amounts of withdrawal behavior in both environments. Behavioral symptoms of withdrawal may be more affected by the environment in male rats than in female rats. These experiments are the first to compare nicotine withdrawal in adult male and female rats.

Alcohol Protracted Withdrawal Syndrome: The Role of Anhedonia

Aims: The aim of the present study is to characterize the relevance of withdrawal symptoms during the first 12 months of abstinence and their relation to anhedonia and craving. Methods: 102 detoxified subjects meeting clinical criteria for Alcohol Dependence in Remission were recruited at various time since the detoxification and subdivided into four groups according to the length of abstinence (group 1: 15–30 days; group 2: 30–90 days; group 3: 90–180 days; group 4: 180–360). Withdrawal symptomatology was assessed through the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). The Visual Analogue Scale (VAS) for craving, the Snaith–Hamilton Pleasure Scale (SHAPS) and the Subscale for Anhedonia in the Scale for the Assessment of Negative Symptoms (SANSanh) where the other instruments employed. Results: Both anhedonia and withdrawal symptoms were identified in all the groups considered. SHAPS score and VAS for craving showed a significant difference between group 1 and groups 2, 3, and 4. As to CIWA-Ar items, apart from “orientation/clouding of sensorium” that was higher in groups 3 and 4 with respect to both groups 1 and 2, withdrawal symptoms were not significantly different between the periods considered. SHAPS and SANSanh were positively correlated to CIWA-Ar total score, “nausea and vomiting,” and “headache/fullness in head.” Discussion: The results of this study suggest the relevance of protracted withdrawal well beyond the limited period following the abrupt cessation of alcohol intake. The clinical dimension of anhedonia cannot be separated from the other behavioral symptoms of withdrawal and should be considered as part of the same process.

WITHDRAWN: “Thermic, behavioral withdrawal symptoms provide further evidence of the addictive nature of sugar in the rat”

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi: 10.1016/j.appet.2006.03.001 . The duplicate article has therefore been withdrawn.

Decreased Signs of Nicotine Withdrawal in Mice Null for the β4 Nicotinic Acetylcholine Receptor Subunit

Withdrawal from chronic exposure to nicotine, the main addictive component of tobacco, produces distinctive symptoms in humans. The appearance of these symptoms is a major deterrent when people try to quit smoking. To study which type of nicotine receptor is relevant for the onset of the withdrawal syndrome, we used a mouse model of nicotine withdrawal. Wild-type mice and mice null for the beta4 (beta4-/-) or the beta2 (beta2-/-) nicotinic acetylcholine receptor subunits were implanted with osmotic minipumps delivering 24 mg x kg(-1) x d(-1) nicotine for 13 d. Subsequently, a single intraperitoneal injection of the nicotinic receptor antagonist mecamylamine induced behavioral symptoms of withdrawal measured as increased grooming, chewing, scratching, and shaking, plus the appearance of some unique behaviors such as jumping, leg tremors, and cage scratching. Mecamylamine injection triggered comparable withdrawal signs in wild-type and in beta2-/- mice, whereas the beta4-/- mice displayed significantly milder somatic symptoms. In addition, nicotine withdrawal produced hyperalgesia in wild-type but not beta4-/- mice. Finally, chronic nicotine produced an increase in epibatidine binding in several areas of the brain in both wild-type and in beta4-/- mice, but such receptor upregulation did not correlate with the severity of withdrawal signs. Our results demonstrate a major role for beta4-containing nicotinic acetylcholine receptors in the appearance of nicotine withdrawal symptoms. In contrast, the beta2 subunit does not seem to greatly influence this phenomenon. We also show that the upregulation of epibatidine binding sites attributable to chronic nicotine, an effect associated with beta2-containing receptors, is probably not related to the mechanisms underlying withdrawal.

Hospitalized patients and alcohol: who is being missed?

Research and clinical experience have shown that alcohol use disorders are neither sufficiently identified nor addressed in hospitalized patients. This study sought to quantify and localize these missed opportunities. The setting was an urban medical center with a Level 1 trauma designation. The only eligibility requirement was a Blood Alcohol Level (BAL) greater than 300 ng/dl upon hospital admission, a “nonsubtle” value more than three times the legal intoxication limit. Charts [58] were retrospectively reviewed for treating service (medical, trauma services, or psychiatric) and evidence of psychological signs or behavioral symptoms of withdrawal. Also assessed were the presence or absence of withdrawal monitoring, withdrawal prophylaxis orders, inpatient addictions consultation, and referral for addictions aftercare. Numerous patients with admission BALs >300 failed to be identified as needing assessment for alcohol-related disorders. Patients admitted to medical or psychiatric services were significantly more likely to be diagnosed than those on trauma services ( P = .02). Patients on medical or psychiatric services were also more likely to be assessed for withdrawal and referred for after-care ( P < .0001) than those cared for on trauma services. The delivery of care for alcohol-related disorders was deficient, particularly for patients with traumatic injuries, even among patients severely intoxicated at admission. Failure to identify such patients represented a missed opportunity to address this vital contributor to trauma. It is suggested that both the origins of this shortfall and its resolution depend not just upon trauma providers but upon the entire medical system.

Metabotropic glutamate receptors and opiate analgesia: Therapeutic implications

Morphine acts at μ-opioid receptors within the brain and spinal cord to induce analgesia. However, tolerance and dependence are potentially undesirable side effects encountered with repeated opiate administration. Opiate withdrawal, the physical correlate of dependence, is involved in the negative reinforcement of opiate addiction. Recently, blockers of ionotropic subtypes of glutamate receptors have been suggested to have therapeutical potential for opiate withdrawal. Fundytus and Coderre have also shown that antagonism of metabotropic glutamate receptors (mGluRs) and δ-opioid receptors can separately alleviate the behavioral symptoms of withdrawal. They propose that mGluRs and δ-opioid receptors share intermediates and products of the same second messenger pathways as μ-opioid receptors, thereby enhancing the desensitization of this receptor. Thus, mGluRs appear to be involved in the development of opiate tolerance and dependence and may provide a key target for adjunct therapy with opiate analgesia.

Differences between haloperidol- and pimozide-induced withdrawal syndrome: a role for Ca 2+ channels

We investigated the behavioral and biochemical events appearing in rats after withdrawal for 24 h or 8–12 days from two classical neuroleptics, haloperidol and pimozide. The neuroleptics were given for 14 days alone or shortly after injection of the Ca 2+ channel blocker nifedipine. We have found that withdrawal effects after haloperidol and pimozide were different. After haloperidol treatment we observed an increase in cortical Ca 2+ channel and limbic dopamine D 1 receptor density and an increase in spontaneous motor activity and apomorphine-induced hyperactivity and stereotypy. In contrast no biochemical changes were observed during pimozide withdrawal, and locomotor activity and responses to apomorphine were depressed. Co-administration of nifedipine with haloperidol prevented the observed biochemical and behavioral symptoms of withdrawal. Nifedipine administration did not change the depressant effects of pimozide. Our results suggest that the voltage-dependent Ca 2+ channel is involved in the observed withdrawal syndrome of neuroleptics, and that the absence of this syndrome after pimozide may be related to its considerable Ca 2+ channel-blocking properties.

Evoked potential changes during ethanol withdrawal in rats.

We have recently observed an increase in central nervous system excitability during intoxication and alcohol withdrawal in alcoholics. Our present results demonstrate a similar phenomenon in rats. The hyper-excitability caused by ethanol withdrawal is still present subsequent to the overt behavioral symptoms of withdrawal.

Ethanol withdrawal in the rat: Involvement of noradrenergic neurons

Ethanol dependence was induced in rats by maintaining them for 3 weeks on a liquid diet containing ethanol. When ethanol was abruptly replaced with sucrose in the diet, animals showed withdrawal symptoms. Eight hours later, the accumulation in brain and heart of 3H-norepinephrine synthesized from 3H-tyrosine, and of 3H-norepinephrine metabolites was greater than in animals not undergoing withdrawal. An injection of ethanol (3 g/kg) 1 1 2 or 5 hours after the initiation of withdrawal resulted in less accumulation of newly synthesized 3H-norepinephrine and of 3H-norepinephrine metabolites in both brain and heart. If the rate of ethanol withdrawal was slow, i.e., the ethanol in the diet was replaced gradually with sucrose over a 3-day period, less accumulation of 3H-norepinephrine and 3H-norepinephrine metabolites occured in heart and brain than as a result of abrupt withdrawal. Also, no behavioral symptoms of withdrawal were observed. These results indicate that (a) gross withdrawal symptoms and the accompanying activation of noradrenergic neurons can be blocked during withdrawal by an acute dose of ethanol, and (b) ethanol withdrawal can be modified by altering the rate of withdrawal, a finding that may prove useful in clinical situations. We conclude that the withdrawal symptoms and the activation of noradrenergic neurons during withdrawal are caused by the sudden lack of ethanol in the system.

Effects of ethanol on the adrenal medulla of the rat.

These studies describe the effects of ethanol on the adrenal medulla of rats. Ethanol intake for 3 weeks in the form of a liquid diet increased catecholamine content by 14 percent; the increase was mainly due to a rise in epinephrine content. Concomitantly, there was a 16-percent increase in PNMT activity. On withdrawal of ethanol from the diet, catecholamine synthesis from 3-H-tyrosine was greatly stimulated; this effect and the behavioral symptoms of withdrawal could be partially prevented by giving an injection of ethanol. Gradual ethanol withdrawal from the diet did not lead to stimulation of the adrenal medulla.