Psychosis with Vicks Formula 44-D abuse.
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Antitussive Agents↗
Biomedical subjects
E M Sellers
Publications and source records attributed to E M Sellers.
Morphine place conditioning is differentially affected by CCKA and CCKB receptor antagonists.
In the present study we have examined the interaction between the selective cholecystokinin (CCK)A and CCKB receptor antagonists, devazepide and L365-260 on morphine conditioned place preference (CPP). Using an unbiased procedure, morphine (1.5 mg/kg) produced a reliable CPP which was observed irrespective of the conditioning compartment type. Pretreatment with devazepide (0.001-0.01 mg/kg s.c.) produced a dose related attenuation of this response. At higher doses (0.1-1 mg/kg) this antagonism became variable and dependent on the training compartment with blockade only observed when conditioning was to the white/rough textured environment. This profile has also been reported for the serotonin (5-HT)3 receptor antagonist ondansetron. The CCKB antagonist L365-260 (0.000001-0.01 mg/kg) failed to antagonize the morphine CPP, if anything a mild potentiation was observed. To study this further we examined the interaction between L365-260 (0.01 mg/kg) and a subthreshold dose of morphine (0.3 mg/kg). At these doses neither drug elicited CPP, however when co-administered a significant CPP was recorded. Finally, L365-260 at 1 mg/kg induced a mild but significant CPP when administered alone. These results suggest a differential role of CCK receptor subtypes on reward-related behaviour and complement previous studies suggesting bimodal effects of CCK systems on mesolimbic dopamine function.
Animals↗
Effect of the 5-HT3 receptor antagonists, MDL72222 and ondansetron on morphine place conditioning.
The purpose of the present study was to reassess the original findings of Carboni et al. (1988) who suggested that 5-HT3 receptor antagonists may block morphine-induced place conditioning in rats. These workers used a biased protocol with treatments allocated to compartments based on initial preference. In the present study we have adopted an unbiased approach with treatments randomly assigned to conditioning compartment in a counter-balanced fashion. Thus treatments were equally paired between distinct environmental cues. Using this protocol, morphine produced a dose-related place preference (0.3-3 mg/kg SC). Thirty-minute pretreatment with the selective 5-HT3 antagonists, MDL72222 (1 mg/kg SC) and ondansetron (0.01 mg/kg SC) before morphine (1.5 mg/kg SC), significantly antagonized the place conditioning to this treatment. However, with higher doses of ondansetron (0.1-1 mg/kg SC), the antagonism of morphine-induced place preference became variable and dependent on the conditioning compartment. This was probably a reflection of the fact that ondansetron when administered alone also appeared to produce an environmentally dependent place conditioning at these doses. Therefore it is concluded that at certain doses, 5-HT3 receptor antagonists may antagonize morphine place conditioning in a manner consistent with a blockade of the appetitive effects of this drug. However, at higher doses, at least with ondansetron, this antagonism became non-specific and dependent on the training environment. It is suggested that other animal models of opioid reinforcement (e.g., self-administration) are now needed to validate the hypothesis that 5-HT3 receptor antagonists may modify opioid reward.
Animals↗
The NMDA antagonist dizocilpine (MK801) attenuates motivational as well as somatic aspects of naloxone precipitated opioid withdrawal.
The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine has recently been reported to antagonize certain overt withdrawal signs in morphine dependent rats. The purpose of the present study was to reassess this response and examine the effect of this drug in a model presumably reflective of the motivational impact of withdrawal using the place conditioning technique. Rats were made opiate dependent by the subcutaneous implantation of a 75 mg morphine pellet. Three-4 days later withdrawal was precipitated by naloxone 0.5 mg/kg. Dizocilpine (0.1-0.5 mg/kg) attenuated many of the subsequent behaviours elicited by naloxone, notably diarrhoea, mouth movements, paw shakes and ptosis. In a separate group of morphine dependent rats, naloxone (0.05 mg/kg) precipitated withdrawal produced a clear place aversion. This place aversion was blocked by dizocilpine (0.02-0.1 mg/kg) pre-treatment prior to conditioning. Therefore dizocilpine may modify both motivational and somatic aspects of opioid withdrawal.
Animals↗
5-HT and alcohol abuse.
Recent experimental data, both in animals and the clinic, suggest that drugs selectively interacting with the 5-HT system may reduce alcohol intake. Although the precise mechanisms underlying these drug effects are unknown, it seems that there are at least two pharmacological strategies available, described in this review by Edward Sellers and colleagues. The first is enhancement of 5-HT neuronal activity using compounds that will release 5-HT, block 5-HT reuptake, or act as selective 5-HT receptor agonists. A second approach involves selective 5-HT3 receptor antagonists. If the initial research findings with these drugs are confirmed and extended, they may present useful therapies for the treatment of alcohol abuse, especially if used in conjunction with psychosocial therapy.
Alcoholism↗
Effect of drugs influencing 5-HT function on ethanol drinking and feeding behaviour in rats: studies using a drinkometer system.
In the present study, we have investigated how various 5-HT agonists (m-chlorophenylpiperazine (mCPP) (0.1-1 mg/kg), 8-hydroxy 2-(di-N-propylamino) tetralin (8-OH DPAT) (0.125-2 mg/kg) and 5-HT (0.5-2 mg/kg)), the 5-HT uptake blocker sertraline (1-10 mg/kg), and the 5-HT uptake blocker and releaser dexfenfluramine (0.5-2.5 mg/kg), affect ethanol intake in a continual access paradigm using Wistar rats. By means of a drinkometer system the effect of each drug on microdrinking parameters (e.g., drink latency, number, and duration of drinking bouts) was assessed. The effect of various 5-HT antagonists (metergoline, ritanserin, ondansetron, and xylamidine) against the dexfenfluramine-induced suppression was studied. Furthermore, threshold doses for the anorectic and the suppressant effects of mCPP, sertraline and dexfenfluramine on ethanol intake were identified. From these studies, it seemed that similar mechanisms may be responsible for the suppressant effects of the various 5-HT agonists studied (direct and indirect) on ethanol and food intake. The 5-HT3 receptor antagonist, ondansetron, also reduced ethanol (but not food) intake. However, the profile of this effect may suggest an alternative means by which 5-HT3 receptors regulate ethanol intake in the rat by comparison to the various 5-HT agonists studied.
Alcohol Drinking↗
Abuse liability of bretazenil and other partial agonists.
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Adult↗
Detoxification for triazolam physical dependence.
The clinical characteristics of a series of patients who developed physical dependence to triazolam has not previously been described. We report five cases of high-dose triazolam abuse in which the daily dosage ranged from 5 to 15 mg (100-300 mg diazepam equivalent) and the duration of use ranged from 3 months to 5 years. Physical dependence usually occurs in the context of a history of alcohol or other drug abuse, a history of panic attacks or anxiety disorder, substitution of triazolam for a longer-acting benzodiazepine, or inappropriate use of triazolam as an anxiolytic agent given as multiple daily doses. A rational approach to the pharmacotherapy of triazolam withdrawal is described. Treatment to replace the triazolam with a long half-life CNS depressant and strategies for this pharmacologic therapy are discussed. The abuse liability of triazolam may be no greater and is most likely less than that of some other benzodiazepines.
Adult↗
Serotonin and alcohol drinking.
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1-Naphthylamine↗
Characteristics of long-term alprazolam users in the community.
The widespread use of benzodiazepines remains a source of concern to the medical profession and the general public, especially as newer compounds come on the market. Our goal was to characterize long-term alprazolam users in the community and to determine whether such use represented abuse or behavioural dependence. We conducted three community surveys to learn about the natural history of long-term alprazolam use. Current long-term alprazolam users (those using the drug for 3 months or longer) were recruited on three separate occasions 1 year apart by identical newspaper advertisements in the metropolitan Toronto area. All respondents were mailed a questionnaire with a stamped, addressed return envelope. Our data from 312 respondents show that: (1) the majority of patients have a substantial history of prior medication use for symptom control (65%), (2) dose escalation is not a characteristic of long-term use, (3) patients change their initial pattern of regular use to one of symptom control only when required, (4) most physicians do not discuss discontinuation of the drug with their patients, (5) patients frequently try to stop their drug use (with a median of 2 attempts) and often report symptoms upon discontinuation, and (6) patients perceive a need for medication use and indicate that alprazolam is effective (75%). We conclude that some patients persistently use alprazolam but that this use does not represent abuse or behavioral dependence.
Alprazolam↗
Comparative drug effects and abuse liability of lorazepam, buspirone, and secobarbital in nondependent subjects.
The pharmacologic effects of lorazepam (2 mg), buspirone (20 mg, 10 mg), secobarbital (100 mg), and placebo were compared in 15 male, experienced, intermittent nontherapeutic drug users. All drugs produced a "drug effect," however, buspirone 20 mg was significantly less liked than were lorazepam, secobarbital, or buspirone 10 mg (p less than .05) but not placebo. Lorazepam was liked better than were other drugs only at 1 hour and only compared with buspirone 20 and placebo. Compared with other drugs, lorazepam drug effects were greater and resulted in more prolonged impairment of a motor tracking task, standing steadiness, and memory. Buspirone 20 mg significantly impaired memory at 1 hour compared with placebo. Subjects were more likely to identify buspirone as unfamiliar. Because buspirone 20 mg was less liked than were other drugs, dose escalation as part of drug abuse is not likely to occur. Lorazepam also was not particularly liked and was not different from placebo on most subjective abuse-relevant measures.
Adult↗
Effects of 5-HT3 receptor antagonists on behavioural measures of naloxone-precipitated opioid withdrawal.
The effect of the selective 5-HT3 receptor antagonists, ondansetron and MDL 72,222, against various behaviours elicited by naloxone-precipitated morphine withdrawal were examined. Rats made dependent upon morphine by the subcutaneous implantation of a 75 mg pellet, when challenged with naloxone (0.5 mg/kg SC), 3 or 4 days later exhibited a wide range of behaviours including wet dog shakes, paw shakes, salivation and a marked weight loss. Pre-treatment with ondansetron (0.01-1 mg/kg SC) or MDL 72,222 (1-3 mg/kg SC) failed to affect the incidence of these responses except weight loss, which was attenuated by both treatments. At doses similar to and below those required to elicit the withdrawal syndrome, naloxone produced a single-trial place aversion in morphine dependent rats. The place aversion produced by naloxone (0.05 mg/kg SC) was antagonized by pre-treatment of ondansetron (0.1-1 mg/kg SC) and MDL 72,222 (1 mg/kg SC) prior to conditioning. Chlordiazepoxide (10 mg/kg IP) but not gepirone (3-10 mg/kg SC) was similarly effective. It is concluded that 5-HT3 antagonists may attenuate some but not all behavioural signs associated with morphine withdrawal. Reasons for this apparent selectivity are discussed.
Animals↗
Pharmacologic aspects of benzodiazepine tolerance and dependence.
Benzodiazepines, which are among the safest and most effective drugs, possess all the characteristic of abuseable compounds. Although there appear to be differences in potency among compounds and variations in sensitivity among individuals, benzodiazepines have clear reinforcing properties. Tolerance to the depressant effects of benzodiazepines is rapid, but tolerance to the anxiolytic effects develops slowly and to a limited extent. Although abusers use very high doses, most long-term users persist at daily doses in the low therapeutic range (10-20 mg of diazepam or its equivalent) without dose escalation. Physical dependence is a risk associated with long-term use, even at therapeutic doses. The withdrawal syndrome is mild at low doses. Continued self-administration of low therapeutic doses is maintained to alleviate withdrawal symptoms. The advances in the recent understanding of the molecular biology of the benzodiazepine receptor gives hope to the development of new anxiolytic compounds with less dependence liability than the present ones.
Animals↗
Enalapril effects on alcohol intake and other consummatory behaviors in alcoholics.
Animal studies suggest that angiotensin-converting enzyme inhibitors decrease alcohol intake. In a double-blind crossover study 42 normotensive alcoholics (36 men and six women) aged 24 to 65 years, consuming 8.2 +/- 2.3 (mean +/- SD) standard alcoholic drinks per day, were randomized to enalapril, 10 mg/day (n = 20) or 20 mg/day (n = 22), and placebo for 4 weeks. They monitored their daily alcohol intake and attended biweekly assessments, but no other treatment or advice was given. Compliance and alcohol intake were verified objectively. Mean daily alcoholic drinks were not significantly different during 10 mg/day enalapril (mean +/- SEM, 7.5 +/- 0.5), and its placebo (7.2 +/- 0.5), but both decreased from baseline (8.1 +/- 0.5; both p less than 0.05). Similarly, mean daily drinks during 20 mg/day enalapril (6.8 +/- 0.6) and its placebo (7.2 +/- 0.4) was not significantly different, but both were lower than baseline (8.3 +/- 0.5; both p less than 0.01). Fourteen (64%) of the patients taking 20 mg/day enalapril decreased alcohol intake from placebo by an average of 21% (range, 1.6% to 78.3%). Self-ratings of interest, desire, craving, and liking for alcohol also decreased from baseline during enalapril and placebo treatments, but the effects of both were similar. Plasma renin activity increased, compared with placebo, after 10 mg/day enalapril (from 0.3 +/- 0.2 [mean +/- SD] to 1.9 +/- 1.5 ng/L/sec) and after 20 mg/day enalapril (from 0.4 +/- 0.3 to 2.8 +/- 4.0 ng/L/sec) (both p less than 0.05). Blood pressure decreased within a normotensive range, compared with placebo, with 10 mg/day enalapril (by 6.0 and 8.5 mm Hg systolic and diastolic blood pressures) and 20 mg/day enalapril (by 7.7 and 5.0 mm Hg, respectively). Side effects were few and mild. No patient characteristic or drug effect correlated with changes in alcohol intake. There were no significant variations in nonalcoholic beverages, cigarette smoking, or body weight. These results indicate that enalapril does not alter alcohol intake in normotensive alcoholics with normal plasma renin activity. Studies with higher doses of enalapril in humans may be limited by increased frequency and severity of side effects.
Adult↗
Drug metabolism and interactions in abuse liability assessment.
The interpretation of acute abuse liability studies and drug interaction studies would be importantly strengthened by the routine inclusion of drug concentration measurements at appropriate sampling times. Reliance on mean kinetic data misrepresents the variation in drug kinetics and fails to take experimental advantage of the natural differences in the population which may represent the extremes of abuse risk. Pharmacokinetic-pharmacodynamic studies to better understand the relationship of plasma drug concentration, drug concentration in the receptor biophase and specific drug reinforced behaviour will ensure proper study design and yield useful theoretic information. Multi- and poly-drug abuse (including heavy smoking and heavy ethanol use) are very common. Such patterns of use can have quite large effects on drug kinetics. Because of the potentially large qualitative and quantitative differences in drug metabolism and kinetics between pre-clinical species and the human, data should be gathered at the earliest possible time with respect to human metabolic rates, patterns, and identification of inhibitors. The availability of human liver microsomes facilitates such studies.
Dose-Response Relationship, Drug↗
Anxiolytics and sedative/hypnotics dependence.
Anxiolytics and sedative/hypnotics are commonly used drugs. Benzodiazepines have largely replaced barbiturate and non-barbiturate anxiolytics and sedative/hypnotics as they are as effective and safer. Experiments in laboratory animals have shown that chronic administration of benzodiazepines tested to date can induce physical dependence. The severity of the withdrawal syndrome is clearly related to the dose, duration of administration and elimination rate of the drugs. It is now also clear that high doses of barbiturates and benzodiazepines can induce physical dependence in humans. In addition, a withdrawal syndrome after discontinuation of chronic benzodiazepine therapeutic treatment, with and without tolerance, has been well characterized. Symptoms may resemble those of anxiety or 'rebound' phenomena but some are typical of withdrawal. A relationship between benzodiazepine discontinuation and self-administration has been well documented. Negative reinforcement associated with a reduction of withdrawal symptoms may play a role supporting persistent benzodiazepine use.
Anti-Anxiety Agents↗
Opportunities for treatment of psychoactive substance use disorders with serotonergic medications.
The authors review both the preclinical and the clinical evidence for a role of serotonin (5-HT) systems in the regulation of drug-taking behavior. Animal studies show that pharmacologic treatments that enhance 5-HT function, notably selective reuptake inhibitors, reduce the self-administration of a variety of substances of abuse, including ethanol and cocaine. These treatments also tend to suppress consummatory behavior in general. In contrast to the broad spectrum of suppression following 5-HT enhancement, selective antagonists at the 5-HT3 receptor subtype have been reported to reduce ethanol but not cocaine or food intake. Although essentially limited to alcohol abusers, clinical studies seem to support the preclinical findings that a number of 5-HT reuptake inhibitors decrease interest in and intake of alcohol in mild-moderate ethanol-dependent individuals. Furthermore, other serotonergic drugs may show utility in the treatment of alcohol abuse. Another way in which serotonergic medications can be used in treating substance abuse is by the treatment of comorbid psychoactive illness for which such drugs are already known to be effective, e.g., depression and anxiety disorders.
Alcoholism↗
Long-term alprazolam use: abuse, dependence or treatment?
Concern about persistent benzodiazepine use should be informed by data about reasons for such use. Consecutive long term alprazolam users (n = 25) admitted to an advertised outpatient program for discontinuation were characterized with respect to alprazolam use patterns and lifetime and current Axis I and II disorders. Patient characteristics were: females 50 percent; mean age, 46 +/- 12 yrs; prior medication use--benzodiazepines, 47 percent, antidepressants, 23 percent; median duration of use 104 +/- 96 wks; median daily dose, 0.5 mg; continued effectiveness of alprazolam 50 percent. Over the duration of use patients shifted their initial pattern of use from as prescribed to a self-controlled "as required" basis (p less than .05). Interviews using the Structured Clinical Interview for DSM-III-R (SCID) yielded diagnoses of DSM-III-R alprazolam dependence in all patients plus at least one additional psychiatric diagnosis in 65 percent (Axis I 65%; Axis II 39%). Most persistent alprazolam use does not represent abuse or addiction as usually understood. These data are most consistent with the interpretation that alprazolam is the most recent benzodiazepine used by patients to help control clinically important psychopathology and that most users make efforts to control or stop use.
Adult↗