Inhibition of agmatine on psychological dependence induced by morphine and the possible mechanism

Agmatine is the endogenous ligand of imidazoline receptor, it enhanced morphine analgesia, inhibited tolerance to and physical dependence on morphine. In the present study, the effect of agmatine on the psychological dependence on morphine and the possible mechanism was evaluated.     

A comparison of the autonomy over tobacco scale and the Fagerström test for nicotine dependence

The Autonomy over Tobacco Scale (AUTOS) is a 12-item theory-based instrument used to measure tobacco dependence in smokers. It provides separate measures of three factors that make smoking cessation more difficult: withdrawal symptoms, psychological dependence, and cue-induced urges to use tobacco. We compared the internal reliability and concurrent validity of the AUTOS to those of the Fagerström Test for Nicotine Dependence (FTND). Adult current smokers (n = 422; 62% female; 86.8% white; mean age 33.3 years, SD = 13.7; 57% daily smokers) completed an anonymous web-based survey that included the AUTOS, the FTND and 11 smoking-related behavioral measures. Cronbach's α was .94 for the AUTOS and α > .75 for each of the 3 subscales; α = .73 for the FTND. The AUTOS and its subscales correlated with all measures of concurrent validity (r = .70 between AUTOS &; FTND). The AUTOS correlated better than the FTND with the Hooked on Nicotine Checklist, the longest period of abstinence, latency to wanting, percentage of time a person smokes because of momentary need, pleasure from smoking, days smoked per month, and concern about deprivation. The measures showed similar correlations with the latencies to craving and needing. The FTND correlated better with the duration of smoking and cigarettes smoked per day. Based on these results and those from prior studies, we conclude that the AUTOS offers researchers a valid and highly reliable, theory-based measure that is more versatile in its applications than the FTND.     

The clinical efficacy and abuse potential of combination buprenorphine–naloxone in the treatment of opioid dependence

Background: Opioid dependence is a chronic relapsing condition for which long-term opioid substitution treatment (OST) is effective. However, safety and community acceptance of OST is compromised by diversion of prescribed medication. The development of a formulation combining buprenorphine and naloxone is designed to reduce the likelihood of intravenous misuse, and the therefore the value of the medication if diverted to the black market. Objective: To evaluate the evidence for 4:1 buprenorphine–naloxone as an efficacious OST, and as a deterrent to diversion and intravenous misuse. Methods: The literature on buprenorphine–naloxone in a 4:1 ratio is reviewed. Results/conclusion: The addition of naloxone does not appear to affect the efficacy of buprenorphine as a maintenance drug. While offering some deterrence of injection through precipitated withdrawal, there are many circumstances where injecting of buprenorphine–naloxone is reinforcing rather than aversive. The combination will reduce, but not eliminate, intravenous misuse; clinicians therefore need to monitor patients in OST, and be selective in providing patients with medication to be taken without observation.     

What aspects of treatment matter to the patient in the treatment of cocaine dependence?

Patient views of the helpful aspects of treatment were examined in the NIDA Collaborative Cocaine Treatment Study, a multi-site trial comparing four psychosocial treatments: individual cognitive therapy (CT), individual supportive expressive dynamic therapy (SE), individual drug counseling, and group drug counseling only, for the treatment of cocaine dependence. Factor analysis of the items of Helpful Aspects of Treatment measure suggested a general therapy factor, a group treatment/education factor, and a treatment structure factor. No differences were found among the four treatments on the ratings of helpfulness of these three factors, common factors, or drug intervention components. However, treatment specific cognitive therapy items (e.g. use of the cognitive model) and treatment structure differentiated individual CT from individual SE, and to a lesser extent from individual drug counseling. Ratings of helpfulness were significantly related to retention and alliance but were largely unrelated to changes in drug use or psychiatric outcomes.     

In-patient setting and long duration for the treatment of alcohol dependence? Out-patient care is as good

A combined narrative/meta-analytic review of the results of a number of well-conducted randomized controlled clinical trials indicates that there is no evidence that usual treatment delivered in an in-patient or residential setting is superior to treatment delivered on an out-patient or non-residential basis for the treatment of alcohol dependence. Nor is there any evidence to support the view that in-patient/residential treatment is superior to day patient intervention, or that longer in-patient treatment is superior to shorter in-patient treatment. The studies suggest that in-patient/residential care should not be considered as a standard setting for intervention for alcohol dependence. However, the results of these trials do not contradict the view that in-patient/residential care remains suitable for specific sub-populations of alcohol dependent individuals, such as those requiring closely supervised detoxification, respite care, or who (because of the extreme severity of dependence on alcohol) may require an intense form of supervised intervention. Research should be conducted to establish whether treatment on an in-patient basis does yield an advantage for this last group.     

Topiramate-induced neuromodulation of cortico-mesolimbic dopamine function: a new vista for the treatment of comorbid alcohol and nicotine dependence?

Alcohol and nicotine dependence are commonly occurring disorders that together represent the most important preventable causes of morbidity and mortality in the United States. While there have been differences of opinion as to which disorder to treat first when they occur, there is growing evidence that a management strategy addressing both conditions contemporaneously would be optimal. Advances in the neurosciences have demonstrated not only that the reinforcing effects of both alcohol and nicotine are mediated by similar mechanisms resulting in enhanced activity of the cortico-mesolimbic dopamine system, but that their neurochemical interactions can lead to an aggregation of these effects. Despite this striking neurobiological overlap between alcohol and nicotine consumption, few studies have sought to take advantage of this commonality by devising a pharmacological approach that serves to treat both disorders. The results of our proof-of-concept study showed that topiramate is a promising medication for the treatment of both alcohol and nicotine dependence, presumably by its ability to modulate cortico-mesolimbic dopamine function profoundly; however, other mechanisms might also contribute to this effect. Further studies are ongoing to establish and extend topiramate's efficacy in the treatment of each and both disorders.     

The Fagerström test for nicotine dependence in two adult population samples-potential influence of lifetime amount of tobacco smoked on the degree of dependence

BACKGROUND: The Fagerstr?m test for nicotine dependence (FTND) has been widely used in clinical samples but seldom in population samples. Data are particularly lacking for a large range of ages. The goal was to describe the FTND sum score distribution in the adult population and to show potential variation according to the number of years of smoking. METHODS: Random adult population samples from two northern areas in Germany were used. Sample 1 included 1460 current smokers aged 20-64 years and sample 2 included 1135 current smokers aged 20-79 years. One cross-sectional and longitudinal and one cross-sectional study were conducted. The FTND was administered during face-to-face computer-aided interviews. RESULTS: The mean FTND sum score for those aged 20-64 was 3.2 among sample 1 and 2.5 among sample 2. The number of years of smoking and age did not affect the FTND sum score whereas it was positively correlated with the lifetime amount of tobacco smoked. CONCLUSIONS: Dependence according to the FTND does not increase with the number of years of smoking. Population-based interventions addressing the needs of dependent smokers across all age groups are needed.     

GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence?

Chronic use of benzodiazepines for the treatment of anxiety has revealed that these drugs can lead to dependence as indicated by withdrawal symptoms following cessation and tolerance to the drugs effects. Together with their reinforcing properties, this has led to them being labelled as scheduled drugs. Our new knowledge regarding the molecular structure of the benzodiazepine binding site and the growing ability to differentiate GABA(A) receptor subtypes, either by genetic manipulation or subtype selective compounds, have begun to facilitate our understanding of what underlies the mechanism of benzodiazepine dependence. In addition, the involvement of GABA(A) receptors in this phenomenon is leading to a greater understanding of other drugs such as alcohol and opiates.     

PPARγ dependence of cyclosporine-isoprenaline renovascular interaction: roles of nitric oxide synthase and heme oxygenase

We previously showed that cyclosporine (CSA) impairs renal vasodilations caused by β-adrenoceptor activation. This study investigated whether the peroxisome proliferator-activated receptor gamma (PPARγ) and related nitric oxide synthase (NOS)/heme oxygenase (HO) signaling mediates the CSA-β-adrenoceptor interaction. The vasodilatory response elicited by a bolus injection of isoprenaline (1 μmole) in phenylephrine-preconstricted perfused kidneys of rats was reduced after prior infusion of zinc protoporphyrin IX (ZnPP, HO inhibitor) or GW9662 (PPARγ antagonist), suggesting the involvement of PPARγ and HO-derived CO in the isoprenaline response. In contrast, the inhibition of NOS activity by N-nitro-l-arginine methyl ester had no effect on isoprenaline responses. CSA (5 μM) significantly attenuated isoprenaline vasodilations, an effect that was abolished in the presence of GW9662 and accentuated by ZnPP. Also, supplementation with the PPARγ agonist pioglitazone or with l-arginine or hemin, substrates for NOS and HO, respectively, eliminated the unfavorable effect of CSA on isoprenaline vasodilations. The protection conferred by pioglitazone against CSA-evoked attenuation of isoprenaline vasodilations was maintained in N-nitro-l-arginine methyl ester-treated kidneys and disappeared after treatment with ZnPP or GW9662. In conclusion, the activation of the HO/CO/PPARγ cascade is probably the cellular mechanism that underlies the beneficial effect of pioglitazone on the CSA-isoprenaline interaction. Further, the facilitation of the HO/CO or NOS/NO pathway seems to offset this harmful effect of CSA.     

Pharmacotherapy for treating tobacco dependence: what is the ideal duration of therapy?

Various forms of nicotine replacement therapy and bupropion have been found to be efficacious and well tolerated for treating patients dependent on tobacco. However, the currently recommended duration of treatment with pharmacotherapy may be insufficient for some smokers to achieve sustained abstinence from tobacco. Extending the use of pharmacotherapy beyond the recommended timeframe may be an effective strategy for helping tobacco users achieve abstinence and for preventing relapse to tobacco use, especially among those who are highly dependent and those who are concerned about bodyweight gain following cessation. Several studies have reported on long-term use of various pharmacotherapies. These studies have demonstrated that such long-term use is not harmful. Moreover, compared with continued smoking, long-term use of pharmacotherapy exposes patients to relatively small amounts of nicotine and none of the cancer-causing chemicals found in cigarettes and other tobacco products. However, more research is needed to further clarify questions regarding the ideal duration of therapy. Two questions have yet to be answered: In what populations of smokers is long-term therapy an effective strategy for achieving abstinence and preventing relapse? Does wider availability of nicotine replacement therapy lead to initiation of nicotine addiction by children and others not using tobacco products? Also, as with all medications, additional documentation of the safety of prolonged use of pharmacotherapy is important. The aim of this review is to present the current evidence supporting the notion that long-term therapy for treating tobacco dependence may be appropriately considered for some tobacco users.     

Rapid detoxification of heroin dependence by buprenorphine

评价丁丙诺啡７－８ｄ递减法治疗海洛因戒断症状（戒毒）的临床疗效．方法：６０例海洛因成瘾者根据依赖程度分为三组，分别给予低、中、高三种剂量丁丙诺啡舌下含服片剂治疗．治疗期间患者戒断症状采用“美国临床研究所麻醉药品评价量表”评价；对海洛因的心理渴求采用“视觉类比量表”自评；丁丙诺啡副作用采用“副反应量表”评价．结果：三组戒毒患者丁丙诺啡平均日消耗量分别为２０，２９和３６ｍｇ．此剂量的丁丙诺啡不仅可有效地控制海洛因戒断症状，且可缩短戒毒时程．结论：丁丙诺啡是一个有希望替代纯阿片受体激动剂的有效、快速戒毒药物．     

Pharmacological characteristics of adenosine-induced inhibition of dog ventricular contractility: dependence on the pre-existing level of β-adrenoceptor activation

Summary Experiments were carried out to characterize the adenosine-induced negative inotropic effect in relation to the extent of -adrenoceptor activation in the isolated dog left ventricular myocardium. Adenosine and R-N⁶-phenylisopropyladenosine inhibited the positive inotropic effect of isoprenaline (10^–7 mol/1 and lower) about 20% of its maximal response, which was antagonized by an A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine in a concentration-dependent manner. The negative inotropic effect of adenosine disappeared and that of R-N⁶-phenylisopro-pyl-adenosine decreased when the isoprenaline concentration was elevated to the level higher than 10^–7 mol/1. Adenosine deaminase (1.5 U/ml) that abolished the negative inotropic effect of adenosine enhanced the effect of R-N⁶-phenylisopropyladenosine, indicating that endogenous adenosine released by high isoprenaline concentration (10^–6 mol/1) modulates the interaction. The maximal response to adenosine and R-N⁶-phenylisopro-pyladenosine determined in the presence of 10^–7 mol/1 isoprenaline was 50% of that of carbachol which elicited the maximal inhibition even in the presence of 10^–6 mol/1 isoprenaline. The negative inotropic effects of R-N⁶-phenylisopropyladenosine and carbachol were additive to the maximal response equivalent to that of carbachol. The difference in the efficiency between the adenosine and muscarinic receptor agonists may be partly ascribed to the difference in densities of the respective receptors in the dog ventricular myocardium. The negative inotropic effect of R-N⁶-phenylisopropyladenosine in the presence of isoprenaline was associated with decrease in cyclic AMP levels elevated previously by isoprenaline. The elevation of cyclic AMP levels caused by isoprenaline (3 × 10^–7 mol/1) was abolished by R-N⁶-phenylisopro-pyladenosine (10^–4 mol/1), while the contractile response was reduced only by 30% with R-N⁶-phenylisopro-pyladenosine. In the absence of -adrenoceptor stimulation R-N⁶-phenylisopropyladenosine elicited a negative inotropic effect without changes in cyclic AMP levels, but this effect was less than 10% of the basal force of contraction. It is concluded that in the dog ventricular myocardium adenosine receptors play a role for the inhibitory regulation of contractility, which is influenced markedly by the pre-existing level of -adrenoceptor activation. Send offprint requests to M. Endoh at the above address     

Is the FTND a measure of physical as well as psychological tobacco dependence?

The Fagerström Test for Nicotine Dependence (FTND) has been developed to assess tobacco dependence from a physical perspective and to match treatments to individuals on the basis of the extent of the physical dependence. This study assessed the extent to which the FTND also measures psychological tobacco dependence. In three independently recruited samples of smokers, FTND scores, scores on indices of psychological dependence and smoking cessation were assessed. The results show that the indices of psychological dependence in all three samples explained about 20% of the variance in FTND scores. Furthermore, the FTND and the indices of psychological dependence both predicted quitting activity prospectively with two quitting measures in all three samples. Lastly, when the FTND and the indices of psychological dependence were combined in one model, the psychological dependence measures predicted quitting activity more consistently than the FTND, although the overlap between the two measures of dependence was small.     

Lack of involvement of δ-opioid receptor in mediating physical dependence at the hypothalamus-pituitary-adrenocortical (HPA) axis in the rat

1. In previous studies, we have demonstrated that δ-opioid receptors are involved both in the acute control of hypothalamus-pituitary-adrenocortical (HPA) axis activity and in the development of neuroendocrine opioid tolerance. In the present work we studied whether central δ-opioid receptors play a role in the development of neuroendocrine physical dependence to opioids in the rat.2. Intracerebroventricular (i.c.v.) administration of the δ-selective agonist DPDPE ([D-Pen²,D-Pen²]enkephalin) produced stimulation of HPA activity, as shown by an increase in corticosterone release. This effect was antagonized by i.c.v. co-administration of ICI 174,864, a selective δ-receptor antagonist, which provide direct evidence that the activation of the HPA axis produced by DPDPE is mediated by central δ-opioid receptor.3. Chronic pretreatment with i.c.v. DPDPE resulted in tolerance to its neuroendocrine effect. Intracerebroventricular injection of ICI 174,864 to DPDPE-tolerant rats produced neither alteration in corticosterone release nor behaviour signs of dependence.4. It was concluded that δ-opioid receptors do not play a role in the development of opioid neuroendocrine physical dependence at the HPA axis.     

Is ecstasy a drug of dependence?

This paper examines the evidence for an MDMA or “ecstasy” dependence syndrome. Animal evidence suggests that MDMA may be a less potent reinforcer than other drugs, but that it does have dependence potential. This suggests that (a) ecstasy dependence might be less likely than dependence upon other drugs; and (b) factors related to the behavioural and psychological aspects of reward and dependence may make a relatively greater contribution for ecstasy than for other drugs, where physically centred (and better understood) features of dependence may be more salient. Human evidence supports this proposition. Some people report problems with their use, but the literature suggests that physical features play a more limited role than psychological ones. Tolerance is apparent, and withdrawal is self-reported, but it is unclear whether these reports distinguish sub-acute effects of ecstasy intoxication from symptoms reflective of neuroadaptive processes underlying a “true” withdrawal syndrome. Studies examining the structure of dependence upon ecstasy suggest it may be different from drugs such as alcohol, methamphetamine and opioids. Consistent with studies of hallucinogens, a two-factor structure has been identified with factors suggestive of “compulsive use” and “escalating use”. Regardless of the nature of any dependence syndrome, however, there is evidence to suggest that a minority of ecstasy users become concerned about their use and seek treatment. Further controlled studies are required to investigate this phenomenon.     

Do smokers of specialty and conventional cigarettes differ in their dependence on nicotine?

Specialty cigarettes, bidis and kreteks, have commonly been viewed by adolescent users as being less harmful than conventional cigarettes. Biochemical studies, however, have shown that the concentration and delivery of nicotine from these tobacco products are not insignificant. The current study tested whether the diagnosis and symptoms for nicotine dependence differed among conventional-only smokers (n = 16 959), specialty-only smokers (n = 313), and poly-tobacco smokers (n = 1288) from the 2002 and 2003 National Surveys on Drug Use and Health. Compared with the specialty-only smokers, the conventional-only and poly-tobacco smokers were more dependent on nicotine, assessed by the Nicotine Dependence Syndrome Scale and a single item from the Fagerstrom Test for Nicotine Dependence. However, after accounting for differences in smoking frequency, the specialty-only smokers had significantly greater odds of being nicotine dependent than the conventional-only smokers. The reversed effect was primarily attributed to the specialty-only smokers who smoked less frequently, but reported a shorter time to their first cigarette. These findings suggest that the nicotine acquired from specialty cigarettes may be sufficient in yielding a sense of urgency to smoke.     

Sensitivity to the effects of opioids in rats with free access to exercise wheels: µ-opioid tolerance and physical dependence

Rationale Exercise stimulates the release of endogenous opioid peptides and increases nociceptive (i.e. pain) thresholds in both human and animal subjects. During chronic, long-term exercise, sensitivity to the effects of morphine and other μ opioids decreases, leading some investigators to propose that exercise may lead to the development of cross tolerance to exogenously administered opioid agonists. Objective The purpose of the present investigation was to examine the effects of chronic exercise on sensitivity to μ opioids, and to determine whether these effects can be attributed to the development of opioid tolerance and dependence. Methods Rats were obtained at weaning and housed singly in standard polycarbonate cages (sedentary) or modified cages equipped with exercise wheels (exercise). After 6 weeks under these conditions, opioids possessing a range of relative efficacy at the μ receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine) were examined in a warm-water tail-withdrawal procedure. Results Morphine, levorphanol and buprenorphine produced maximal levels of antinociception in both groups of rats, but all were more potent in sedentary rats than in exercising rats. Butorphanol and nalbuphine produced maximal levels of antinociception in sedentary rats under some conditions in which they failed to produce antinociception in exercising rats. Sensitivity to the effects of buprenorphine was decreased in sedentary rats that were transferred to cages equipped with exercise wheels, and increased in exercising rats that were transferred to sedentary housing conditions. In the latter group, exercise output prior to housing reassignment was positively correlated with increases in sensitivity to buprenorphine following housing reassignment. Naloxone administration precipitated a mild withdrawal syndrome in exercising rats that was not readily apparent in sedentary rats. Conclusions These data suggest that chronic exercise leads to the development of μ-opioid tolerance and physical dependence, and that these effects are similar to those produced by chronic opioid administration.     

Do personality characteristics and risk taking mediate the relationship between paternal substance dependence and adolescent substance use?

This longitudinal study examined whether adolescent personality characteristics and risk taking mediate the relationship between paternal substance dependence and adolescent substance use. At Time 1, the sample included 249 15-19 year-old adolescents and their fathers. These individuals also were assessed 5 years later (Time 2). Results indicated that paternal substance dependence directly and indirectly (via personality and risk taking) predicted adolescent substance use. Paternal substance dependence had significant direct effects on age when the adolescent first used marijuana and significant indirect effects on age when regular drinking began, age when first used marijuana, and frequency of drinking to get "high" or "drunk." All of the indirect personality effects were via adolescent disinhibition. In addition, adolescent risk taking further mediated personality and adolescent substance use. Results from this study are discussed in relation to an epigenetic perspective of human development.