Genders and the concurrent use of cocaine and alcohol: Pharmacological aspects.

AIMS: Gender-related differences in the pharmacological effects of addictive drug are an emerging issue. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of alcohol and cocaine intake since they cause complex pharmacological interactions, not least the formation of the active metabolite cocaethylene. METHODS: The MEDLINE database was searched from 1990 to 2014 in order to find articles related to gender differences in alcohol, cocaine and cocaethylene pharmacokinetics and pharmacodynamics. RESULTS: Besides the well known gender differences in alcohol pharmacokinetics, women appear more susceptible to alcohol-mediated brain damage and seem to suffer more than men the acute effects of alcohol on hepatic and gonadal hormones. No significant gender differences have been found in the pharmacokinetics of cocaine taken alone; yet, in women pharmacological sensitivity to the drug seems to vary in relation to menstrual cycle; moreover, progesterone attenuates subjective effects of cocaine in women. Higher ratings at a subjective measure of mental/physical well-being have been observed in women when given cocaine and alcohol, alone or in combination. Finally, among subjects dependent on both alcohol and cocaine, men only benefit from naltrexone, whereas women used more cocaine during the trial and were less compliant to therapy than men. CONCLUSIONS: The observed subtle gender differences in the pharmacokinetics and pharmacodynamics of both alcohol and cocaine may have no subtle influence on the natural history of the co-abuse of the two drugs by women.

Validity of the Italian version of the Severity of Dependence Scale (SDS) for nicotine dependence in smokers intending to quit.

The objective was to test the psychometric properties of an Italian version of the Severity of Dependence Scale, a five-item measure designed to assess the compulsive dimension of drug dependence. 635 smokers enrolled in a tobacco dependence treatment program served as the participants. The Fagerström Test for Nicotine Dependence was used as a comparative measure. Dimensionality of the Severity of Dependence Scale and the Fagerström Test for Nicotine Dependence was assessed by factor analysis. Prediction of smoking at one year was evaluated by logistic regression. Factor analysis yielded a two-factor solution; however, the second factor explained very little variance. Factor 1 had a Cronbach's alpha of .66 (overall Scale coefficient = .44). The total Severity of Dependence Score predicted smoking at one year (OR = 1.10).

Pivaloylcodeine, a new codeine derivative, for the inhibition of morphine glucuronidation. An in vitro study in the rat.

We have previously found that phenanthrenic opioids, including codeine, modulate morphine glucuronidation in the rat. Here codeine and five of its derivatives were compared in their effects on the synthesis of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) from morphine by rat liver microsomal preparations, and by primary cultures of rat hepatocytes previously incubated for 72 h with either codeine or its derivatives. Acetylcodeine and pivaloylcodeine shared the capability of the parent compound of inhibiting the synthesis of M3G by liver microsomes through a noncompetitive mechanism of action. Their IC50 were 3.25, 2.27, and 4.32 µM, respectively. Dihydrocodeine, acetyldihydrocodeine, and lauroylcodeine were ineffective. In all the experimental circumstances M6G was undetectable in the incubation medium. In primary hepatocyte cultures codeine only inhibited M3G formation, but with a lower efficacy than that observed with microsomes (IC50 20.91 vs 4.32 µM). Preliminary results show that at micromolar concentrations codeine derivatives exhibit a low rate of affinity for µ opiate receptors. In conclusion, acetyl and pivaloyl derivatives of codeine noncompetitively inhibit liver glucuronidation of morphine interacting with microsomes. This study further strengths the notion that phenanthrenic opioids can modulate morphine glucuronidation independently from their effects on µ opiate receptors.

Cigarette smoking knowledge and perceptions among students in four Italian medical schools.

INTRODUCTION: Tobacco smoking is the leading cause of premature death in the developed world. Advice and assistance by physicians help smokers quit, but little attention has been paid to the topic of tobacco dependence in the curricula of Italian medical schools. Consequently, few physicians follow the clinical practice guidelines for treating dependence. METHODS: This study was conducted on 439 students at 4 Italian medical schools in 2010. Students were asked to complete a 60-item questionnaire. Two scores were computed: Score 1 assessed knowledge of the epidemiology of smoking, risks associated with smoking, and benefits of cessation. Score 2 assessed knowledge of tobacco dependence treatment guidelines and the effectiveness of treatments. A score of less than 60% indicated insufficient knowledge. RESULTS: Medical students had limited knowledge of the epidemiology of smoking, attributable morbidity and mortality, and the benefits of cessation. This limited knowledge was reflected by the finding that 70% of students had a total Score 1 less than 60% of available points. Knowledge of clinical guidelines, perceived competence in counseling smokers, and treatment of addiction was also insufficient, as 76% of students achieved a total Score 2 of less than 60%. CONCLUSIONS: Our data demonstrate that Italian medical students have limited knowledge about tobacco dependence, how to treat it, and the critical role of the physician in promoting cessation. Taken together with research from other countries, these findings suggest that medical schools do not offer adequate training in tobacco dependence and provide a rationale for modifying the core curriculum to include more information on tobacco dependence treatment.

Psychobiology of drug-induced religious experience: from the brain "locus of religion" to cognitive unbinding.

The recent interest in the psychopharmacological underpinnings of religious experiences has led to both the laboratory characterizations of drug-induced mystical events and psychobiological models of religious experiences rooted in evolution and fitness. Our examination of this literature suggests that these theories may be congruent only within more modern religious and cultural settings and are not generalizable to all historical beliefs, as would be expected from an evolutionarily conserved biological mechanism. The strong influence of culture on the subjective effects of drugs as well as religious thoughts argues against the concept of a common pathway in the brain uniquely responsible for these experiences. Rather, the role of personal beliefs, expectations and experiences may interject bias into the interpretation of psychoactive drug action as a reflection of biologically based religious thought. Thus, psychobiological research proposing specific brain mechanisms should consider anthropological and historical data to address alternative explanations to the "fitness" of religious thought. A psychobiological model of the religious experience based on the concept of cognitive unbinding seems to accommodate these data better than that of a specific brain locus of religion.

A smoking ban in public places increases the efficacy of bupropion and counseling on cessation outcomes at 1 year.

INTRODUCTION: Legal restrictions have contributed to the decline in smoking prevalence in several European countries. We investigated the impact of the Italian 2005 indoor smoking ban on the efficacy of counseling alone or in combination with bupropion for smoking cessation. METHODS: Before and after the introduction of the ban (2001-2006), 550 smokers were enrolled in the smoking cessation program in Rome and were asked to choose between a 6-week group counseling therapy (GCT) given alone or in combination with 7 weeks of daily bupropion. Follow-up was completed 12, 26, and 52 weeks after the quit day. Due to the observational nature of the study, we used propensity scores to match 138 and 290 subjects (pre-/postban) in the bupropion- and GCT-only groups, respectively. RESULTS: Covariate balance in the two matched samples was adequate for all variables except "coffee consumption" in the GCT-only group. The regression adjusted odds ratios indicated that the introduction of the ban resulted in 52% reduced odds of continued smoking at 12 months among the GCT + bupropion group and 41% reduced odds in the GCT-only group. We observed that the ban was associated with both increased 12-month abstinence rates and motivation to quit. In a mediation analysis, we determined that the total effect of the smoking ban on the abstinence rate was reduced after controlling for motivation, which confirmed that motivation was a partial mediator. DISCUSSION: The introduction of an indoor smoking ban improved the efficacy of smoking cessation treatments by possibly providing a setting that increased the level of motivation to stop smoking.

Haloperidol both prevents and reverses quinpirole-induced nonregulatory water intake, a putative animal model of psychogenic polydipsia.

RATIONALE: Polydipsia is a severe complication of long-term schizophrenia and, despite its unknown pathogenesis, is empirically treated with typical or atypical antipsychotics. In the rat, nonregulatory water intake is induced by repeated administration of amphetamine-like compounds or by the D2/3 agonist, quinpirole. OBJECTIVE: This study is aimed at determining the potential activity of antipsychotic compounds with different affinities for D2 receptors in preventing and/or reversing quinpirole-induced polydipsia. MATERIALS AND METHODS: Male Sprague-Dawley rats were treated with five injections of quinpirole (0.5 mg/kg i.p.) to induce polydipsia. The oral effects of haloperidol, olanzapine, clozapine, and ST2472 on QNP-induced polydipsia were analyzed in the following two schedules. In the preventive schedule, haloperidol (0.2, 0.4, and 0.8 mg/kg), olanzapine (1.5, 3, and 6 mg/kg), ST2472 (1 and 2 mg/kg), and clomipramine (5, 10, and 20 mg/kg) were given in combination with quinpirole from day 1 to day 5. In the reversal schedule, rats showing quinpirole-induced polydipsia on the third day received haloperidol (0.4 mg/kg), olanzapine (1.5 and 3 mg/kg), clozapine (10, 20, and 40 mg/kg), ST2472 (1, 2, 5, and 10 mg/kg), and clomipramine (5, 10, and 20 mg/kg) before quinpirole on days 4 and 5. RESULTS: Haloperidol both prevented and reversed quinpirole-induced polydipsia, whereas olanzapine and ST2472 only reversed it. Clomipramine prevented but did not reverse quinpirole-induced polydipsia, and clozapine did not reverse it either. CONCLUSIONS: We suggest that, once developed, polydipsia is governed by dopaminergic D2 mechanisms. In contrast, either an increase in the serotoninergic tone or an inhibition of D2 receptors can modulate the development of quinpirole-induced excessive drinking.

The influence of cost manipulation on water contrafreeloading induced by repeated exposure to quinpirole in the rat.

RATIONALE: Quinpirole (QNP), a D2/D3 dopaminergic receptor agonist, was found to elicit an apparently antieconomical drinking behavior called contrafreeloading (CFL). The perseverative operant responding observed may represent a compulsive-like behavior prompted by sensitization to the effects of QNP. OBJECTIVES: In the present study, we investigated the effect of different response costs on instrumental behavior and CFL in rats repeatedly treated with QNP (0.5 mg/kg i.p.). Moreover, we studied the consummatory components of ingestive behavior in no-choice paradigms and the role of learned operant conditioning in free drinking. MATERIALS AND METHODS: In experiment 1, rats were trained to perform under three different fixed ratio schedules of reinforcement (FR1, FR3, and FR10) and were given a choice between operant and free access to water. In experiment 2, rats were divided into four groups, each one resembling experiment 1 in one or more features, with no choice available and water consumption measured at an interval of 0-60 min. RESULTS: (a) Increasing FR significantly reduced CFL % in saline -- but not in QNP-injected groups; (b) under free-drinking conditions, QNP caused a progressive hypodipsic effect which was, however, contrasted by maintaining cues formerly contingent on operant access to water; and (c) under CFL conditions QNP-treated rats drank more than under free access conditions. CONCLUSIONS: QNP confers rigidity in responding for water, impeding adaptation to different contingencies for access to the resource. In QNP-treated rats, CFL behavior appears adaptive as far as it allows animals to partially circumvent the hypodipsic effect of the drug.

Opposite environmental regulation of heroin and amphetamine self-administration in the rat.

RATIONALE: The circumstances of drug taking are thought to play a role in drug abuse but the evidence of it is anecdotal. Previous studies have shown that the intravenous self-administration of cocaine is facilitated in rats non-residing in the test chambers relative to rats that live in the test chambers at all times. We investigated here whether environmental context could exert its modulatory influence on heroin and amphetamine self-administration as well. MATERIALS AND METHODS: Independent groups of rats were given the possibility to self-administer different doses of heroin or amphetamine (12.5, 25.0, or 50.0 microg/kg). Some animals were housed in the self-administration chambers (resident groups) whereas other rats were transported to the self-administration chambers only for the test sessions (non-resident groups). RESULTS: Amphetamine-reinforcing effects were more pronounced in non-resident rats than in resident rats, as previously reported for cocaine. Quite unexpectedly, the opposite was found for heroin. Because of this surprising dissociation, some of the rats trained to self-administer amphetamine were later given the opportunity to self-administer heroin. Also in this case, resident rats took more heroin than non-resident rats. CONCLUSIONS: These findings suggest an unforeseen dissociation between opioid and psychostimulant reward and demonstrate that even in the laboratory rat some contexts are associated with the propensity to self-administer more opioid than psychostimulant drugs and vice versa, thus indicating that drug taking is influenced not only by economical or cultural factors but also can be modulated at a much more basic level by the setting in which drugs are experienced.

Non-opioid induction of morphine-6-glucuronide synthesis is elicited by prolonged exposure of rat hepatocytes to heroin.

BACKGROUND: Liver metabolism of morphine leads to the formation of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the latter possessing strong opioid activity that however differs from that of the parent compound. In previous studies conducted in rats we have shown that repeated in vivo exposure to phenanthrene class of mu opioid receptor (MOR) agonists or antagonists (heroin, morphine, and naltrexone), but not to non-phenanthrene class of MOR agonist methadone, affects morphine glucuronidation by liver microsomes. METHODS: In the present study, we measured the in vitro formation of M3G and M6G by rat hepatocytes incubated for 120 min with morphine (0.1-1.0 mM) after 72h pre-incubation with one of the following MOR agonists: heroin (3.3 or 6.6 microM), morphine (7.8 microM), or methadone (12 microM). The MOR antagonist naltrexone (10 or 25 microM) was also tested, alone or in combination with heroin. The amount of M3G and M6G synthesized was then measured by HPLC method. RESULTS: Heroin inhibited M3G synthesis and induced the formation of M6G, which under basal conditions is not synthesized in rats. Heroin effects were not blocked by naltrexone. Morphine, but not methadone, produced effects similar to those of heroin but more modest in intensity. Pre-incubation with naltrexone alone slightly increased M3G synthesis, but had no effect on M6G formation. CONCLUSIONS: These results are in agreement with those of previous ex vivo studies and indicate that exposure to heroin or, to a lesser extent, morphine, can affect morphine glucuronidation via direct non-opioid actions on the hepatocytes.

Modulatory effect of environmental context and drug history on heroin-induced psychomotor activity and fos protein expression in the rat brain.

The goal of the present study was to investigate the role of environmental context and drug history in modulating the effects of heroin on locomotor activity and Fos protein expression in the neocortex and striatal complex of the rat. It was found that (1) repeated i.p. administrations of a relatively low dose of heroin (1 mg/kg, i.p.) induced psychomotor sensitization only when the treatment was administered in a relatively 'novel' environment (ie, a unique test environment distinct from the home cage) but not when the same treatment was administered in the home cage; (2) environmental novelty facilitated heroin-induced Fos expression in the caudate, particularly in its most caudal regions; (3) environmental context also modulated heroin-induced Fos expression in the nucleus accumbens and in the neocortex; (4) repeated exposures to heroin dramatically altered its effects on Fos expression in the caudate and in the neocortex; and (5) Fos protein levels in the postero-dorsal caudate, in the shell of the nucleus accumbens, and in the barrel field cortex predicted most of the variance in heroin-induced activity scores, as shown by multiple regression analysis. The present report demonstrates that environment and drug history powerfully interact in shaping the neurobehavioral response to heroin, as previously shown for amphetamine and cocaine. Thus, a full understanding of the mechanisms responsible for the neurobehavioral adaptations produced by addictive drugs will also require taking into due consideration the environment in which drugs are experienced.

Environmental modulation of cocaine self-administration in the rat.

RATIONALE: Previous studies have shown that environmental context can powerfully modulate the induction of psychomotor sensitization to cocaine in the rat. Rats that receive repeated administrations of cocaine in association with environmental novelty exhibit greater psychomotor sensitization than animals that receive the same treatments in their home cages. OBJECTIVES: The goal of the present study was to investigate whether environmental context can exert its modulatory influence also on cocaine self-administration. MATERIALS AND METHODS: Independent groups of rats with intravenous catheters were given the possibility to self-administer different doses of cocaine (0.0, 0.2, 0.4, and 0.8 mg/kg per infusion) under two environmental conditions. Some animals were housed in the self-administration cages (home groups), whereas other rats were transported to the self-administration cages only for the test sessions (novelty groups). RESULTS: Environmental "novelty" facilitated the acquisition of cocaine self-administration at the doses of 0.2 and 0.4 mg/kg per infusion. When rats were given access to a higher dose of cocaine (0.8 mg/kg per infusion), there were no significant group differences in drug taking. Environmental context had no effect on the self-administration of the vehicle. Thus, it appears that environmental "novelty" produced a shift to the left in the dose-effect curve for cocaine self-administration. Furthermore, "novelty" enhanced the motivation of the rats to work for cocaine, as indicated by the results of a progressive ratio procedure. CONCLUSIONS: The present findings demonstrate for the first time that the environment surrounding drug taking can alter both the intake of and motivation for cocaine.

Compulsive-like effects of quinpirole on drinking behavior in rats are inhibited by substituting ethanol for water.

We have previously reported that in rats given the choice between operant and free access to water (contrafreeloading: CFL), repeated administrations of quinpirole, a D2/D3 dopamine receptor agonist, shifted the animals towards the operant access and inhibited water intake. The purpose of the present study was to investigate the influence of substituting different concentrations of ethanol (2, 4, 6%) for water on the effects of repeated daily administrations of vehicle or quinpirole (0.5mg/kg i.p.) in rats that for 6 days were given access to the fluid according to an FR3 schedule of reinforcement and for the following 9 days were given the choice between operant and free access to the fluid. On the first day quinpirole completely suppressed operant behavior, which however progressively increased in the subsequent sessions, approaching control levels by day 6. Ethanol presentation did not alter these effects of quinpirole. When the resource was also freely available, quinpirole produced the expected shift from free to operant access to water (CFL). Substituting ethanol for water resulted in a concentration-related reduction of the over-responding and, consequently, of CFL induced by quinpirole. In vehicle-injected subjects ethanol did not affect responding and only marginally reduced fluid intake. Thus, ethanol appears to prevent perseveration in performing needless instrumental behavior induced by repeated activation of D2/D3 receptors.

Compulsive-like effects of repeated administration of quinpirole on drinking behavior in rats.

We have previously reported that repeated administrations of quinpirole, a D2/D3 dopamine receptor agonist, facilitate instrumental behavior in rats given the choice between operant and free access to water (contrafreeloading: CFL). The goal of the present study was to investigate the effects of repeated daily administrations of quinpirole (0.5 mg/kg i.p.) on the appetitive versus the consummatory component of water-reinforced behavior, under two experimental conditions. Under one condition, the rats were given access to tap water according to an FR3 schedule of reinforcement. Under the second condition, the rats were given the choice between operant and free access to water. Five major findings were obtained. First, acutely quinpirole suppressed operant behavior and, therefore, water intake for at least 1h. Second, upon repeated administrations tolerance developed to the suppressant effect of quinpirole on instrumental behavior but only to a lesser extent to the antidipsic effect, dissociating the appetitive from the consummatory components of water-reinforced behavior. Third, in CFL conditions quinpirole induced a progressively larger preference for the operant access. Fourth, even when the rats were given the choice between free access to highly palatable saccharine (0.05 or 0.01%) solutions and operant access to tap water, quinpirole shifted the animals towards the operant access. Fifth, repeated quinpirole produced lasting consequences on drinking behavior, since after rehydration and under drug-free conditions quinpirole-pretreated rats ingested larger amounts of water than control rats. In conclusion, the repeated activation of D2/D3 receptors appears to induce the rats to perseverate in performing needless instrumental behavior.

Social isolation selectively reduces hippocampal brain-derived neurotrophic factor without altering plasma corticosterone.

It is well known that housing conditions may alter several physiological and behavioral parameters. In this study, we have investigated whether a prolonged period of partial social isolation can modify central brain-derived neurotrophic (BDNF) concentrations. Male Sprague-Dawley rats were singly housed for 8 weeks before hippocampi, prefrontal cortices and striata were collected for BDNF determination. Compared to rats housed two per cage, isolated rats showed a significant reduction on BDNF protein concentrations in the hippocampus while no changes were observed in the other brain regions examined. Moreover, housing condition had no effect on basal plasma corticosterone. On the basis of the proposed etiological participation of reduced central BDNF concentrations in affective disorders, our results would candidate social isolation as a model for the study of antidepressant treatments.

Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin.

Cannabidivarin (CBDV) and cannabidiol (CBD) have recently emerged among cannabinoids for their potential antiepileptic properties, as shown in several animal models. We report the case of a patient affected by symptomatic partial epilepsy who used cannabis as self-medication after the failure of countless pharmacological/surgical treatments. Clinical and video electroencephalogram (EEG) evaluations were periodically performed, and the serum levels of CBDV, CBD, and Δ9-tetrahydrocannabinol were repeatedly measured. After cannabis administration, a dramatic clinical improvement, in terms of both decrease in seizure frequency and recovery of cognitive functions, was observed, which might parallel high CBDV plasma concentrations. To widen the spectrum of CBDV possible mechanisms of action, electrophysiological methods were applied to investigate whether it could exert some effects on γ-aminobutyric acid (GABA)A receptors. Our experiments showed that, in human hippocampal tissues of four patients affected by drug-resistant temporal lobe epilepsy (TLE) transplanted in Xenopus oocytes, there is decrease of current rundown (i.e., reduction of use-dependent GABAA current) after prolonged exposure to CBDV. This result has been confirmed using a single case of Rasmussen encephalitis (RE). Our patient's electroclinical improvement supports the hypothesis that cannabis could actually represent an effective, well-tolerated antiepileptic drug. Moreover, the experimental data suggest that CBDV may greatly contribute to cannabis anticonvulsant effect through its possible GABAergic action.

Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole.

RATIONALE: Compulsive symptoms develop in patients exposed to pramipexole (PPX), a dopaminergic agonist with high selectivity for the D3 receptor. Consistently, we demonstrated that PPX produces an exaggerated increase in contrafreeloading (CFL) for water, a repetitive and highly inflexible behavior that models core aspects of compulsive disorders. OBJECTIVES: Given the role of the hippocampus in behavioral flexibility, motivational control, and visuospatial working memory, we investigated the role of hippocampus in the expression of PPX-induced CFL. To this aim, rats were subjected to CFL under chronic PPX, and then examined for the electrophysiological, structural, and molecular properties of their hippocampus. METHODS: We measured long-term potentiation (LTP) at CA1 Schaffer collaterals, dendritic spine density in CA1 pyramidal neurons, and then glutamate release and expression of pre and postsynaptic proteins in hippocampal synaptosomes. The effects of PPX on hippocampal-dependent working memory were assessed through the novel object recognition (NOR) test. RESULTS: We found that PPX-treated rats showing CFL exhibited a significant decrease in hippocampal LTP and failed to exhibit the expected increase in hippocampal spine density. Glutamate release and PSD-95 expression were decreased, while pSYN expression was increased in hippocampal synaptosomes of PPX-treated rats showing CFL. Despite a general impairment of hippocampal synaptic function, working memory was unaffected by PPX treatment. CONCLUSIONS: Our findings demonstrate that chronic PPX affects synaptic function in the hippocampus, an area that is critically involved in the expression of flexible, goal-centered behaviors. We suggest that the hippocampus is a promising target in the pharmacotherapy of compulsive disorders.

Effect of repeated administrations of heroin, naltrexone, methadone, and alcohol on morphine glucuronidation in the rat.

RATIONALE: Heroin is rapidly metabolized to morphine that in turn is transformed in morphine-3-glucuronide (M3G), an inactive metabolite, and morphine-6-glucuronide (M6G), a potent mu-opioid receptor (MOR) agonist. We have found that heroin addicts exhibit higher M6G/M3G ratios relative to morphine-treated control subjects. We have also shown that heroin-treated rats exhibit measurable levels of M6G (which is usually undetectable in this species) and reduced levels of M3G. OBJECTIVE: We investigated the role of MOR in these effects of heroin, by examining the effects of methadone, a MOR agonist, and of naltrexone, a MOR antagonist, on morphine glucuronidation. We also investigated the effects of alcohol, which is known to alter drug metabolism and is frequently coabused by heroin addicts. METHODS: Morphine glucuronidation was studied in liver microsomes obtained from rats exposed daily for 10 days to saline, heroin (10 mg/kg, i.p.), naltrexone (20-40 mg/kg, i.p.), heroin + naltrexone (10 mg/kg+20-40 mg/kg, i.p.), methadone (5-20 mg/kg, i.p.), or 10% ethanol. RESULTS: Heroin induced the synthesis of M6G and decreased the synthesis of M3G. Naltrexone exhibited intrinsic modulatory activity on morphine glucuronidation, increasing the synthesis of M3G via a low-affinity/high-capacity reaction characterized by positive cooperativity. The rate of M3G synthesis in the heroin + naltrexone groups was not different from that of the naltrexone groups. Methadone and ethanol induced a modest increase in M3G synthesis and had no effect on M6G synthesis. CONCLUSION: The effects of heroin on morphine glucuronidation are not shared by methadone or alcohol (two drugs that figure prominently in the natural history of heroin addiction) and do not appear to depend on the activation of MOR.

High levels of morphine-6-glucuronide in street heroin addicts.

RATIONALE: In the body, heroin is rapidly transformed to 6-acetylmorphine (6-AM) and then to morphine, that in turn is mainly metabolized to morphine-3-glucuronide (M3G) and, at lesser extent, to morphine-6-glucuronide (M6G). Unlike M3G, M6G is a potent opioid agonist. Intravenous heroin abusers (IHU) are exposed to a wide array of drugs and contaminants that might affect glucuronidation. OBJECTIVES: We assessed plasma and urine concentrations of M3G and M6G in four groups of subjects: the first two included long-term IHU either exposed to street heroin ( n=8) or receiving a single IV injection of morphine ( n=4), while the other two groups included non-IHU patients receiving acute IV ( n=8) or chronic oral ( n=6) administrations of morphine. METHODS: After solid phase extraction plasma and urine concentrations of morphine metabolites were determined by HPLC analyses. RESULTS: M3G accounted for the greater part of morphine glucuronides detected in body fluids of non-IHU patients treated with morphine. This pattern of metabolism remained stable across 15 days of oral administration of incremental doses of morphine. In contrast, the two groups of IHU (street heroin taking or morphine-treated subjects) showed a reduction of blood and urine M3G concentrations in favor of M6G. Consequently, M6G/M3G ratio was significantly higher in the two IHU groups in comparison with the non-IHU groups. CONCLUSIONS: Chronic exposure to street heroin causes a relative increase in concentrations of the active metabolite, M6G. Since the pattern of M6G action seems closer to heroin than to morphine, the increased synthesis of M6G observed in IHU may prolong the narrow window of heroin effects.

Environmental modulation of the interoceptive effects of amphetamine in the rat.

The aim of the present study was to investigate the effect of environmental novelty on amphetamine discrimination. Two groups of rats (home group and novelty group) were trained to perform water-reinforced operant behavior in cages equipped with two levers and a retractable liquid dipper (0.1cc cup). The experimental procedures for the two groups were identical except for the fact that home rats were housed and tested in the operant cages whereas novelty rats were transferred daily to these cages for the testing sessions (25min). The rats were trained to discriminate one of two doses of amphetamine (0.25 and 0.5mg/kg) from saline. Saline and amphetamine were administered intraperitoneally immediately before each daily session according to a semi-random schedule for a total of 50 sessions. Reinforcements were delivered according to a fixed ratio that was increased daily from 2 to 30. Successful drug discrimination was achieved when activity on the appropriate lever before the first reinforcement was greater than 80% of total activity, on at least seven out of eight consecutive sessions. When training was conducted with 0.25mg/kg of amphetamine, no home rat acquired drug discrimination whereas 56% of novelty rats reached criterion. When training was conducted with 0.5mg/kg of amphetamine, drug discrimination was achieved by 50% of home rat versus 86% of novelty rats. These findings indicate that environmental novelty can alter the ability of amphetamine to produce interoceptive cues.