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.

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.

Association between positivity and smoking cessation.

The literature documents that personality characteristics are associated with healthy lifestyles, including smoking. Among positive traits, Positivity (POS), defined as a general disposition conducive to facing experience under a positive outlook has shown robust associations with psychological health. Thus, the present study investigated the extent to which POS is able to predict (i) relapse after quitting smoking and (ii) the desire to smoke again. All participants (481) had previously attended a Group Counselling Program (GCP) for Smoking Cessation (from 2005 through 2010). They were contacted through telephone interview. Among participants, 244 were ex-smokers (age: years 56.3 ± 10.08, 52% female) and 237 were still-smokers (age: years 55.0 ± 9.63; 63.5% female). The association of POS with "craving to smoke" levels was assessed with multivariate linear regression analysis while controlling also for important differences in personality such as conscientiousness and general self-efficacy, as well as for gender and age. Results showed that POS was significantly and negatively associated with smoking status and with craving to smoke. Among covariates (i.e., conscientiousness, generalized self-efficacy), gender was associated with smoking status and with craving to smoke. Altogether these findings corroborate the idea that POS plays a significant role in sustaining individuals' efforts to quit smoking.

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.

Knowledge about health effects of cigarette smoking and quitting among Italian university students: the importance of teaching nicotine dependence and treatment in the medical curriculum.

Aims of the study were to compare medical students (MS) to non-MS with respect to their knowledge of smoking and to investigate the effect of a short educational intervention on MS knowledge. MS (n = 962) and students of architecture and law (n = 229) were asked to complete a 60-item questionnaire addressing knowledge of smoking epidemiology and health effects ("Score 1"), and effectiveness of cessation treatments ("Score 2"). Upon completion of questionnaire, fourth year MS received a lecture on tobacco dependence. These students were asked to complete the same questionnaire one and two years later. Mean values for Score 1 were 48.9 ± 11.5% in MS and 40.5 ± 11.4% in non-MS (P < 0.001; d = 0.69). Respective values for Score 2 were 48.1 ± 10.8% and 42.6 ± 10.6% (P < 0.001; d = 0.50). Fifth year students who had attended the lecture in year 4 scored higher than students who had not attended the lecture. Significant differences were noted one but not two years after the educational intervention. In conclusion, MS know slightly more about smoking-related diseases and methods to achieve cessation than nonmedical students; a short educational intervention was associated with better knowledge one year later, but the effect was moderate and short-lived.

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).

Differences in the structure of drinking, cart expression and dopamine turnover between polydipsic and non polydipsic rats in the quinpirole model of psychotic polydipsia.

RATIONALE: Dopaminergic D2/D3 agonist quinpirole (QNP) elicits nonregulatory drinking in rats, a model of psychotic polydipsia. Why only a fraction of QNP-treated rats responds to the treatment becoming polydipsic is still unclear. OBJECTIVES: To unveil possible factors contributing to such variability, we analyzed drinking microstructure in saline and QNP-treated rats, the hypothalamic expression of the cocaine and amphetamine regulated transcript (CART), and the monoaminergic turnover in selected brain areas. METHODS: Rats were daily treated with saline or QNP 0.5 mg/kg, and their 5-h water intake was measured for five consecutive days. The number of bouts and episodes of licking, and their duration, were also measured. Brain CART expression was measured by in situ hybridization and monoamines turnover by HPLC analysis of tissue extracts. Based on the amount of water ingested during the 5-h session, QNP-treated rats were post hoc grouped in polydipsic (PD) and in nonpolydipsic (NPD) rats, and the results compared accordingly. RESULTS: The number of drinking bouts and episodes increased in PD rats, while NPD rats behaved as the controls. CART expression decreased in the arcuate nucleus of the hypothalamus of the PD rats. In contrast, both PD and NPD rats showed a reduction of DA turnover in both ventral tegmental area (VTA) and nucleus accumbens (NAcc). No difference was detected in the turnover of 5HT and NA. CONCLUSIONS: Microstructure analysis confirms that QNP acts on the appetitive component of drinking behavior, making it compulsive. CART expression reduction in response to dopaminergic hyperstimulation might sustain excessive drinking in PD rats.

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.

In vitro morphine metabolism by rat microglia.

Morphine is mainly transformed to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the liver. Glucuronidation is also performed by rat brain homogenates and UDP-glucuronosyltransferases (UGTs) are present in the brain. Here we investigated the possibility that microglia transforms morphine into its metabolites M3G and M6G. Primary cultures of neonatal rat microglia were incubated for different intervals of time in basal conditions or with different concentrations of morphine. The following measures were performed on these cultures and/or in the medium: (i) morphine as well as M3G and M6G concentrations; (ii) levels of mRNA coding for UGT1A1, UGT1A6, UGT1A7, and UGT2B1 as well as their protein levels; (iii) released prostaglandin (PG)E2 and nitrite concentrations. Results show that in basal conditions morphine and M3G are produced by microglia; accordingly, these cells expressed UGT1A1, UGT1A6 and UGT1A7, but not UGT2B1. When cultures were exposed to different concentrations of exogenous morphine, M6G was also synthesized. This shift in the glucuronidation was associated with variations in the expression of UGT isozymes. In particular, UGT1A7 expression was rapidly upregulated and this event was translated into enhanced protein levels of UGT1A7; lesser effects were exerted on UGT1A1 and UGT1A6. Upon prolonged exposure to morphine, microglial cell UGT expression returned to baseline conditions or even to reduced levels of expression. Morphine exposure did not affect the synthesis of both PGE2 and nitrites, ruling out a generalized priming of microglia by morphine. In conclusion, this study suggests that morphine glucuronides found in the cerebrospinal liquor upon peripheral morphine administration may at least in part be brain-born, reconciling the conceptual gap between the high hydrophilic features of morphine glucuronides and their presence beyond the blood-brain barrier.

Polydrug abuse by intravenous use of heroin and tropicamide-containing eyedrops.

BACKGROUND: Drug abuse is rarely limited to a single substance; polydrug use is the norm rather than the exception. In many cases, the misuse of potentially psychoactive substances can lead to serious intoxications and results in addictive behavior. CASE DESCRIPTION: A 22-year-old heroin-addicted woman presented in our clinic reporting a 2-year history of intravenous injection of an eyedrop solution containing 1% tropicamide, an antimuscarinic agent. She reported injecting tropicamide because it attenuated symptoms and signs of opiate withdrawal and it also has hallucinogenic and euphorigenic effects. Despite the large amounts (up to 1.5 g), the rapidity of injection, and the long-term use, tropicamide was relatively well tolerated, without life-threatening consequences.An outpatient detoxification program was performed without any sign or symptom caused by discontinuing tropicamide. CONCLUSIONS: The present case claims a role for pharmacological interactions, in addition to rewarding effects, in influencing drug association in polyabuse pattern. Moreover, this case underlines the need for physicians to be aware of the potential emergence of tropicamide as a drug of misuse, to prevent further harm.

Effects of the 5HT2C antagonist SB242084 on the pramipexole-induced potentiation of water contrafreeloading, a putative animal model of compulsive behavior.

RATIONALE: In rats, quinpirole, a dopaminergic D2/D3 receptor agonist, elicits both hyperdipsia and water "contrafreeloading" (CFL), a putative model of compulsivity. The role of D3 receptors in this effect remains unclear. Clomipramine (CIM) was found to contrast both hyperdipsia and CFL, but the role of serotonin in this effect requires further investigation. OBJECTIVES: We studied the effects of the preferential D3 agonist pramipexole (PPX) in both models. Furthermore, we tested the sensitivity of PPX-induced CFL to CIM and to the 5HT2c antagonist SB242084. METHODS: In experiment 1, drinking was measured at 2 and 5 h after eight daily injections of PPX (0 to 1.0 mg/kg intraperitoneally). In the CFL study, every other third lever press, the rat was reinforced by the delivery of water. On days 1-6, water was only available upon lever pressing. On days 7-15, choice between response-contingent and free access was provided. PPX doses as in the experiment 1 were given. In two further experiments, PPX (0.5 mg/kg) was administered alone or in combination with CIM (5 or 10 mg/kg) or SB242084 (0.3 or 1.0 mg/kg). RESULTS: PPX did not produce hyperdipsia but enhanced spontaneous CFL. SB242084 attenuated PPX-induced CFL more effectively than CIM, restoring the preference for free access to water. CONCLUSIONS: CFL, but not polydipsia, was induced by preferential D3 activation, an effect prevented by 5HT2c receptor blockade. Since PPX interferes with decision making and 5HT2c receptor supersensitivity is involved in the expression of compulsive behaviors, this study supports the compulsive nature of dopaminergic-induced CFL.

Repeated exposure to codeine alters morphine glucuronidation by affecting UGT gene expression in the rat.

We have previously found that phenantrenic opioids, such as heroin or naltrexone, modulate morphine glucuronidation in the rat. Here we further investigated the effects of phenantrenic opioids on morphine glucuronidation comparing the effects of codeine and heroin. In particular, we measured the synthesis of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) from morphine: in the liver microsomal preparations obtained from rats repeatedly treated with two different doses of codeine (ex vivo study); in primary cultures of rat hepatocytes previously incubated for 72h with codeine, or heroin (in vitro study); in the latter conditions, the levels of expression of genes coding for uridine-5'-diphosphate-glucuronosyltransferases (UGTs) A1, A6, A7 and 2B1 were also determined; finally, the levels of glucuronic acid in rat hepatocytes previously incubated for 72h with codeine or heroin were assessed. The ex vivo study shows that codeine exposure in vivo stimulated liver microsomal M3G formation and de novo synthesis of M6G. Differently, in primary hepatocyte cultures both codeine and heroin inhibited M3G formation, whereas heroin only stimulated de novo synthesis of M6G; moreover, codeine significantly reduced UGT2B1 expression at 6h and caused a trend toward inhibition of UGT1A1 expression at 72h; heroin enhanced UGT2B1 expression and inhibited that of UGT1A1 at 72h; finally, both codeine and heroin depleted UDPGA content of hepatocytes. In conclusion, codeine affects liver glucuronidation of morphine enlightening the possible contribution of changes in the spectrum of UGT gene expression and co-factor synthesis in this phenomenon.

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.

Induction of morphine-6-glucuronide synthesis by heroin self-administration in the rat.

RATIONALE: Heroin is rapidly metabolized to morphine that in turn is transformed into morphine-3-glucuronide (M3G), an inactive metabolite at mu-opioid receptor (MOR), and morphine-6-glucuronide (M6G), a potent MOR agonist. We have found that rats that had received repeated intraperitoneal injections of heroin exhibit measurable levels of M6G (which is usually undetectable in this species). OBJECTIVE: The goal of the present study was to investigate whether M6G synthesis can be induced by intravenous (i.v.) heroin self-administration (SA). MATERIALS AND METHODS: Rats were trained to self-administer either heroin (50 µg/kg per infusion) or saline for 20 consecutive 6-h sessions and then challenged with an intraperitoneal challenge of 10 mg/kg of heroin. Plasma levels of heroin, morphine, 6-mono-acetyl morphine, M3G, and M6G were quantified 2 h after the challenge. In vitro morphine glucuronidation was studied in microsomal preparations obtained from the liver of the same rats. RESULTS: Heroin SA induced the synthesis of M6G, as indicated by detectable plasma levels of M6G (89.7 ± 37.0 ng/ml vs. 7.35 ± 7.35 ng/ml after saline SA). Most important, the in vitro V (max) for M6G synthesis was correlated with plasma levels of M6G (r (2) = 0.78). Microsomal preparations from saline SA rats produced negligible amounts of M6G. CONCLUSION: Both in vivo and in vitro data indicate that i.v. heroin SA induces the synthesis of M6G. These data are discussed in the light of previous studies conducted in heroin addicts indicating that in humans heroin enhances the synthesis of the active metabolite of heroin and morphine.

Development and validation of an analytical method based on high performance thin layer chromatography for the simultaneous determination of lamotrigine, zonisamide and levetiracetam in human plasma.

Methods based on HPLC technology are the most frequently adopted for monitoring blood levels of novel antiepileptics. Here a rapid method based on HPTLC was developed for quantitative determination of lamotrigine (LTG), zonisamide (ZNS) and levetiracetam (LVT) in human plasma and compared with HPLC and LC-MS/MS methods. Chromatographic separation was achieved on silical gel 60F(254) plates using ethylacetate:methanol:ammonia (91:10:15v/v/v) as mobile phase. Quantitative analysis was carried out by densitometry at a wavelength of 312, 240 and 210nm for LTG, ZNS and LVT, respectively. Calibration curves were linear over range of 0-200ng for LTG and ZNS and 0-400ng for and LVT. The limit of quantification of LTG, ZNS and LTV was found to be 3.69, 3.7 and 6.85µg/ml, respectively. Intra and inter-assay precision provided relative standard deviations lower than 10% for all three analytes. Correlation and Bland-Altman plot showed general agreement between HPTLC and LC-MS/MS quantification, with a mean bias of -0.25, -0.46 and 0.5µg/ml for LTG ZNS and LVT, respectively. Likewise, comparison between HPLC-UV and LC-MS/MS showed good agreement for all the three compounds analyzed. In conclusion, the proposed HPTLC method is simple, rapid, precise and accurate. It therefore is appropriate for the routine quantification of therapeutic levels of LTG, ZNS and LVT in human plasma.

Clomipramine, but not haloperidol or aripiprazole, inhibits quinpirole-induced water contrafreeloading, a putative animal model of compulsive behavior.

RATIONALE: Repeated administrations of the D2/D3 agonist quinpirole (QNP) to rats elicit an antieconomical pattern of drinking called "contrafreeloading" (CFL), a putative model of compulsive-like behavior. OBJECTIVES: We tested the sensitivity of QNP-induced CFL to haloperidol (HAL), aripiprazole (ARI), and clomipramine (CIM), the latter proven effective in the treatment of obsessive-compulsive disorder (OCD). METHODS: Rats were trained under a schedule of reinforcement (FR3) for water. On days 1-6, water was only available through lever pressing. On days 7-15, a choice between operant and free access was provided. QNP 0.5 mg/kg was administered alone or in combination with HAL (0.1 or 0.2 mg/kg), ARI (0.3 or 1 mg/kg), or CIM (5 or 10 mg/kg). RESULTS: Acutely QNP suppressed operant behavior and, therefore, water intake; upon repeated administrations, tolerance developed to this suppressant effect on responding but only to a lesser extent to the antidipsic effect. In choice conditions, QNP induced a progressive preference for the operant access (CFL). HAL per se, but not CIM and ARI, significantly reduced both responding and drinking (operant phase). In the choice phase, HAL and CIM inhibited CFL, but only the latter reinstated total water intake. ARI, in combination with QNP, increased responding. CONCLUSIONS: CIM reinstates control patterns of drinking, while HAL and ARI where partially or not effective at all, respectively. As far as CIM is considered a first line treatment in OCD, these results further strengthen the notion that QNP-induced CFL belongs to the realm of dopaminergic drug-induced compulsive behaviors.

The role of setting in the oral self-administration of alcohol in the rat.

RATIONALE: We have previously found that rats that were kept at all times in the self-administration (SA) chambers (resident group) self-administered more heroin than rats that were transferred to the SA chambers immediately before testing (Non-Resident group). Alcohol resembles heroin in its ability to produce, at recreational doses, mood elevation, euphoria, drowsiness, and sedation. Furthermore, alcohol presents some similarities with the mechanisms of action of heroin at the levels of the mesostriatal circuitry. Therefore, we predicted that, as for heroin, alcohol intake would be greater in the Resident than in the Non-Resident group. MATERIALS AND METHODS: In Experiment 1, oral self-administration of ethanol and wine solutions (2.5%, 5%, and 10%, v/v) was assessed in Resident and Non-Resident rats using both one-bottle (three sessions) and two-bottle (seven sessions) tests. In addition, we also assessed the intake of water (Experiment 2) and of 0.04% saccharin-0.003% quinine solution (Experiment 3). RESULTS: During the one-bottle sessions, alcohol intake of Resident rats was up to two times that of Non-Resident rats. During the two-bottle sessions, Resident rats drank two times more 5% alcohol than water, whereas Non-Resident rats took equal amount of the two fluids. The average daily intake of pure ethanol for Resident rats given access to 5% solutions was 0.71 ± 0.076 vs. 0.46 ± 0.078 g/kg for Non-Resident rats. No group differences in the intake of water and of saccharin-quinine solution were found. CONCLUSION: The present report demonstrates at a preclinical level the importance of setting for alcohol self-administration.

Effectiveness of varenicline for smoking cessation: a 1-year follow-up study.

We examined the rate of smoking cessation associated with 6 weeks of group counseling therapy (GCT) given alone or in combination with 12 weeks of varenicline (VAR) in 112 smokers. Follow-ups were conducted at 12, 26, and 52 weeks post enrollment. Since participants chose the treatment, differences between the two groups were adjusted using propensity matching. Only 33.3% completed VAR treatment, yet at 1 year, the abstinence rate among participants who were not compliant was not different from subjects who were compliant. VAR resulted in a 23% improvement in the abstinence rates at 26 and 52 weeks (GCT + VAR rates were 62.5% and 56.3%, respectively; GCT-only rates were 39.6% and 33.3%, respectively). Increased carbon monoxide concentration, cigarette consumption, and Beck Depression Inventory score were associated with continued smoking. In conclusion, we found that the combination of counseling and VAR is effective at promoting abstinence at 1 year even when compliance with the medication is not 100%.

The effects of clozapine on quinpirole-induced non-regulatory drinking and prepulse inhibition disruption in rats.

RATIONALE: The biological underpinnings of schizophrenic polydipsia are poorly understood. OBJECTIVES: This study is aimed at fulfilling the requisites of an experimental model of this syndrome through the quinpirole (QNP) induction of non-regulatory drinking in rats. METHODS: In a first experiment, clozapine (10 and 40 mg/kg p.o.) was substituted for haloperidol during the last 5 days of 10 days QNP (0.5 mg/kg i.p.) administration and water intake measured at 5 h. In a second experiment, animals treated with QNP alone or in combination with clozapine were assessed for water intake and prepulse inhibition (PPI). Expression of genes coding for the dopaminergic D2 receptor, as well as for the early genes BDNF (brain-derived neurotrophic factor) and c-Fos in prefrontal cortex, hippocampus, and striatum was also evaluated. RESULTS: Clozapine prevented QNP-induced drinking at 10 and 40 mg/kg, but only at 40 mg/kg when it was substituted for haloperidol. In the second experiment, QNP-treated rats showed both non-regulatory drinking and PPI disruption. Both these effects were prevented by clozapine 40 mg/kg. QNP-reduced BDNF expression in the hippocampus and increased c-Fos in the prefrontal cortex. This effect was prevented by clozapine. Given by itself, clozapine reduced the expression of both D2 receptors and BDNF in the prefrontal cortex and striatum. CONCLUSIONS: The present study lends further support to the hypothesis that non-regulatory drinking induced by QNP in rats is a robust and reliable pharmacological effect that might model psychotic polydipsia also in its sensitivity to clozapine.

Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia.

RATIONALE: Repeated administration of the dopamine D2/D3 agonist quinpirole (QNP) progressively increases non-regulatory water intake. This effect may model psychotic polydipsia, a potentially fatal but poorly understood condition. OBJECTIVES: The growing evidence for a role of orexin in mediating arousal and cognition has linked this peptide to schizophrenia, hence we examined whether manipulations of dopaminergic and orexinergic systems, as well as of setting, would further characterize the model. METHODS: Water intake was measured in rats sequentially tested in home and then operant conditioning setting, with chronic administration of D2 antagonist haloperidol (Hal) prior to QNP treatment. A group of rats similarly treated was also assessed for orexin A (OxA) expression in the cortex. Finally, the effect of the orexin-1 receptor antagonist SB-334867 on QNP-induced polydipsia was evaluated. RESULTS: In rats made polydipsic by QNP the amount of water drank during the first 4 h was strongly correlated with the degree of dissociation between appetitive and consummatory components of drinking behavior in the following hour of operant access to water. Hal 0.2 mg/kg prevented both polydipsia and the dissociation, while 0.1 mg/kg only blocked the dissociation. Chronic QNP treatment increased, in a Hal-reversible way, OxA expression in the somatosensory cortex (SI). Moreover, pretreatment with SB-334867 sped up and potentiated QNP-induced polydipsia. CONCLUSIONS: Results disclose compulsive components in QNP-induced polydipsia that are mediated by dopamine D2 receptors. QNP also regulates OxA expression in the SI, while the block of orexin-1 receptors enhances QNP-induced polydipsia. We suggest that dopamine and OxA play opposite roles in QNP-induced polydipsia.