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Varenicline decreases nicotine but not alcohol self-administration in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats
Full text linkBackground: Alcohol and nicotine are largely co-abused. Here, we investigated whether concurrent exposure to both addictive drugs influences each other's consumption and whether varenicline attenuates alcohol consumption in the presence of nicotine. Methods: Marchigian Sardinian alcohol-preferring (msP) rats trained to simultaneously self-administer oral alcohol (10% v/v) and intravenous nicotine (30. μg/kg/inf) were used. Additional groups of rats were trained to self-administer either alcohol or nicotine. Further, msP rats were also trained to self-administer nicotine followed by 22-h/day access to alcohol and water in a two bottle free choice paradigm or water alone. The effects of varenicline (0.0, 0.3, 1.0, 3.0. mg/kg, p.o.) on alcohol and nicotine consumption were tested. Results: In a self-administration paradigm, msP rats showed a significantly high level of alcohol and nicotine intake when the drugs were administered alone. However, when access to both drugs occurred concomitantly, the number of nicotine infusions self-administered was significantly decreased. Nicotine self-administration was markedly reduced by varenicline regardless of whether it was self-administered alone or concurrently with alcohol. In a two bottle choice test, varenicline significantly decreased nicotine self-administration but had no influence on alcohol consumption. Conclusion: Varenicline is highly efficacious in decreasing nicotine self-administration either alone or in combination with alcohol. However, varenicline failed to influence both operant responding for alcohol and home-cage alcohol drinking in msP animals. Taken together, our findings suggest that the effects of varenicline could be specific to nicotine under conditions where excessive alcohol drinking is facilitated by genetic factors as in msP rats
La Neurobiologia del gioco d’azzardo patologico
No full textQuesto articolo di revisione offre una sintesi aggiornata del lavoro fatto su un argomento di crescente impatto
sociale, medico e scientifico quale il gioco d’azzardo patologico (GAP). Anche se il GAP è classificato
come un disordine del controllo degli impulsi nel DSM IV, il comportamento di gioco d’azzardo patologico è
stato recentemente riconcettualizzato ed è ora considerato una vera e propria dipendenza comportamentale perché
presenta notevoli affinità con i disordini di dipendenza da sostanze. Questa ricategorizzazione del problema
ha fortemente contribuito a una migliore comprensione dei meccanismi che sono alla base della sua eziologia e
mantenimento. In questo articolo sono prima rivisitati l’impatto sociale e gli aspetti epidemiologici del GAP con
particolare riferimento alla situazione italiana. Poi, gli aspetti comportamentali caratteristici del disturbo come l’elevata
impulsività, i deficit nella capacità di prendere decisioni associate a rischio e la tendenza al comportamento
compulsivo sono descritti e discussi nell’ambito di una dettagliata presentazione dei modelli clinici e preclinici
comunemente utilizzati nello studio del disordine. Inoltre, sono raccolte le più significative evidenze sperimentali
che fanno luce sui meccanismi neurobiologici che regolano il GAP in termini di alterata funzionalità cerebrale ed
attività neurotrasmettitoriale. La descrizione del fenomeno è completata da un’attenta rivisitazione degli agenti
farmacologici sperimentati finora nel trattamento di questa patologia
Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats.
No full textA dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking.
METHODS:
We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20 mg/kg, i.p.) was tested on alcohol consumption.
RESULTS:
Intermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake.
CONCLUSIONS:
Pharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence
Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: reduced appetite for calories and suppression of addictive-like behaviors.
No full textRATIONALE:
The hypothalamic neuropeptide melanin-concentrating hormone and its MCH1 receptor have been implicated in regulation of feeding and energy homeostasis, as well as modulation of reward-related behaviors. Here, we examined whether the MCH system plays a role both in caloric and motivational aspects of sugar intake.
MATERIALS AND METHODS:
The non-peptide MCH1-R antagonist GW803430 (3, 10, 30 mg/kg, i.p.) was first tested on self-administration under a fixed ratio schedule of reinforcement of both a caloric (10% w/v sucrose) and a non-caloric (0.06% w/v saccharin) sweet solution. GW803430 was then tested for its ability to alter motivational properties and seeking of sucrose. Lastly, the drug was tested to concurrently examine its effects on the escalated consumption of both sugar and food in animals following intermittent sugar access.
RESULTS:
The MCH1-R antagonist reduced sucrose- but not saccharin-reinforced lever pressing, likely reflecting a decreased appetite for calories in GW803430-treated rats. GW803430 reduced sucrose self-administration under a progressive ratio schedule, and suppressed cue-induced reinstatement of sucrose seeking, suggesting effects on rewarding properties of sucrose. GW803430 attenuated food intake in rats on intermittent access to sucrose at all doses examined (3, 10, 30 mg/kg), while reduction of sugar intake was weaker in magnitude.
CONCLUSION:
Together, these observations support an involvement of the MCH system in regulation of energy balance as well as mediation of sucrose reward. MCH may be an important regulator of sugar intake by acting on both caloric and rewarding components
L’esposizione cronica al THC in eta’ adolescenziale ha azione ansiogenica e causa alterazioni di espressione genica a livello della corteccia prefrontale: Uno studio condotto nel ratto in astinenza.
No full textI derivati della cannabis sono fra le sostanze piu’ diffusamente utilizzate in eta’ periadolescenziale.
Nella letteratura scientifica il potenziale di abuso del 9-THC (THC) e’ ben documentato; meno
note sono le conseguenze dell’esposizione cronica a questa sostanza in eta’ giovanile e l’insorgenza
di patologie della sfera psichica e cognitiva. Qui abbiamo condotto una serie di esperimenti nel ratto
nei quali sono stati analizzati i cambiamenti di espressione genica nella corteccia prefrontale dopo
72 ore dall’interruzione di un trattamento cronico con THC in eta’ adolescenziale. Questa area
cerebrale e’ stata scelta poiché e’ fortemente coinvolta nella regolazione nelle risposte cognitive e
nella regolazione degli stati affettivi. Inoltre in eta’ adolescenziale essa e’ caratterizzata da una
fortissima plasticità neuronale per cui potrebbe essere particolarmente sensibile agli effetti tossici
del THC. Contemporaneamente, trascorse 72 ore dall’interruzione del trattamento sono stati
condotti studi di tipo comportamentale per valutare se l’esposizione al THC possa aumentare i
livelli di comportamenti riferibili a stati d’ansia
I risultati di questo lavoro hanno dimostrato che nel ratto giovane, trattato due volte a giorno a dosi
crescenti di THC dai giorni 35-46 di eta’, si verificano forti cambiamenti di espressione genica nella
corteccia prefrontale. Numerosi geni associati alla risposta immunitaria, neuroinfiammatoria e
apoptotica vengono sovraregolati. Mentre l’espressione di alcuni geni che intervengono nella
risposta neurotrofica sono sotto regolati. A distanza di una settimana dall’interruzione del
trattamento gli animali hanno dimostrato delle alterazioni comportamentali riconducibili ad
aumentati livelli di ansia rispetto ai ratti di controllo (trattati con il veicolo del THC).
Complessivamente questi dati suggeriscono che l’esposizione cronica ai derivati della cannabis in
eta’ adolescenziale puo’ causare profonde alterazioni neurofunzionali potenzialmente di tipo
degenerativo ed essere la causa di un aumentato rischio di insorgenza di patologie riconducibili ad
una aumentato stato di ansia
Chronic THC during adolescence increases the vulnerability to stress-induced relapse to heroin seeking in adult rats.
No full textCannabis derivatives are among the most widely used illicit substances among young people. The addictive potential of delta-9-tetrahydrocannabinol (THC), the major active ingredient of cannabis is well documented in scientific literature. However, the consequence of THC exposure during adolescence on occurrence of addiction for other drugs of abuse later in life is still controversial. To explore this aspect of THC pharmacology, in the present study, we treated adolescent rats from postnatal day (PND) 35 to PND-46 with increasing daily doses of THC (2.5-10mg/kg). One week after intoxication, the rats were tested for anxiety-like behavior in the elevated plus maze (EPM) test. One month later (starting from PND 75), rats were trained to operantly self-administer heroin intravenously. Finally, following extinction phase, reinstatement of lever pressing elicited by the pharmacological stressor, yohimbine (1.25mg/kg) was evaluated. Data revealed that in comparison to controls, animals treated with chronic THC during adolescence showed a higher level of anxiety-like behavior. When tested for heroin (20μg per infusion) self-administration, no significant differences were observed in both the acquisition of operant responding and heroin intake at baseline. Noteworthy, following the extinction phase, administration of yohimbine elicited a significantly higher level of heroin seeking in rats previously exposed to THC. Altogether these findings demonstrate that chronic exposure to THC during adolescence is responsible for heightened anxiety and increased vulnerability to drug relapse in adulthood
Activation of the nociceptin/orphanin FQ system is unable to reverse CRF2 receptor mediated anorexia in the rat.
No full textCentral injection of Nociceptin/Orphanin FQ (N/OFQ), inhibits the anorectic effect of corticotropin-relasing factor (CRF) and stress in rats. Recently, Urocortin II (Ucn II) and Urocortin III (Ucn III), two selective CRF(2) receptor agonists, have been identified. Here, we investigated the effect of intracerebroventricular (ICV) injection of 0.25, 0.75, 1.50 or 3 nmol/rat of Ucn II or Ucn III on food and water intake in food deprived rats. The effect of N/OFQ on Ucn II and UCNIII-induced anorexia was also studied. Results showed a greater inhibition of food consumption by Ucn II than Ucn III. Pretreatment with N/OFQ (0.25-2.0 nmol/rat) did not block the effects of Ucn II and UCNIII. Conversely, injection of N/OFQ (0.25-2.0 nmol/rat) blocked the anorectic effect of CRF (0.1 nmol/rat). These findings suggest that N/OFQ selectively prevent the anorectic effect mediated by activation of the CRF(1) receptor system
Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.
No full textFor centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists
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