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STUDY OBJECTIVE: In the present study, a number of compounds were tested to evaluate their efficacy in exerting a protective effect on gamma-hydroxybutyric acid (GHB)-induced mortality in mice. The drugs investigated were the gamma-aminobutyric acid B (GABA B ) receptor antagonist SCH 50911, the GABA A receptor antagonist bicuculline, the benzodiazepine receptor antagonist flumazenil, the putative GHB receptor antagonist NCS-382, the opioid receptor antagonist naltrexone, and the amino acid and possible neuromodulator, taurine. METHODS: All mice were initially treated with a lethal dose of GHB (7 g/kg, administered intragastrically). Once mice had displayed clear signs of GHB intoxication, animals from each group were treated acutely with either SCH 50911 (vehicle; 75, 150, and 300 mg/kg, administered intraperitoneally), bicuculline (vehicle; 2, 4, 6, and 8 mg/kg, administered intraperitoneally), flumazenil (vehicle; 1, 3, and 10 mg/kg, administered intraperitoneally), NCS-382 (vehicle; 50 and 200 mg/kg, administered intraperitoneally), naltrexone (vehicle; 3 and 10 mg/kg, administered intraperitoneally), or taurine (vehicle; 250 and 750 mg/kg, administered intraperitoneally). The various doses of each single drug were administered to 10 mice, randomly allocated throughout the experimental groups. Mortality was recorded every hour for the first 9 hours and subsequently 12, 18, and 24 hours after GHB injection. RESULTS: In each experiment, all vehicle-treated mice died within 24 hours of GHB injection. Doses of 150 and 300 mg/kg SCH 50911 produced a marked protection on GHB-induced mortality, evidenced by the death of only 0 of 10 and 2 of 10 mice in the 150- and 300-mg/kg SCH 50911 groups, respectively. In contrast, at all doses tested, bicuculline, flumazenil, NCS-382, naltrexone, and taurine were not observed to exert any protective effect on GHB-induced mortality (9 to 10/10 mice died in each treatment group). CONCLUSION: These results suggest an involvement of the GABA B receptor, at least in rodents, in the mediation of the lethal effects of GHB. [ABSTRACT FROM AUTHOR]

The present study was designed to extend to the newly synthesized rac-BHFF [(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofu ran-2-one] the investigation on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol self-administration in rats. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to respond on a lever [on a fixed ratio 4 (FR4) schedule of reinforcement] to orally self-administer alcohol (15%, v/v) or sucrose (0.7%, w/v) in daily 30-min sessions. Once responding reached stable levels, the effect of rac-BHFF (0, 50, 100, and 200mg/kg; i.g.) on responding for alcohol and sucrose was determined. Pretreatment with rac-BHFF produced a dose-dependent suppression in responding for alcohol; reduction in the total number of responses for alcohol, in comparison to vehicle-treated rats, averaged approximately 30%, 65%, and 90% in 50, 100, and 200mg/kg rac-BHFF-treated rats, respectively. Pretreatment with 200mg/kg rac-BHFF markedly increased the latency to the first response on the alcohol lever. The effect of pretreatment with rac-BHFF on alcohol self-administration was highly specific, since (a) responding for sucrose was reduced (to approximately 50%, in comparison to vehicle-treated rats) only by pretreatment with 200mg/kg rac-BHFF, and (b) latency to the first response on the sucrose lever was completely unaltered by any rac-BHFF dose. Treatment with rac-BHFF did not alter spontaneous locomotor activity in an independent group of sP rats. The present data constitute a further piece of evidence on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol's reinforcing properties in rats. [ABSTRACT FROM AUTHOR]

As sex-gender differences have been described in the responses of patients to certain medications, we hypothesized that the responses to medications recommended for neuropathic pain may differ between men and women. We conducted a literature review to identify articles reporting potential sex-gender differences in the efficacy and safety of these medications. Only a limited number of studies investigated potential sex-gender differences. Our results show that women seem to achieve higher blood concentrations than men during treatment with amitriptyline, nortriptyline, duloxetine, venlafaxine, and pregabalin. Compared to men, higher rates of women develop side effects during treatment with gabapentin, lidocaine, and tramadol. Globally, the sex-gender differences would suggest initially administering smaller doses of these medications to women with neuropathic pain compared to those administered to men. However, most of these differences have been revealed by studies focused on the treatment of other diseases (e.g., depression). Studies focused on neuropathic pain have overlooked potential sex-gender differences in patient responses to medications. Despite the fact that up to 60% of patients with neuropathic pain fail to achieve an adequate response to medications, the potential role of sex-gender differences in the efficacy and safety of pharmacotherapy has not adequately been investigated. Targeted studies should be implemented to facilitate personalized treatments for neuropathic pain.

Recent studies have demonstrated the ability of the positive allosteric modulator (PAM) of the GABA B receptor (GABA B PAM), KK-92A, to suppress operant alcohol self-administration and reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to scrutinize the suppressing effects of KK-92A on alcohol-related behaviors; to this end, four separate experiments were conducted to address just as many new research questions, some of which bear translational value. Experiment 1 found that 7-day treatment with KK-92A (0, 5, 10, and 20 mg/kg, intraperitoneally [i.p.]) effectively reduced alcohol intake in male sP rats exposed to the home-cage 2-bottle "alcohol (10% v/v) vs. water" choice regimen with 1 hour/day limited access, extending to excessive alcohol drinking the ability of KK-92A to suppress operant alcohol self-administration. Experiment 2 demonstrated that the ability of KK-92A to reduce lever-responding for alcohol was maintained also after acute, intragastric treatment (0, 20, and 40 mg/kg) in female sP rats trained to lever-respond for 15% (v/v) alcohol under the fixed ratio 5 schedule of reinforcement. In Experiment 3, acutely administered KK-92A (0, 5, 10, and 20 mg/kg, i.p.) dampened alcohol-seeking behavior in female sP rats exposed to a single session under the extinction responding schedule. Experiment 4 used a taste reactivity test to demonstrate that acute treatment with KK-92A (0 and 20 mg/kg, i.p.) did not alter either hedonic or aversive reactions to a 15% (v/v) alcohol solution in male sP rats, ruling out that KK-92A-induced reduction of alcohol drinking and self-administration could be due to alterations in alcohol palatability. Together, these results enhance the behavioral pharmacological profile of KK-92A and further strengthen the notion that GABA B PAMs may represent a novel class of ligands with therapeutic potential for treating alcohol use disorder., Competing Interests: Declarations of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

COR659 is a new compound, the action of which is exerted via a dual mechanism: positive allosteric modulation of the GABAB receptor; antagonism or inverse agonism at the cannabinoid CB1 receptor. Recent lines of experimental evidence have indicated that COR659 potently and effectively reduced operant self-administration of and reinstatement of seeking behaviour for a chocolate-flavoured beverage. The present study was designed to assess whether the ability of COR659 to diminish these addictive-like, food-motivated behaviours extended to a rat model of overeating palatable food. To this end, rats were habituated to feed on a standard rat chow for 3 h/day; every 4 days, the 3-hour chow-feeding session was followed by a 1-hour feeding session with highly palatable, calorie-rich Danish butter cookies. Even though satiated, rats overconsumed cookies. COR659 (0, 2.5, 5, and 10 mg/kg, i.p.) was administered before the start of the cookie-feeding session. Treatment with all 3 doses of COR659 produced a substantial decrease in intake of cookies and calories from cookies. These results extend the anorectic profile of COR659 to overconsumption of a highly palatable food and intake of large amounts of unnecessary calories., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Exposure to an enriched environment (EE) has been reported to generate multiple beneficial effects in rodents, including - among the many - amelioration of anxiety-related behaviors. The present study investigated whether living in an EE produced anxiolytic effects also in selectively bred Sardinian alcohol-preferring (sP) rats. The relevance of this research question relied on two factors: sP rats displayed an inherent, high anxiety-like state under different experimental conditions; exposure to EE reduced operant, oral alcohol self-administration in sP rats. Starting from weaning, male sP rats were kept under 3 different housing conditions: impoverished environment (IE; single housing with no environmental enrichment); standard environment (SE; 3 rats/cage with no environmental enrichment); EE (6 rats/cage with various elements of environmental enrichment). At the age of approximately 80 days, rats were exposed to an elevated plus maze test for assessment of anxiety-related behaviors. Compared to IE and SE rats, EE rats displayed higher basal levels of exploratory activity (i.e., increased number of entries into closed arms). Compared to IE and SE rats, EE rats also displayed a less "anxious" profile, as suggested by the increase in percent number of entries into open arms (OAs), percent time spent in OAs, number of head dips, and number of end-arm explorations in OAs. These data extend the protective (anxiolytic) effects of EE to a proposed animal model of comorbid alcohol use disorder and anxiety disorders., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α 2 -adrenoceptor antagonists rescue dopamine deficit and improve the antipsychotic efficacy of D 2 -receptor antagonists. In anesthetized male rats, we investigated how the blockade of α 2 - and D 2 -receptors by atipamezole and raclopride, respectively, modified the firing of noradrenergic neurons in the locus coeruleus (LC) and dopaminergic neurons in the ventral tegmental area (VTA). In freely moving rats, we studied how atipamezole and raclopride modified extracellular noradrenaline, dopamine, and DOPAC levels in the medial prefrontal cortex (mPFC) through microdialysis. When administered alone, atipamezole activated LC noradrenaline but not VTA dopamine cell firing. Combined with raclopride, atipamezole activated dopamine cell firing above the level produced by raclopride. Atipamezole increased extracellular dopamine to the same level, whether administered alone or combined with raclopride. In the presence of the noradrenaline transporter (NET) inhibitor, atipamezole combined with raclopride increased extracellular dopamine beyond the level produced by either compound administered alone. The results suggest that a) the D 2 -autoreceptor blockade is required for LC noradrenaline to activate VTA cell firing; b) the level of dopamine released from dopaminergic terminals is determined by NET; c) the elevation of extracellular dopamine levels in the mPFC is the resultant of dopamine uptake and release from noradrenergic terminals, independent of dopaminergic cell firing and release; and d) LC noradrenergic neurons are an important target for treatments to improve the prefrontal deficit of dopamine in neuropsychiatric pathologies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sagheddu, Devoto, Aroni, Saba, Pistis and Gessa.)

Exposure of Sardinian alcohol-preferring (sP) rats to an enriched environment (EE) reduced different aspects of operant alcohol self-administration. The present study was aimed at expanding investigation of the effect of EE exposure upon a model of binge drinking composed of daily 1-h drinking sessions with unpredictable access to multiple alcohol concentrations; binge-like alcohol intakes were observed when the drinking session occurred at the last hours of the dark phase of the light/dark cycle. Starting from postnatal day (PND) 21, male sP rats were kept under three different housing conditions: impoverished environment (IE; single housing with no environmental enrichment); standard environment (SE; 3 rats/cage and no environmental enrichment); EE (6 rats/cage and multiple elements of environmental enrichment). From PND 69, rats were exposed daily to a 1-hour drinking session under the 4-bottle "alcohol (10%, 20%, and 30%, v/v) vs. water" choice regimen, during the dark phase, and with timing of alcohol exposure changed each day. In all three rat groups (IE, SE, and EE), alcohol intake increased progressively as the drinking session moved from the first to last hours of the dark phase. The slope of the regression line was steeper in EE than IE and SE rats, suggestive of higher intakes of alcohol in EE than IE and SE rats when the drinking session occurred over the last hours of the dark phase. These results are discussed hypothesizing that the stressful attributes of alcohol expectation were potentiated by the increased "emotionality" that rats living in a comfortable environment (i.e., EE) may experience when facing new, challenging events or environments. Blood alcohol levels, assessed at the end of a final drinking session occurring at the 12th hour of the dark phase, did not differ among the three rat groups and averaged approximately 150 mg%, confirming that this experimental procedure may generate intoxicating levels of alcohol drinking in sP rats., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Recent work has demonstrated that acute administration of the novel positive allosteric modulator of the GABA B receptor, COR659, reduces several alcohol-related behaviors in rodents. Objective: To assess whether COR659 continues to lessen alcohol intake after repeated administration, a fundamental feature of drugs with therapeutic potential. Methods: Male C57BL/6J mice (n = 40) were exposed to daily 2-hour drinking sessions (20% (v/v) alcohol) under the 1-bottle "drinking in the dark" protocol and male Sardinian alcohol-preferring rats (n = 40) were exposed to daily 1-hour drinking sessions under the 2-bottle "alcohol (10%, v/v) vs water" choice regimen. COR659 (0, 10, 20, and 40 mg/kg in the mouse experiment; 0, 5, 10, and 20 mg/kg in the rat experiment) was administered intraperitoneally before 7 consecutive drinking sessions. Results: Alcohol intake in vehicle-treated mice and rats averaged 2.5-3.0 and 1.5-1.6 g/kg/session, respectively, indicative of high basal levels. In both experiments, treatment with COR659 resulted in an initial, dose-related suppression of alcohol intake (up to 70-80% compared to vehicle treatment; P  < .0005 and P  < .0001 in mouse and rat experiments, respectively). The magnitude of the reducing effect of COR659 on alcohol drinking diminished progressively, until vanishing over the subsequent 2-4 drinking sessions. Conclusion: COR659 effectively reduced alcohol intake in two different rodent models of excessive alcohol drinking. However, tolerance to the anti-alcohol effects of COR659 developed rapidly. If theoretically transposed to humans, these data would represent a possible limitation to the clinical use of COR659.

Neurochemical, electrophysiological and behavioral evidence indicate that the potent α 2 -adrenoceptor antagonist RS 79948 is also a dopamine (DA) D 2 receptor antagonist. Thus, results from ligand binding and adenylate cyclase activity indicate that RS 79948 binds to D 2 receptors and antagonized D 2 receptor-mediated inhibition of cAMP synthesis at nanomolar concentrations. Results from microdialysis indicated that RS 79948 shared with the selective α 2 -adrenergic antagonist atipamezole the ability to increase the co-release of DA and norepinephrine (NE) from noradrenergic terminals in the medial prefrontal cortex (mPFC), except that RS 79948-induced DA release persisted after noradrenergic denervation, unlike atipamezole effect, indicating that RS 79948 releases DA from dopaminergic terminals as well. Similarly to the D 2 antagonist raclopride, but unlike atipamezole, RS 79948 increased extracellular DA and DOPAC in the caudate nucleus. Electrophysiological results indicate that RS 79948 shared with raclopride the ability to activate the firing of ventral tegmental area (VTA) DA neurons, while atipamezole was ineffective. Results from behavioral studies indicated that RS 79948 exerted effects mediated by independent, cooperative and contrasting inhibition of α 2 -and D 2 receptors. Thus, RS 79948, but not atipamezole, prevented D 2 -autoreceptor mediated hypomotility produced by a small dose of quinpirole. RS 79948 potentiated, more effectively than atipamezole, quinpirole-induced motor stimulation. RS 79948 antagonized, less effectively than atipamezole, raclopride-induced catalepsy. Future studies should clarify if the dual α 2 -adrenoceptor- and D 2 -receptor antagonistic action might endow RS 79948 with potential therapeutic relevance in the treatment of schizophrenia, drug dependence, depression and Parkinson's disease., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Living in an enriched environment (EE) produces a notable impact on several rodent behaviors, including those motivated by drugs of abuse. This picture is somewhat less clear when referring to alcohol-motivated behaviors. With the intent of contributing to this research field with data from one of the few rat lines selectively bred for excessive alcohol consumption, the present study investigated the effect of EE on operant oral alcohol self-administration in Sardinian alcohol-preferring (sP) rats. Starting from Postnatal Day (PND) 21, male sP rats were kept under 3 different housing conditions: impoverished environment (IE; single housing in shoebox-like cages with no environmental enrichment); standard environment (SE; small colony cages with 3 rats and no environmental enrichment); EE (large colony cages with 6 rats and multiple elements of environmental enrichment, including 2 floors, ladders, maze, running wheels, and shelter). From PND 60, rats were exposed to different phases of shaping and training of alcohol self-administration. IE, SE, and EE rats were then compared under (i) fixed ratio (FR) 4 (FR4) schedule of alcohol reinforcement for 20 daily sessions and (ii) progressive ratio (PR) schedule of alcohol reinforcement in a final single session. Acquisition of the lever-responding task (shaping) was slower in EE than IE and SE rats, as the likely consequence of a "devaluation" of the novel stimuli provided by the operant chamber in comparison to those to which EE rats were continuously exposed in their homecage or an alteration, induced by EE, of the rat "emotionality" state when facing the novel environment represented by the operant chamber. Training of alcohol self-administration was slower in EE than IE rats, with SE rats displaying intermediate values. A similar ranking order (IE>SE>EE) was also observed in number of lever-responses for alcohol, amount of self-administered alcohol, and breakpoint for alcohol under FR4 and PR schedules of reinforcement. These data suggest that living in a complex environment reduced the reinforcing and motivational properties of alcohol in sP rats. These results are interpreted in terms of the reinforcing and motivational properties of the main components of EE (i.e., social interactions, physical activities, exploration, novelty) substituting, at least partially, for those of alcohol., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Cannabidiol (CBD) is a major cannabinoid extracted from Cannabis sativa with no abuse potential. Data from recent rodent studies suggest that amelioration of alcohol-motivated behaviors may be one of the numerous pharmacological effects of CBD. This study was designed to contribute to this research, assessing the effect of CBD on operant oral alcohol self-administration in selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of excessive alcohol consumption. In addition, this study investigated the effect of CBD on operant self-administration of a highly palatable chocolate solution in Wistar rats. Materials and Methods: Male sP rats were trained to lever respond for alcohol (15% v/v) under the fixed ratio 4 (FR4) schedule of reinforcement. Once lever responding had stabilized, rats were exposed to test sessions under the FR4 and progressive ratio (PR) schedules of reinforcement. Test sessions were preceded by acute treatment with CBD (0, 6.25, 12.5, and 25 mg/kg or 0, 25, 50, and 100 mg/kg, i.p.; each dose range was tested in an independent experiment). Male Wistar rats were trained to lever respond for a chocolate solution (5% w/v chocolate powder) under the FR10 schedule of reinforcement. Once lever responding had stabilized, rats were exposed to test sessions under the same schedule. Test sessions were preceded by acute treatment with CBD (0, 6.25, 12.5, and 25 mg/kg or 0, 25, 50, and 100 mg/kg, i.p., in two independent experiments). Results: Under the FR schedule, treatment with doses of CBD ≥12.5 mg/kg markedly reduced lever responding for alcohol and amount of self-administered alcohol. Under the PR schedule, treatment with CBD produced a slight tendency toward a decrease in lever responding and breakpoint for alcohol. Finally, no dose of CBD affected lever responding for the chocolate solution and amount of self-administered chocolate solution. Discussion: These results extend previous data on CBD ability to affect alcohol-motivated behaviors to an animal model of genetically-determined proclivity to high alcohol consumption. Because of the predictive validity of sP rats, these results may be of relevance in view of possible future studies testing CBD in patients affected by alcohol use disorder.

Literature data suggest that activation and blockade of the GABAB receptor may produce similar effects on several reward-related behaviours. Accordingly, the present study was designed to investigate whether treatment with the GABAB receptor antagonist, SCH 50911, reproduced the suppressing effect of the GABAB receptor agonist, baclofen, and several positive allosteric modulators of the GABAB receptor on operant oral alcohol self-administration in rats. To this end, Sardinian alcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under the fixed ratio (FR) 4 (FR4) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions preceded by treatment with SCH 50911 (0, 25, 50, and 100 mg/kg; i.p.). Two independent experiments were conducted, differing solely in the set of rats used. Selectivity of SCH 50911 effect on alcohol self-administration was assessed by evaluating the effect of SCH 50911 (0, 25, 50, and 100 mg/kg; i.p.) on self-administration of a sucrose solution (0.7% w/v) in sP rats exposed to the FR4 schedule. In both 'alcohol' experiments, treatment with SCH 50911 reduced lever-responding for alcohol and amount of self-administered alcohol. SCH 50911 effect was characterized by large interindividual variability, with several instances of dose-unrelated reductions, and frequent occurrence of complete suppression of lever-responding for alcohol. Similar data were collected in the 'sucrose' experiment. These results extend to alcohol self-administration with the notion that activation and blockade of GABAB receptor may produce unidirectional effects on reward-related behaviours; these similarities are discussed in terms of differential contribution of pre- and postsynaptic GABAB receptors., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Binge drinking (BD) is a widespread drinkingpattern that may contribute to promote the development of alcohol use disorder (AUD). The comprehension of its neurobiological basis and the identification of molecules that may prevent BD are critical. Preclinical studies demonstrated that positive allosteric modulators (PAMs) of the GABA B receptor effectively reduced, and occasionally suppressed, the reinforcing and motivational properties of alcohol in rodents, suggesting their potential use as pharmacotherapy for AUD, including BD. Recently, we demonstrated that COR659, a novel GABA B PAM, effectively reduced (i) alcohol drinking under the 2-bottle choice regimen, (ii) alcohol self-administration under both fixed and progressive ratio schedules of reinforcement, and (iii) cue-induced reinstatement of alcohol-seeking behavior in Sardinian alcohol-preferring (sP) rats., Objectives: The present study investigated whether the "anti-alcohol" properties of COR659 extend to binge-like drinking in rodents., Methods: COR659 was tested on the "drinking in the dark" (DID) paradigm in C57BL/6J mice and the 4-bottle "alcohol [10%, 20%, 30% (v/v)] versus water" choice regimen with limited and unpredictable access to alcohol in sP rats., Results: Acute administration of non-sedative doses of COR659 (10, 20, and 40 mg/kg; i.p.) effectively and selectively suppressed the intake of intoxicating amounts of alcohol (> 2 g/kg) consumed by C57BL/6J mice and sP rats exposed to these binge-like drinking experimental procedures., Conclusions: The present data demonstrate the ability of COR659 to suppress binge-like drinking in rodents and strengthen the hypothesis that GABA B PAMs may represent a potentially effective pharmacotherapy for alcohol misuse., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Positive allosteric modulators (PAMs) of the GABA B receptor (GABA B PAMs) are of interest in the addiction field due to their ability to suppress several behaviors motivated by drugs of abuse. KK-92A is a novel GABA B PAM found to attenuate intravenous self-administration of nicotine and reinstatement of nicotine seeking in rats. This present study was aimed at extending to alcohol the anti-addictive properties of KK-92A. To this end, Sardinian alcohol-preferring rats were trained to lever-respond for oral alcohol (15% v/v) or sucrose (0.7% w/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding behavior had stabilized, rats were exposed to tests with acutely administered KK-92A under FR5 and progressive ratio schedules of reinforcement and cue-induced reinstatement of previously extinguished alcohol seeking. KK-92A effect on spontaneous locomotor activity was also evaluated. Treatment with 10 and 20 mg/kg KK-92A suppressed lever-responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol. Treatment with 20 mg/kg KK-92A reduced sucrose self-administration. Combination of per se ineffective doses of KK-92A (2.5 mg/kg) and the GABA B receptor agonist, baclofen (1 mg/kg), reduced alcohol self-administration. Treatment with 5, 10, and 20 mg/kg KK-92A suppressed reinstatement of alcohol seeking. Only treatment with 80 mg/kg KK-92A affected spontaneous locomotor activity. These results demonstrate the ability of KK-92A to inhibit alcohol-motivated behaviors in rodents and confirm that these effects are common to the entire class of GABA B PAMs. The remarkable efficacy of KK-92A is discussed in terms of its ago-allosteric properties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Maccioni, Kaczanowska, Lawrence, Yun, Bratzu, Gessa, McDonald and Colombo.)

Sardinia is an Italian island in the Mediterranean characterized by secular isolation and the singular genetic characteristics of its inhabitants. Findings obtained in populations with diverse genetic make-up and cultural background indicate gender differences and/or similarities in drinking characteristics of patients with alcohol use disorder (AUD). Knowledge of these characteristics in AUD patients is useful to improve access to treatments. This paper investigated the drinking characteristics of 66 female and 282 male outpatients with AUD, born from 1937 to 1991, living in Sardinia, and compared their characteristics with those of AUD patients living in other countries. Most Sardinian patients were men, approximately 3 years younger than women; women consumed lower amounts of alcohol than men but did not differ from men in the severity of AUD. Men were more often single than women, while a higher proportion of women reported that their mother or spouse was affected by AUD. Anxiety and depression were more prevalent among women while a higher proportion of men were affected by substance use disorders. Women were older than men at the age of first drink, regular drinking, and onset of AUD, and progressed faster than men from regular use to AUD onset. Women did not differ from men in age at first request for care, and in the lapse from AUD onset to first request for care. Women and men waited for more than 8 and 9 years, respectively, before receiving medical treatment. Gender differences progressively decreased among younger patients. Although the scarce number of women in some cohorts limits the strength of these findings, drinking characteristics of Sardinian patients did not vary significantly from those of AUD patients living in other countries. These results suggest that the number of Sardinian women with AUD is increasing and services for treatment of AUD should (a) consider women's specific needs, and (b) realize effective policies to reduce latency prior to accessing medical treatment for both men and women with AUD.

COR659 is a recently synthesized positive allosteric modulator (PAM) of the GABA B receptor. Similarly to all GABA B PAMs tested to date, COR659 has been reported to suppress different alcohol-related behaviors in rodents. The present study was designed to assess whether the anti-addictive properties of COR659 extend to drugs of abuse other than alcohol. Specifically, it investigated the effect of COR659 on cocaine-, amphetamine-, nicotine-, and morphine-induced locomotor hyperactivity in mice. To this aim, independent groups of CD1 mice were acutely pretreated with COR659 (0, 10, and 20 mg/kg; i.p.), then acutely treated with cocaine (0 and 10 mg/kg, s.c.), amphetamine (0 and 5 mg/kg; s.c.), nicotine (0 and 0.05 mg/kg; s.c.), or morphine (0 and 20 mg/kg; s.c.), and finally exposed for 60 min to a photocell-equipped motility cage. When given alone, both doses of COR659 were ineffective on spontaneous locomotor activity. Pretreatment with COR659 reduced, or even suppressed, the increase in motility counts induced by cocaine, amphetamine, nicotine, and morphine. Since locomotor hyperactivity is an attribute common to drugs of abuse, the results of the present study constitute the first line of evidence on the extension of the preclinical, anti-addictive profile of COR659 to cocaine, amphetamine, nicotine, and morphine., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Pharmacotherapy for Alcohol Dependence (AD) is underutilized. Barriers preventing the use of AD medications include high prices, lack of access to prescribing physicians, and a limited number of available medications., Objective: The study evaluated the use of AD medications in a sample of Italian outpatients who received these medications free of charge, had access to physicians during office hours, and for whom substitution therapy [gamma-hydroxybutyrate (GHB)] was available. We also evaluated the rate of patients who received a combination of non-pharmacological and pharmacological treatments among participants who were still drinking., Methods: SCID for AD and questionnaire were filled by to AD outpatients during a face-to-face interview., Results & Discussion: 345 AD outpatients were interviewed: 58.8% were currently receiving at least one AD medication (GHB: 34.3%, disulfiram: 29.6%, acamprosate: 5.9%; naltrexone: 2.5%; more than one medication: 16.7%). Less than 30% of participants who were still drinking, received a combination of non-pharmacological and pharmacological treatments. Nonetheless, we found higher use of AD medications compared to previous studies conducted in other countries. This higher use of AD medications may be due to access to free medications, prescribing physicians' style, and a larger number of available medications., Conclusion: Our results confirm the underutilization of AD medications, as less than 60% of AD outpatients received medications, and less than 30% of those who were still drinking, received a combination of non-pharmacological and pharmacological treatments. These findings may be useful in improving our knowledge of the barriers that prevent the use of AD medications in clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Previous results indicate that dopamine (DA) release in the medial prefrontal cortex (mPFC) is modified by α 2 adrenoceptor- but not D2 DA receptor- agonists and antagonists, suggesting that DA measured by microdialysis in the mPFC originates from noradrenergic terminals. Accordingly, noradrenergic denervation was found to prevent α 2 -receptor-mediated rise and fall of extracellular DA induced by atipamezole and clonidine, respectively, in the mPFC. The present study was aimed to determine whether DA released by dopaminergic terminals in the mPFC is not detected by in vivo microdialysis because is readily taken up by norepinephrine transporter (NET). Accordingly, the D2-antagonist raclopride increased the electrical activity of DA neurons in the ventral tegmental area (VTA) and enhanced extracellular DOPAC but failed to modify DA in the mPFC. However, in rats whose NET was either inactivated by nisoxetine or eliminated by noradrenergic denervation, raclopride still elevated extracellular DOPAC and activated dopaminergic activity, but also increased DA. Conversely, the D2-receptor agonist quinpirole reduced DOPAC but failed to modify DA in the mPFC in control rats. However, in rats whose NET was eliminated by noradrenergic denervation or inhibited by locally perfused nisoxetine, quinpirole maintained its ability to reduce DOPAC but acquired that of reducing DA. Moreover, raclopride and quinpirole, when locally perfused into the mPFC of rats subjected to noradrenergic denervation, were able to increase and decrease, respectively, extracellular DA levels, while being ineffective in control rats. Transient inactivation of noradrenergic neurons by clonidine infusion into the locus coeruleus, a condition where NET is preserved, was found to reduce extracellular NE and DA in the mPFC, whereas noradrenergic denervation, a condition where NET is eliminated, almost totally depleted extracellular NE but increased DA. Both transient inactivation and denervation of noradrenergic neurons were found to reduce the number of spontaneously active DA neurons and their bursting activity in the VTA. The results indicate that DA released in the mPFC by dopaminergic terminals is not detected by microdialysis unless DA clearance from extracellular space is inactivated. They support the hypothesis that noradrenergic terminals are the main source of DA measured by microdialysis in the mPFC during physiologically relevant activities., (Copyright © 2020 Devoto, Sagheddu, Santoni, Flore, Saba, Pistis and Gessa.)

Aims: Treatment with saikosaponin A (SSA)-an ingredient of the medicinal herb, Bupleurum falcatum-has been reported to suppress several addictive-like behaviors, including morphine, cocaine, alcohol and chocolate self-administration in male rats. The aim of this investigation was to investigate whether saikosaponins of B. falcatum other than SSA affect alcohol and chocolate self-administration in rats., Methods: Ovariectomized female Sardinian alcohol-preferring (sP) and Wistar rats were trained to self-administer alcohol (15%, v/v) and a chocolate solution [5% (w/v) Nesquik® in water], respectively, under fixed ratio schedules of reinforcement. The following saikosaponins were compared to SSA: saikosaponin D (SSD; epimer of SSA), saikosaponin C (SSC), saikosaponin B2 (SSB2) and saikosaponin B4 (SSB4). All saikosaponins were tested acutely at the doses of 0, 0.25, 0.5 and 1 mg/kg (i.p.)., Results: Treatment with SSA and SSD resulted in highly similar, marked reductions in alcohol self-administration; SSC failed to alter lever-responding for alcohol, while SSB2 and SSB4 produced intermediate reductions. Only SSA and SSD reduced chocolate self-administration, with SSC, SSB2 and SSB4 being ineffective., Conclusions: The wide spectrum of efficacy of saikosaponins in reducing alcohol and chocolate self-administration suggests that even relatively small structural differences are sufficient to produce remarkable changes in their in vivo pharmacological profile. Together, these results confirm that roots of B. falcatum may be an interesting source of compounds with anti-addictive potential., (© The Author(s) 2020. Medical Council on Alcohol and Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The diagnosis of substance use disorder is currently based on the presence of specifically identified behavioral symptoms. In addition, other psychiatric signs and symptoms accompany addictive behavior, contributing to the full picture of patients' psychopathologic profile. Historically, such symptoms were confined within the framework of "comorbidity", as comorbid psychiatric disorders or personality traits. However, an alternative unitary view of the psychopathology of addiction, inclusive of related psychiatric symptoms, has been claimed, with the support of epidemiological, neurobiological, and neuropsychological evidence. In the present article, we highlight the research advancements that strengthen this unified perspective. We then give an account of our group's definition of a specific SCL-90-based construct of the psychopathology of addiction. Lastly, we discuss the benefits that can be expected to be acquired in the evaluation and treatment of patients with a longitudinal approach including psychological/psychiatric predisposing features, addictive behavior, and psychiatric manifestations.

There are conflicting results about sex differences in the response to opioids for pain control and the role of potential influencing factors of these differences has not been investigated. We meta-analyzed differences and similarities between men and women in opioid response for pain control and investigated the potential influence of baseline pain intensity, age, body weight, and other factors in these findings. PubMed, Scopus, and Cochrane CENTRAL were searched through January 15, 2019, for clinical studies in which opioids were administered for pain control. We included clinical studies in which (a) opioids were used to treat acute or chronic pain, (b) the response to opioids was broken down for men and women, and (c) the response to opioids was reported as (i) difference between baseline and final Visual Analog Scale of Pain Intensity (VASPI) score 30 min after opioid administration (Delta-VASPI at 30'), or daily dose of opioids (ii) self-administered by patients (patient-controlled analgesia PCA), or (iii) administered by physicians. Risk of bias was evaluated using ROBINS-I and the overall quality of evidence for primary outcomes was evaluated using the GRADE system. Globally, we included 40 comparisons (6794 patients). Regarding acute pain, we found moderate quality of evidence that women and men do not differ in their response to opioids 30 min after their administration [Delta-VASPI at 30': mean difference, MD = 0.42 (-0.07; 0.91)]. We also found moderate quality of evidence that women self-administer lower daily amounts of opioids [daily PCA: standardized mean difference, SMD = -0.30 (-0.41; -0.18)]. Regarding chronic pain, we found low quality of evidence that women receive lower daily doses for non-cancer pain [MD = -36.42 (-57.86; -14.99)]. By contrast, we found very low quality of evidence that women and men do not differ in the daily dose of opioids for cancer pain [MD = -16.09 (-40.13; 7.94)]. Age, comorbid mental disorders, type of administration, type of opioids, type of patients, and body weight significantly modified these results. In conclusion, the results of the present meta-analysis suggest that men and women may differ in the response to opioids for pain relief, but these differences as well as similarities are significantly influenced by factors like age and comorbid mental disorders. However, the role of these factors is not usually evaluated in the prescription of opioids for pain control. There is an urgent need to conduct clinical trials on the use of opioid medications for pain, in which information about all possible influencing factors are provided and broken down for men and women., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In various psychiatric disorders, deficits in dopaminergic activity in the prefrontal cortex (PFC) are implicated. Treatments involving selective augmentation of dopaminergic activity in the PFC primarily depend on the inhibition of α 2 -adrenoreceptors singly or in combination with the inhibition of the norepinephrine transporter (NET). We aimed to clarify the relative contribution of dopamine (DA) release from noradrenergic and dopaminergic terminals to DA output induced by blockade of α 2 -adrenoreceptors and NET. To this end, we assessed whether central noradrenergic denervation modified catecholamine output in the medial PFC (mPFC) of rats elicited by atipamezole (an α 2 -adrenoreceptor antagonist), nisoxetine (an NET inhibitor), or their combination. Intraventricular administration of anti-dopamine-beta-hydroxylase-saporin (aDBH) caused a loss of DBH-positive fibers in the mPFC and almost total depletion of tissue and extracellular NE level; however, it did not reduce tissue DA level but increased extracellular DA level by 70% in the mPFC. Because noradrenergic denervation should have caused a loss of NET and reduced NE level at α 2 -adrenoceptors, the actual effect of an aDBH-induced lesion on DA output elicited by blockade of α 2 -adrenoceptors and NET was evaluated by comparing denervated and control rats following blockade of α 2 -adrenoceptors and NET with atipamezole and nisoxetine, respectively. In the control rats, extracellular NE and DA levels increased by approximately 150% each with 3 mg/kg atipamezole; 450% and 230%, respectively, with 3 mg/kg nisoxetine; and 2100% and 600%, respectively, with combined atipamezole and nisoxetine. In the denervated rats, consistent with the loss of NET, nisoxetine failed to modify extracellular DA level, whereas atipamezole, despite the lack of NE-induced stimulation of α 2 -adrenoceptors, increased extracellular DA level by approximately 30%. Overall, these results suggest that atipamezole-induced DA release mainly originated from noradrenergic terminals, possibly through the inhibition of α 2 -autoreceptors. Furthermore, while systemic and local administration of the α 2 -adrenoceptor agonist clonidine into the mPFC of the controls rats reduced extracellular NE level by 80% and 60%, respectively, and extracellular DA level by 50% and 60%, respectively, it failed to reduce DA output in the denervated rats, consistent with the loss of α 2 -autoreceptors. To eliminate the possibility that denervation reduced DA release potential via the effects at dopaminergic terminals in the mPFC, the effect of systemic administration of the D 2 -DA antagonist raclopride (0.5 mg/kg IP) on DA output was analyzed. In the control rats, raclopride was found to be ineffective when administered alone, but it increased extracellular DA level by 380% following NET inhibition with nisoxetine. In the denervated rats, as expected due to the loss of NET, raclopride-alone or with nisoxetine-increased DA release to approximately the same level as that observed in the control rats after NET inhibition. Overall, these results suggest that noradrenergic terminals in the mPFC are the primary source of DA released by blockade of α 2 -adrenoreceptors and NET and that α 2 -autoreceptors, and not α 2 -heteroreceptors, mediate DA output induced by α 2 -adrenoceptor blockade., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A recent study found that COR659 (methyl 2-[(4-chlorophenyl)carboxamido]-4-ethyl-5-methylthiophene-3-carboxylate) reduced operant alcohol and chocolate self-administration in rats; COR659 also suppressed cue-induced reinstatement of chocolate seeking in rats. COR659 apparently exerts its effects via a composite mechanism, including positive allosteric modulation of the GABA B receptor and an action at the cannabinoid CB 1 receptor. The present study investigated whether the reducing effect of COR659 on alcohol and chocolate self-administration was maintained after repeated treatment and if COR659 affected cue-induced reinstatement of alcohol seeking; additionally, it evaluated the ability of 9 structural analogues of COR659 - designed modifying the substituents on the phenylcarboxamido moiety and replacing the thiophene with the pyridine ring - to affect alcohol and chocolate self-administration. Alcohol self-administration experiments employed Sardinian alcohol-preferring (sP) rats trained to lever-respond for alcohol (15% v/v). Chocolate self-administration experiments employed Wistar rats trained to lever-respond for a chocolate solution (5% w/v Nesquik ® ). In the reinstatement experiment, previously extinguished lever-responding for alcohol in sP rats was reinstated by the non-contingent presentation of an alcohol-associated complex of cues. All drugs were tested at the doses of 0, 2.5, 5, and 10 mg/kg (i.p.). 10-Day treatment with COR659 produced a dose-related reduction of both alcohol and chocolate self-administration, with limited loss of efficacy on continuing treatment. Acute COR659 suppressed reinstatement of alcohol seeking. Among the 9 tested analogues, only COR657 (methyl 2-(benzoylamino)-4-ethyl-5-methylthiophene-3-carboxylate) decreased alcohol self-administration similarly to COR659; all other compounds produced modest, or even no, effect on alcohol self-administration. COR659 excluded, no compound altered chocolate self-administration. These results confirm and extend the ability of COR659 to reduce several behaviors motivated by alcohol and palatable food in rats. Comparison of COR659 to its analogues provided disparate results that do not currently allow any conclusive structure-activity relationship to be hypothesized, as their diverse pharmacological profile apparently does not depend on physicochemical properties., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This paper summarizes the several lines of experimental evidence demonstrating the ability of the prototypic GABA B receptor agonist, baclofen, to suppress multiple alcohol-related behaviors in laboratory rodents and non-human primates exposed to validated experimental models of alcohol use disorder (AUD). Specifically, treatment with baclofen has repeatedly been reported to suppress alcohol-induced locomotor stimulation, alcohol drinking (including binge- and relapse-like drinking), operant oral alcohol self-administration, alcohol seeking, and reinstatement of alcohol seeking in rats and mice. Treatment with baclofen also reduced operant oral alcohol self-administration in baboons. Several of these effects appear to be mediated by GABA B receptors located in the ventral tegmental area. The often observed co-occurrence of "desired" pharmacological effects and "unwanted" sedative effects represents the major drawback of the preclinical, anti -alcohol profile of baclofen. Collectively, these data underline the role of the GABA B receptor in the mediation of several alcohol-related behaviors. These data possess remarkable translational value, as most of the above effects of baclofen have ultimately been reproduced in AUD patients.