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Innovative pharmacological strategies for treatment of binge-type eating disorders
No full textBinge eating (BE) episodes are a common behavioral feature of clinically diagnosed eating disorders, including Bulimia Nervosa (BN), Binge Eating Disorder (BED) and the binge/purge subtype of Anorexia Nervosa (AN). BE is characterized by uncontrollable, distressing eating of a large amount of highly palatable food (HPF) in a short period of time, accompanied by feeling of disgust, depression, being guilty. Recent data indicate that BE is the most common eating disorder, affecting approximately 5% of the USA population; BE may greatly contribute to obesity, Medications that at present have been reported to reduce BE in clinical studies, like topiramate or sibutramine, are associated with a variety of adverse side effects, which represent a serious problem during chronic treatment. Fluoxetine has been approved by the Food and Drug Administration for BN, but evidence for its efficacy is inconclusive. Hence, BED and BN represent a still largely unmet medical need. Well-characterized animal models are necessary to study the neuro- and psychobiology of BE, the motivational alterations associated with compulsive eating behaviors, as well as to develop novel treatment strategies. According to the hypothesis that dieting and stress are key etiological determinants of BE, a new animal model of BE has been recently developed in female rats at the School of Pharmacy of the University of Camerino (Cifani et al. 2009), in which BE episodes are evoked by 3 cycles of food restriction/re-feeding followed by stress. Stress is elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Since a certain degree of variability was observed in the BE response in the Cifani model, a preliminary interest of my research program was to understand the causes of this variability in order to improve the reliability of the method. In particular, it was evaluated whether the ovarian cycle of female rats may be responsible for the observed variability. It was found that BE episodes do not occur during the estrus phase of the ovarian cycle and the observed variability in the BE response can be almost completely abolished if female rats in estrus are not included in the statistical evaluation. Then, the effects of several compounds, targeting stress and CRF mechanisms, were evaluated on this BE model: natural anti-stress products such as dry extracts of Rhodiola rosea and of Hypericum perforatum, the CRF-1 receptor antagonist R121919, Corticosterone (CORT), the CORT synthesis inhibitor metyrapone, and finally Nociceptin/orfanin FQ (N/OFQ, a functional CRF antagonist). Using the same BE model, orexin receptor antagonists were investigated since orexin appear to be involved both in stress and in reward mechanisms. Lastly, based on the observation that drugs that affect compulsive alcohol consumption can also influence BE, a further study was carried out to assess the effect on BE of A2A adenosine receptors (A2AARs) agonists, that have been shown to suppress voluntary alcohol intake and alcohol self-administration in alcohol- preferring rats. The results obtained confirmed that the combination of stress and repeated episodes of food restriction is able to induce in female rats a pronounced BE response for HPF. The natural extract of Rhodiola rosea, as well as its active principle salidroside, exerted a pronounced and selective suppression of HPF intake in rats expressing BE, apparently reducing the response to stress. Also Hypericum perforatum extracts selectively reduced BE, but without modifying serum CORT levels; thus their effect on BE may be related to suppression of addictive-like behaviors, rather than to anti-stress activity. The CRF-1 receptor antagonist R121919 completely abolished BE in the experimental model adopted, without affecting HPF intake in the groups of rats that did not express BE. These findings suggest that CRF-1 receptor antagonists may represent very interesting agents, endowed with marked and highly selective effect, for the pharmacotherapy of bingeing-related eating disorders. CRF may likely exert its role on BE in extrahypothalamic sites, since CORT, the hormone released by hypothalamic-pituitary axis activation, failed to evoke BE in rats exposed to cycles of food restriction/re-feeding and metyrapone, a CORT synthesis inhibitor, failed to suppress BE. On the other hand, the functional CRF antagonist N/OFQ was not able to evoke a relevant suppression of BE. Following repeated food restrictions, an increase in responsiveness to the hyperphagic effect of N/OFQ was found, which may account for its failure to suppress BE. Interestingly, cycles of food restriction/re-feeding increase the response to several orexigenic mechanisms (in the present study this was observed for N/OFQ and for NPY); this phenomenon may be responsible for failure of dieting cycles as a strategy to reduce body weight and it may predispose to binge type-eating disorders. On the other hand, OX1R blockade selectively reduced BE for HPF without affecting standard food pellet intake, and could represent a novel interesting strategy for the treatment of BE related disorders. Further studies are necessary to evaluate their mechanism of action of OX1R antagonists, in particular whether their effect may be mediated by interaction with stress or reward mechanisms. A2AAR agonists proved to exert a rather general effect on food intake, suppressing HPF intake not only in animals expressing BE, but also in controls. Moreover they inhibited also the homeostatically driven intake of food pellets in response to food deprivation. In relation to the finding that A2AARs influenced D2 DA receptors, it may be speculated that the suppressive effect on BE of A2AAR agonists tested may be due to interference with DA mechanisms. In conclusion, the experimental model adopted to evoke BE, which is endowed with face, contruct and predictive validity, was made highly reliable and reproducible by selecting the experimental animals on the basis of the ovarian cycle. The studies carried out in this model have allowed the evaluation of several pharmacological agents, that proved to be highly effective in suppressing BE. Particularly pronounced and selective effects were evoked by the CRF-1 receptor antagonist and the OX1R antagonist tested, that evoked effects of clear interest in the perspective of treating binge-type eating disorders. Interestingly, also the herbal products Rodiola rosea and Hypericum perforatum proved to be very effective, but the receptor mechanisms mediating their effects remain to be elucidated
The Legal Highs of Novel Drugs of Abuse
Full text linkAbstract
The abuse of drugs is a widespread and growing issue, both in United States
and Europe, as a number of synthetic drugs have raised popularity over the past
years for recreational use. Moreover, the nature of addiction is often debated
as either a lifestyle choice that may underline a physiological vulnerability, or a
chronic brain disease with remarkable epigenetic, neurodevelopmental and
sociocultural components. Consciousness and treatment of new drugs of abuse
give challenges for health care practitioners primarily due to a lack of quantitative
reports. As law enforcements struggle to ban these often referred as “legal highs”,
new compounds are produced. Also, a major problem in tracking these drugs is
that they are easily available through head shops, the web and other sources,
therefore giving rise to a high risk of suspected intoxication. The aim of this
article is to highlight the pharmaco-toxicological features of some common drugs
of abuse such as central nervous system stimulants as synthetic cannabinoids,
synthetic cathinones, gabapentin, acetyl fentanyl, phenethylamine called NBOMe,
hallucinogenic mushrooms, piperazines, tryptamines, salvia, methoxetamine,
kratom and performance-enhancing drugs. The tremendous heterogeneity of
these drugs results in variable pharmacokinetic and pharmacodynamic effects,
thus suspected intoxication is a priority diagnosis in order to ensure safety
of patients and needs to be handled with the guide of the patient’s symptoms
through specific and detailed urine and blood analysis.
Keywords: Drugs of abuse; Cannabinoids; Cathinones; Salvia; Kratom; Gabapenti
A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to highly palatable food
No full textPreclinical models are needed to investigate the neurobiology and psychobiology of binge eating (BE) and to identify innovative pharmacotherapeutic strategies. BE episodes are characterized by uncontrollable, distressing eating of a large amount of highly palatable food (HPF). These episodes represent a central feature of bingeing-related eating disorders, such as binge eating disorder, bulimia nervosa, and binge/purge subtype anorexia nervosa.
In line with the hypothesis that dieting and stress are key etiological determinants of BE the proposed model combines cycles of food restriction–refeeding and acute stress to evoke BE for sweet HPF. Four groups of female rats were employed: group 1 was normally fed and not stressed on the test day (25th); group 2 was fed normally but was exposed to an acute stress on day 25; group 3 was exposed to three cycles (4 days 66% of chow intake+4 days food ad libitum) of yo-yo dieting but not stressed; and group 4 was exposed to cyclic yo-yo dieting and then stressed. All groups were fed highly palatable food (HPF) for 2 h on days 5–6 and 13–14. Acute stress was elicited by exposing rats to HPF, but preventing them from access to it for 15 min, even though they were able to see it and to smell its odor. The combination of cyclic food restriction and stressful exposure to food markedly increased HPF intake.
To test the predictive validity of this model, three drugs were evaluated: sibutramine, fluoxetine, and topiramate, chosen since clinical studies have reported that they may be effective in the treatment of bingeing-related eating disorders. Topiramate selectively inhibited compulsive HPF intake in rats submitted to caloric restriction and stress, thus, its effect was evident only in conditions in which binge-type eating occurred.
Sibutramine and fluoxetine inhibited food intake in all conditions suggesting that their effect is a general effect on appetite and/or satiety and is not selective on the binge-type behavior.
Midazolam was included to assess whether an anxiolytic benzodiazepine might reduce BE in response to a stressful procedure. Midazolam did not modify binge eating BE rats, but increased HPF intake in the other three groups of rats, as previously observed in animals and humans. Pharmacological results suggest that this model, in addition to face validity as an isomorphic model of human binge eating, is endowed with good predictive validity. Thus, the present model may be useful to evaluate new pharmacological strategies for the treatment of bingeing related eating disorders
Role of CRF system in a model of binge eating in female rats
No full textBinge eating (BE) may be caused by a unique interaction between dieting and stress. Hence we considered interesting to evaluate the role of corticotrophin releasing factor 1 receptor (CRF-1R) mechanisms in BE.
Four groups of female rats were used: NR+NS was normally fed and not stressed on the test day (d25); NR+S was fed as NR+NS and stressed on d25; R+NS was exposed to 3 cycles of yo-yo dieting but not stressed; R+S was fed as R+NS and stressed on d25. All groups were fed with highly palatable food (HPF) for 2 h on day 5-6 and 13-14. Stress was induced by preventing access to HPF for 15 min, while rats were able to see and smell it. After the stressful procedure the rats had free access to HPF and standard chow.
BE was observed only in the R+S group and injections of R121919 (10-20 mg/kg, s.c.) significantly reduced it
Endocrinological analysis revealed marked increase of CORT levels under R+S conditions. On the other hand, metyrapone (50 and 100 mg/kg), a CORT synthesis inhibitor, did not prevent BE, neither CORT injection (2.5 and 10 mg/kg) induced it.
When CRHR1 gene expression was monitored, an up-regulation in the BNST, central (CeA) and basolateral amygdala (BLA) of R+S rats was found. Of note, bilaterally injection of the non selective CRF receptor antagonist D-Phe-CRF(12-41) (50 ng/rat) into the BNST potently and selectively reduced BE.
Altogether these findings demonstrated that extra-hypothalamic CRF-1R related mechanisms rather than the endocrine function of these receptors are involved in BE
Selective antagonism at CRF1 receptor as a novel pharmacological treatment for binge eating and other eating disorders with a compulsive component
No full textEpisodes of binge eating (BE) in humans are characterized by compulsive, non-homeostatic consumption of an unusually large quantity of highly palatable food (HPF) in a short period of time. Considerable evidence suggests that BE may be caused by a unique interaction between dieting and stress. The present study evaluated the role of the corticotrophin releasing factor 1 receptor (CRF-1R) system in female rats, in which BE for HPF was evoked by stress and repeated food restrictions (Cifani et al. (2009) Psychopharmacology 204:113-25).
Four groups of female Sprague-Dawley rats were used: NR+NS was normally fed and not stressed on the test day (d25); NR+S was fed as NR+NS and stressed on d25; R+NS was exposed to 3 cycles of yo-yo dieting (8-day cycles of food restriction/refeeding (4d 66% of the standard chow food intake, 4d food ad libitum) but not stressed; R+S was fed as R+NS and stressed on d25. All groups were fed HPF for 2 h on day 5-6 and 13-14. Stress was induced by preventing access to HPF for 15 min, while rats were able to see and smell it. After the stressful procedure the rats had free access to HPF and standard chow.
Results revealed that BE was selectively elicited in R+S, that showed a marked increase in HPF intake in comparison to NR+NS. Intake of standard chow pellets was not significantly modified. HPF intake in R+NS and NR+S was not significantly different from that of NR+NS. Systemic injections of the selective CRF-1R antagonist R121919 (10-20 mg/kg) significantly reduced HPF intake in the R+S, but had no effect in the other 3 groups.
To explore the significance of hypothalamic CRF related mechanisms in BE, HPA axis activity in the R+S and NR+NS groups was monitored by measuring serum corticosterone (CORT) levels. Data showed a marked increase of CORT levels in the R+S group that lasted for about 30 min. On the other hand, treatment with metyrapone (50 and 100 mg/kg), a CORT synthesis inhibitor, failed to prevent BE. Consistent with this finding, CORT injection (2.5 and 10 mg/kg) did not induce BE.
In a subsequent in situ hybridization experiment the expression of CRHR1 transcript in the R+S and NR+NS groups was monitored. Results revealed an up regulation of CRHR1 mRNA signal in the BNST, central (CeA) and basolateral amygdala (BLA) of R+S rats. No significant differences were observed in the other regions examined (ventral tegmental area, medial amygdala, hypothalamic arcuate nucleus, lateral hypothalamus, dorsomedial hypothalamic nucleus, paraventricular thalamic nucleus). Of note, when the non selective CRF receptor antagonist D-Phe-CRF (50 ng/rat) was bilaterally injected into the BNST it significantly and selectively reduced BE in the R+S group thus replicating the results obtained following systemic administration of R121919
Altogether these findings demonstrated that extra-hypothalamic CRF-1R mechanisms rather than the endocrine function of these receptors are involved in BE. Selective antagonism at CRF1 receptor could represent a novel pharmacological treatment for binge eating and other eating disorders with a compulsive component
A(2A) adenosine receptor agonists reduce both high-palatability and low-palatability food intake in female rats
No full textThe present study examined the effect of two A2A adenosine receptor (AR) agonists, CGS 21680 and VT 7, on high-palatability food (HPF) intake in a model of binge eating in sated rats and on low-palatability food (LPF) intake in food-deprived rats. Binge eating was induced in female rats by three 8-day cycles of food restriction/refeeding, followed by acute stress. Two groups of rats were used: NR+NS rats normally fed and not stressed and R+S rats exposed to cycles of food restriction/refeeding and then stressed. R+S rats had higher intake of HPF than the NR+NS controls. The two A2AAR agonists were tested at doses of 0.1 and 0.05 mg/kg intraperitoneally; VT 7 did not modify locomotor activity at either dose, whereas CGS 21680 only slightly reduced it at the higher dose tested. The injection of 0.1 mg/kg of both agonists markedly reduced HPF intake both in R+S and in NR+NS rats. The dose of 0.05 mg/kg was inactive. CGS 21680 and VT 7, 0.1 mg/kg, also reduced the standard LPF intake in 24 h food-deprived rats; however, they did not reduce water intake, indicating that their effect on food intake is selective. The dose of 0.05 mg/kg was inactive. Thus, A2AAR agonists exert a rather general effect on food intake, inhibiting both HPF intake in sated rats and LPF intake in food-deprived rats. They may potentially be useful pharmacological agents to control binge-related eating disorders and to reduce food overconsumption associated with obesity
Novel rat model of gaming disorder: assessment of social reward and sex differences in behavior and c-Fos brain activity
No full textRationale: In 2018, the International Classification of Diseases (ICD-11) classified Gaming Disorder (GD) as a mental disorder. GD mainly occurs among adolescents, who, after developing addiction, show psychopathological traits, such as social anxiety, depression, social isolation, and attention deficit. However, the different studies conducted in humans so far show several limitations, such as the lack of demographic heterogeneity and equal representation of age, differences in the type of game and in the follow-up period. Furthermore, at present, no animal models specific to GD are available. Objectives: To address the lack of an experimental model for GD, in the present work, we proposed a new GD rat model to investigate some peculiar tracts of the disorder. Methods: Two-month-old Wistar Kyoto rats, both males and females, were subject to a five-week training with a new innovative touch-screen platform. After five weeks of training, rats were assessed for: (a) their attachment to the play under several conditions, (b) their hyperactivity during gaming, and (c) the maintenance of these conditions after a period of game pause and reward interruption. After sacrifice, using immunohistochemistry techniques, the immunoreactivity of c-Fos (a marker of neuronal activity) was analyzed to study different neural areas. Results: After the training, the rats subjected to GD protocol developed GD-related traits (e.g., hyperactivity, loss control), and the behavioral phenotype was maintained consistently over time. These aspects were completely absent in the control groups. Lastly, the analysis of c-Fos immunoreactivity in prelimbic cortex (PrL), orbitofrontal cortex (OFC), nucleus Accumbens, amygdala and bed nucleus of stria terminalis (BNST) highlighted significant alterations in the GD groups compared to controls, suggesting modifications in neural activity related to the development of the GD phenotype. Conclusions: The proposal of a new GD rat model could represent an innovative tool to investigate, in both sexes, the behavioral and neurobiological features of this disorder, the possible role of external factors in the predisposition and susceptibility and the development of new pharmacological therapies
Effects of A(2A) adenosine receptor blockade or stimulation on alcohol intake in alcohol-preferring rats.
No full textRationale A2A adenosine receptors (A2AARs) have been
proposed to be involved in drug addiction; however,
preclinical studies about the effects of A2AAR ligands on
alcohol consumption have provided inconsistent results.
Objectives The present study evaluated the effect of intraperitoneal
injections of the A2AAR antagonist ANR 94, and the
A2AAR agonists CGS 21680 and VT 7 on voluntary
drinking and operant self-administration of 10% ethanol in
Marchigian Sardinian alcohol-preferring (msP) rats.
Results Voluntary ethanol drinking was increased by ANR 94
in acute and subchronic experiments, while it was reduced by
A2AAR agonists. The effect of CGS 21680 was abolished by
a low dose of ANR 94, confirming its mediation by A2AARs.
Ethanol self-administration was reduced by CGS 21680 and
VT 7, while ANR 94 slightly but significantly increased it.
Blood alcohol levels were not modified by A2AAR agonists,
indicating that their effect is not related to ethanol pharmacokinetics.
The effect of VT 7 on ethanol drinking was
behaviourally selective; ethanol and food intake were
reduced, but water intake was increased, and total fluid
intake was not different from that of controls. Moreover, VT7 did not affect locomotor activity. CGS 21680 (0.1 mg/kg)
did not modify total fluid intake, but 0.2 and 0.3 mg/kg
reduced total fluid intake and locomotor activity.
Conclusion These results provide evidence that A2AAR
agonists reduce ethanol consumption in msP rats, which
represent an animal model of alcohol abuse related to stress,
anxiety and depression. A2AARs may represent a potential
target for treatment of alcohol abuse
Effect of the selective CRF-1 receptor antagonist R121919 in an animal model of binge eating.
No full textEpisodes of binge eating (BE) in humans are characterized by compulsive, non-homeostatic consumption of an unusually large quantity of highly palatable food (HPF) in a short period of time. Considerable evidence suggests that BE may be caused by a unique interaction between dieting and stress. The present study evaluated the effect of the corticotrophin releasing factor 1 receptor (CRF-1R) antagonist R121919 in female rats, in which BE for HPF was evoked by stress and repeated food restrictions (Cifani et al. (2009) Psychopharmacology 204:113-25). The model employs female rats in relation to the higher prevalence of binge eating disorders in women than in men. Four groups of female Sprague-Dawley rats were used: NR+NS was normally fed and not stressed on the test day (d25); NR+S was fed as NR+NS and stressed on d25; R+NS was exposed to 3 cycles of yo-yo dieting (8-day cycles of food restriction/refeeding (4d 66% of the standard chow food intake, 4d food ad libitum) but not stressed; R+S was fed as R+NS and stressed on d25. All groups were fed HPF for 2 h on day 5-6 and 13-14. Stress was induced by preventing access to HPF for 15 min, while rats were able to see and smell it. After the stressful procedure the rats had free access to HPF and standard chow. R121919 was injected subcutaneously 1 h before access to HPF. BE was selectively observed in R+S, that showed a marked increase in HPF intake in comparison to NR+NS. Intake of standard chow pellets was not significantly modified. HPF intake in R+NS and NR+S was not significantly different from that of NR+NS. R121919 (10-20 mg/kg) significantly reduced HPF intake in R+S, but had no effect in the other 3 groups. After the stressful procedure, rats showed increased serum corticosterone (CORT) levels. To asses whether CORT is involved in the BE response, R+S and NR+NS were treated with metyrapone, a CORT synthesis inhibitor at the doses of 50 and 100 mg/kg. It failed to prevent BE. Lastly, CORT injection (2.5 and 10 mg/kg) did not induce BE in R+NS, in comparison to NR+NS. These findings suggest that CRF-1R mechanisms are involved in the BE response following stress and food restrictions; this effect is likely related to its extrahypothalamic functions rather than to its regulatory role in HPA axis activity
Hypothalamic expression of inflammatory mediators in an animal model of binge eating
No full textBinge eating episodes are characterized by uncontrollable, distressing eating of a large
amount of highly palatable food and represent a central feature of bingeing related eating
disorders. Research suggests that inflammation plays a role in the onset and maintenance of
eating-related maladaptive behavior. Markers of inflammation can be selectively altered in discrete
brain region where they can directly or indirectly regulate food intake. In the present study we
measured expression levels of different components of cytokine systems (IL-1, IL-6, IL-18, TNF-
and IFN-ɣ) and related molecules (iNOS and COX2) in the preoptic and anterior-tuberal parts of
the hypothalamus of a validated animal model of binge eating. In this animal model, based on the
exposure to both food restriction and frustration stress, binge-like eating behavior for highly
palatable food is not shown when animals are exposed to the frustration stress during the estrus
phase. We found a characteristic down-regulation of the IL-18/ IL-18 receptor system (with
increased expression of the inhibitor of the pro-inflammatory cytokine IL18, IL-18BP, together with
a decreased expression of the binding chain of the IL-18 receptor) and a three-fold increase in the
expression of iNOS specifically in the anterior- tuberal region of the hypothalamus of animals that
develop a binge-like eating behavior. Differently, when food restricted animals were stressed
during the estrus phase IL-18 expression increased while iNOS expression was not significantly
affected. Considering the role of this region of the hypothalamus in controlling feeding related
behavior, this can be relevant in eating disorders and obesity. Our data suggest that by targeting
centrally selected inflammatory markers, we may prevent that disordered eating turns into a full
blown eating disorder
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