1,721,175 research outputs found
Development and pharmacological characterization of models of binge eating in laboratory animals
No full textIntroduction and aim of the studies: Binge eating disorder (BED) is a more
recently defined syndrome that features recurrent episodes of overeating,
without inappropriate compensatory behaviors.
The development of an animal model is an important step for understanding
the aetiology of BED, and for developing effective treatments. Most
importantly, the utility of an animal model lies in its face validity or
embodiment of the characteristics prevalent in clinical populations. During my
studies I worked to reproduce two animal models of binge eating described in
literature: 1) Key synergistic role of past caloric restriction and stress;
2) Contrast-induced cycling: consummatory and emotional dependence on
preferred food. A model of intermittent excessive behavior.
and to develop two new animal models of binge eating with the
pharmacological characterization: 3) Exposure to environmental-food
associated cues elicited compulsive behavioural response to actively obtain
food rewards in female rats; 4) Exposure to food related cues induced
overeating in female rats exposed to cyclic dieting
5) I studied also the susceptibility of congenic DA.WOKW rats to develop
binge eating as possible model to elucidate the genetics of binge eating
disorder.
Results: 1) We were able to obtain binge eating by combining repeated
caloric restrictions and electric foot-shock stress only in msP rats with
maternal separation. This animal study might support the clinical hypothesis
that severe stress during childhood leads to vulnerability to abnormal eating
behavior in response to stress in later life in humans.
2) The present study failed to replicate the work by Cottone and co-workers.
In particular we have not been able to detect significant difference in body
weight gain between control and High-Palatable food exposed rats. To
investigate the reasons of these discrepancies would require a detailed
analysis of several variables. We decided, therefore, to develop an
alternative model to use for drug test purposes.
3) This model used was developed exploiting food cues-induced overeating
under operant self-administration condition. Prior presentation of cues
predictive of food reward engage the animal into a food-seeking state
resulting in overfeeding occurring at beginning of the food delivery session.
This increase of responding over baseline condition may reflect an increased
“craving” for food resulting in loss of control reaction to food cues.
Rimonabant and Sibutramine reduced food intake in both cue-preexposed
and nonpreexposed rats suggesting a general inhibition of appetitive
behaviour following drug administrationof these drugs.
Fluoxetine and Topiramate, on the other hand, more potently affected food
self-administration in cue preexposed rats. This effect is indicative of a more
selective action of these compound in the regulation of food-seeking
behaviour rather than in the control of satiety mechanisms.
4) In this model electric foot-shock of Hagan’s model was substituted with a
different stress, related to lack of control over environmental circustances
induced by allowing rats to see and to smell the palatable food but
preventing them from access to it for 15 min. We obtained a clear binge
eating response in rats that was confirmed for all the experiments.
In this model the treatment with fluoxetine (3 mg/Kg) is able to reduce HP
food intake in the group of R + P and not in NR + NP showing a specific effect
in reducing the loss of control in overeating after the pre-exposure to HP food
with a history of restriction.
5) DA.WOKW 16, DA.WOKW 5a, and DA.WOKW 3a, did not develop binge
eating while DA, WOKW and DA.WOKW 3b developed binge eating. It will be
necessary more studies to well correlate these genetics results and
behavioural studies.
Conclusion: The development of this animal model of binge eating should
prove useful in identifying and assessing further critical enviromental triggers
and specific physiological changes that precipitate and maintain the behavior
and eventually, in guiding better prevention and treatment strategies for binge
eating disorders
The role of the nucleus accumbens in the incubation of methamphetamine craving after voluntary abstinence
Full text linkWe recently introduced an animal model to study incubation of drug craving after prolonged
voluntary abstinence, mimicking the human condition of relapse after successful contingency
management treatment. Here we studied the role of the nucleus accumbens (NAc) in this model.
We trained rats to self-administer a palatable solution (sucrose+maltodextrin 1%, 6 h/day, 6 days)
and methamphetamine (6 h/day, 12 days). We then evaluated relapse to methamphetamine seeking
after 1 and 15 days of voluntary abstinence, achieved via a discrete choice procedure between the
palatable solution and methamphetamine (14 days). We used RNAscope in-situ hybridization to quantify
the co-labeling of the neuronal activity marker Fos, and dopamine Drd1- and Drd2-expressing medium
spiny neurons (MSNs) in NAc core and shell during the incubation tests. Next, we determined the effect
of pharmacological inactivation of NAc core and shell by either GABAA and GABAB agonists
(muscimol+baclofen, 50+50 ng/side), Drd1-Drd2 antagonist (flupenthixol, 10 μg/side) or the selective
Drd1 or Drd2 antagonists (SCH39166 1.0 μg/side or raclopride 1.0 μg/side) during the relapse tests.
Incubated methamphetamine seeking after voluntary abstinence was associated with a selective
increase of Fos expression in the NAc core, but not shell, and Fos was co-labeled with both Drd1- and
Drd2-MSNs. NAc core, but not shell, injections of muscimol+baclofen, flupenthixol, SCH39166, and
raclopride reduced methamphetamine seeking after 15 days of abstinence.
Together, our results suggest that dopamine transmission through Drd1 and Drd2 in NAc core is
critical to the incubation of methamphetamine craving after voluntary abstinence
The effects of social isolation and environmental modulation on the glutamatergic cortico-accumbens synaptic plasticity
No full textPrevious studies in our laboratory have highlighted the importance of the setting in
which drug is taken. We used an in vivo animal model in which one group of rats is
transferred to the self-administration (SA) chambers during the 3 hour test sessions (Non
Resident rats) and a second group literally lives in the SA chambers (Resident rats). Using
this model we have seen that the setting modulates heroin self-administration (Caprioli et al.
2008), the choice between heroin and cocaine (Caprioli et al., 2009), the relapse (Montanari
et al., 2015), as well as the internal state of the rats (Avvisati et al., 2016). Also the
neurobiological effects of heroin are a function of the setting as previously demonstrated
(Paolone et al. 2007; Celentano et al. 2009) using in situ hybridization and
immunohistochemistry experiments.
Thus, in the present study we have hypothesized the setting may influence also the
synaptic plasticity in the cortico-accumbens circuit, areas involved in the impaired ability of
addicts to regulate drug seeking, taking and relapse (Jentsch and Taylor, 1999; Luscher and
Malenka, 2011; Nestler 2001; Kalivas and Volkow, 2011; Kalivas and O’Brien, 2008;
Kalivas et al., 2004; Self et al., 2004). We trained independent groups of rats self
administering heroin (25μg/kg/infusion) and saline for 10 sessions (3 hour each). After 14
days of abstinence rats underwent a cue induced reinstatement test. We also exposed single
housed rats (IH) to Residence and Non Residence condition and we compared these rats with
grouped house rats (GH). Using ex vivo field recordings on parasagittal slice we found that
Heroin SA Resident rats showed an impairment in the capability to induce LTP (fEPSP
amplitude 140% of baseline) when compared to Heroin SA Non Resident rats (fEPSP
amplitude about 160% of baseline). Moreover saline SA, as well, single housed rats showed
an impairment in the capability to induce LTP (fEPSP amplitude about 120% of baseline)
when compared with grouped house rats (fEPS amplitude about 160%).
This suggests that 1) cortico-accumbens synaptic plasticity is impaired in isolated rats
and 2) heroin produces a recovering in the LTP response in both Non Resident and Resident
rats even if Resident rats showed a non complete LTP recovering maybe due to the more
rewarding effect of the drug in this environment.
Further elucidations on how drugs of abuse alter cortico-accumbens plasticity will be
necessary for the development of new therapies especially studies based on the use of heroin
administration since most of the articles in literature have used cocaine
Anxiolytic-like effects of nociceptin/orphanin FQ in the elevated plus maze and in the conditioned defensive burying test in rats
No full textEffect of Fenfluramine on yohimbine- and pellet priming-induced reinstatement of food seeking in female rats: Implications for the predictive validity of the reinstatement model
No full textRelapse to maladaptive eating habits during dieting is often provoked by stress or acute re-exposure to palatable foods. Until recently, this clinical problem was not systemically addressed in animal models. To address this issue, we recently adapted a rat reinstatement model (commonly used to study relapse to drugs of abuse) to study relapse to palatable food seeking induced by food priming (non-contingent exposure to small amounts food pellets) or injections of yohimbine (a prototypical alpha-2 adrenoceptor antagonist that causes stress-like responses in humans and non-humans). Here, we assessed the predictive validity of the food reinstatement model by studying the effect of the serotonin releaser fenfluramine on reinstatement of food seeking. In humans, fenfluramine is an effective dietary treatment that decreases food intake and body weight.
We trained food-restricted female rats to lever-press for 45 mg food pellets (3-h sessions) and first assessed the effect of fenfluramine (1.5 and 3.0 mg/kg, i.p.) on food-reinforced responding. Subsequently, we extinguished the food-reinforced responding and tested fenfluramine’s effect on reinstatement of food seeking induced by yohimbine injections (2 mg/kg i.p.) or pellet priming (4 non-contingent pellets). Fenfluramine decreased yohimbine- and pellet priming-induced reinstatement in a dose-related manner. As expected, fenfluramine also decreased food-reinforced responding, but control experiments indicate that fenfluramine’s effects on lever-presses are not due to performance deficits.
The present data provide evidence for the predictive validity of the food reinstatement model and suggest that the model can be used to identify medications for prevention of relapse induced by stress or acute exposure to palatable food during dietary treatments
A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate and midazolam
No full textRationale: Preclinical models are needed to investigate the
neurobiology and psychobiology of binge eating and to
identify innovative pharmacotherapeutic strategies.
Objectives: A modification of the model based on the
combination of cyclic caloric restrictions and acute stress
was developed to further increase its face validity and
reliability and, for the first time, to assess its predictive value.
Materials and methods: 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.
Results: The combination of cyclic food restriction and
stressful exposure to food markedly increased HPF intake.
Sibutramine and fluoxetine inhibited food intake in all
conditions. Topiramate selectively inhibited compulsive
HPF intake in rats submitted to caloric restriction and
stress. Midazolam increased HPF intake.
Conclusions: 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
Chronic intracerebroventricular infusion of nociceptin/orphanin FQ increases food and ethanol intake in alcohol-preferring rats
No full textCentral administration of low doses of nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, have been shown to reduce ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behavior in alcohol preferring rats. The present study evaluated the effect of continuous (7 days) lateral brain ventricle infusions of N/OFQ (0, 0.25, 1, 4, and 8 microg/h), by means of osmotic mini-pumps, on 10% ethanol intake in Marchigian-Sardinian alcohol-preferring (msP) rats provided 2h or 24h access to it. N/OFQ dose-dependently increased food intake in msP rats. On the other hand, in contrast to previous studies with acute injections, continuous lateral brain ventricle infusion of high doses of N/OFQ increased ethanol consumption when the ethanol solution was available for 24h/day or 2h/day. The present study demonstrates that continuous activation of the opioidergic N/OFQ receptor does not blunt the reinforcing effects of ethanol. Moreover, the data suggest that continuous activation of the opioidergic N/OFQ receptor is not a suitable way to reduce alcohol abuse
Commercially available lipid formulations of amphotericin B: are they bioequivalent and therapeutically equivalent?
Full text linkAmphotericin B is a polyene macrolide derived from Streptomyces nodosus. Introduced into therapy in 1957, for decades amphotericin B has been the “gold standard” for fighting systemic fungal infections. In order to facilitate its systemic use, much attention has been paid to the development of pharmaceutical forms that could reduce its toxicity, especially for the kidney. Because of its low solubility in water and excellent solubility in lipids, amphotericin B is an ideal candidate for lipid-based formulations. Three different lipid formulations for intravenous infusion are currently commercially available: liposomal amphotericin (AmBisome®),Amphotericin lipid complex (Abelcet®) and Amphotericin colloidal dispersion (Amphocil®). The three lipid formulations of amphotericin B show significantly different structural, physical, chemical, pharmacokinetic, pharmacodynamic and toxicological characteristics. Several lines of evidence indicate that the three formulations of amphotericin B are not therapeutically equivalent. First, they are not bioequivalent. Second, even though a complete picture of controlled clinical research designed to compare effectiveness and safety of the three lipid formulations is not available, all the clinical studies analyzed report clear differences in toxicity between the three formulations. AmBisome® appears to be clearly less toxic than the other two formulations, in terms of nephrotoxicity and of incidence of infusion-related adverse events. Third, the therapeutic non-equivalence of the three lipid formulations of amphotericin B is further supported by statements of Conferences and Scientific Societies that in their recommendations have awarded different grading to the three lipid formulations
Oxidative damage in rat erythrocyte membranes following ethanol intake: effect of ethyl pyruvate
No full textAlcoholic patients and experimental animals exposed to ethanol display biochemical signs of oxidativedamage, suggesting a possible role of free radicals in causing some of the toxic effects of alcohol. The ester derivative, ethylpyruvate (EP) is stable in solution and should function as an antioxidant and energy precursor. In the present study, the effect of ethanol intake on plasma membrane fluidity, lipid oxidation and antioxidant enzyme activities (GPx, CAT and SOD) were first evaluated. Secondly, the consequences of ethylpyruvate treatment on the physico-chemical properties of erythrocyte plasma membranes were investigated.
The results obtained demonstrate that ethanol induces an increase in lipid peroxidation, a reduction of GPx activity and fluidity in the hydrophilic–hydrophobic region of the bilayer, moreover an increase of fluidity in hydrophobic part of the plasma membrane was measured. When rats were treated with ethylpyruvate a partially protective effect can be observed for the hydrophilic–hydrophobic region tested by Laurdan, while EP cannot restore the DPH anisotropy values to the control values.
In summary, our data indicate that treatment with EP can only partially reduce ethanol plasma membrane perturbation. Since this study shows an ethylpyruvate dose-dependent effect, it is important to consider the amount of EP required to maintain the right level of membrane fluidity and polarity. These results could be interesting in order to investigate if EP, due to its radical scavenging effect, can prevent oxidativedamage induced by ethanol intake and can protect against injure related with ethanol intake
- …
