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RationaleEvidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory.ObjectivesThe aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion.ConclusionsThe evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.

RationaleAnalysis of lick pattern for sucrose and NaCl and of the forced swimming response after dopamine antagonist administration led us to suggest that dopamine on D1-like receptors is involved in behavioural activation, and the level of activation is “reboosted” on the basis of an evaluation process involving D2-like receptors. Although some studies investigated licking microstructure for water after dopamine antagonists, the within-session time course of their effect was never investigated.ObjectivesThe aims of this study were to further investigate the role of dopamine receptors in the mechanisms governing water ingestion, focussing on the within-session time course of the microstructure parameters, and to test the proposed hypothesis.Materials and methodsThe effects of the dopamine D1-like receptor antagonist SCH 23390 (0.01–0.04 mg/kg) and of the dopamine D2-like receptor antagonist raclopride (0.025–0.25 mg/kg) on licking microstructure for water were examined in 20-h water-deprived rats in 30-min sessions.ResultsAs previously observed with sucrose and NaCl, SCH 23390 reduced licking by reducing burst number, suggesting reduced behavioural activation. Moreover, it resulted in an increased burst size. Raclopride reduced the size of licking bursts, while their number was either increased or decreased depending on the dose.ConclusionThe results support the suggestion that D1 receptors are involved in behavioural activation and D2 receptors are involved in a related evaluation process. Within the framework of the proposed hypothesis, the increased burst size after D1-like receptor blockade might be interpreted as a pro-hedonic effect consequent to the increased cost of the activation of the licking response.

RationalePreclinical and clinical studies suggest the potential use of memantine in the treatment of binge eating disorder. The aim of this study was to further investigate the mechanisms by which memantine influences the motivational aspects of ingestion through the analysis of licking microstructure. To interpret treatment effects in relation to drug action at specific functionally relevant times, we compared the effect of two different administration schedules.MethodsMemantine was administered daily for a week, either 1 h before or immediately after a 30-min daily session. The effects on the microstructure of licking for a 10% sucrose solution in rats were examined in the course of treatment and for 15 days after treatment discontinuation.ResultsTreatment before testing reduced ingestion due to reduced burst size and increased latency in the first session. However, a progressive increase in burst number across sessions led to a full recovery of ingestion levels by the end of treatment. Daily post-session administration induced a dramatic decrease of activation of licking behaviour, indicated by reduced burst number, accompanied to reduced burst size. A slow recovery of ingestion took place after treatment discontinuation.ConclusionThese results suggest a reduced hedonic/reward evaluation response, an effect likely due to NMDA receptor blockade occurring during the testing time and support the hypothesis that memantine interferes with the hedonic/non-homeostatic mechanisms regulating food intake and food-seeking. The effect of post-session administration might be explained by the development of conditioned taste aversion.

In a between-subject comparison of two memantine administration schedules we observed that treatment with the NMDA receptor antagonist memantine before testing sessions reduced ingestion of a 10% sucrose solution in rats, due to reduced licking burst size, thus suggesting a blunted hedonic response. Conversely, daily post-session administration reduced burst number, indicating a reduced level of behavioural activation, likely due to the development of conditioned taste aversion (CTA). In this study, the effect of pre-session and post-session memantine administration was investigated within-subjects. Memantine was administered in daily intraperitoneal injections for 13 days, on alternate days, either 1-h before-\"before testing\" sessions-or immediately after a 30-min session-\"after testing\" sessions. The effects on the microstructure of licking for a 10% sucrose solution were examined in the course of treatment and for 21 days after treatment discontinuation. The results show reduced burst size in the \"before testing\" sessions, without effects on the intra-burst lick rate, an index of motoric effects. Moreover, burst number was reduced since the third session of both administration conditions until the end of treatment. Interestingly, the effect of memantine of reducing the activation of ingestive behaviour was less pronounced in this study with respect to that observed with the previous study post-session administration schedule, in spite of the longer treatment. This apparent paradox might be explained if one considers these effects as instances of a memory-related effect, such as the development of CTA. In the framework of this hypothesis, the \"before testing\" sessions, not being followed by memantine administration, can be considered as extinction sessions performed every other day. Moreover, the animals treated with memantine at the highest dose failed to recover to pre-treatment ingestion levels 21 days after treatment discontinuation, while the animals treated after testing sessions in the previously published study showed a complete recovery well before the 15.sup.th day test. Within the same interpretative framework, this might depend by the reduced number and frequency of the extinction trials-i.e. the number of the sessions run after treatment discontinuation-in the present study. These results provide further support to the conclusion that memantine administration before sessions reduce burst size, an effect which is likely due to blockade of NMDA receptors occurring during behavioural testing. The observation that this effect can be obtained even in absence of a reduced intra-burst lick rate, which rules out the involvement of motor impairment, provides an important piece of evidence in support to the interpretation of this effect as a blunted hedonic response. Moreover, these results provide further evidence that burst number reduction is due to a memory-related effect induced by memantine administration after sessions.

We previously reported that treatment with the prototypical antidepressant imipramine induced a dose-dependent reduction of the ingestion of a 10% sucrose solution, due to reduction of the licking burst number, thus suggesting reduced motivation and/or increased satiation. Importantly, the experimental sessions were performed in an alternate order, either 1-h or 24-h after imipramine administration. The observation that imipramine effect was more pronounced in the “1-h after-treatment” sessions, i.e. at the time of the brain drug C max , led us to suggest that it was likely related to brain drug levels at testing time. However, such an experimental design does not allow to rule out the alternative possibility that the observed effect might be due to post-session administration, as previously observed with memantine. To determine whether imipramine-induced decrease of sucrose ingestion could be observed even in absence of post-session administration, we examined the effect of a daily 22 day treatment with imipramine (5, 10 and 20 mg/kg). In the first half of the treatment period all behavioural tests were performed 1-h after administration. In the second half of the treatment period, tests were performed alternatively either 1-h or 24-h after imipramine administration. The results confirm that imipramine reduces sucrose ingestion due to a reduction of the licking burst number. Most importantly, these results demonstrate that this effect does not require imipramine post-session administration, since it was present before the beginning of post-session administrations. This supports the interpretation of the reduction of sucrose ingestion as a consequence of reduced motivation and/or increased satiation. Thus, these findings, taken together with the results of our previous study, might be relevant in explaining the effects of imipramine in models of drug-seeking and in body weight gain reduction in rats, but not in accounting for the antidepressant therapeutic effect. At variance with the results of our previous study, an increase in burst size was present in the first half of the treatment period, which might be interpreted as a prohedonic effect and/or as a compensatory effect.

Natural α-glucosidase inhibitors from plant-based foods such as catechins offer an attractive strategy for their potential anti-diabetic effects. In this study, infusions of three different tea types (green, white, and oolong) were investigated for their total phenolic (TPC) and catechins (EGCG, ECG, EGC, and EC) content, and for their α-glucosidase inhibitory activities. We observed that the level of TPC in white tea was significantly higher compared to oolong and green tea, which suggests higher content of EGCG and ECG catechins in fresh young leaves. Our findings showed that the higher content of such catechins in the infusion of white tea well correlated with a strong inhibition of α-glucosidase, and such inhibition was demonstrated to be more effective than the FDA-approved drug acarbose. Then, we computationally explored the molecular requirements for enzyme inhibition, especially for the most active catechins EGCG and ECG, as well as their disposition/stability within the active site.

Over the past 80 years, research on dopamine has undergone significant evolution, reshaping our understanding of its roles in the brain and the body [...].Over the past 80 years, research on dopamine has undergone significant evolution, reshaping our understanding of its roles in the brain and the body [...].

We previously observed that dopamine D2-like receptor blockade in rats licking for sucrose produced a within-session decrement of the emission of licking bursts similar to the effect of either reward devaluation, or neuroleptics, on operant responding for different rewards, which, accordingly, we interpreted as an extinction-like effect. This implies that exposing animals to reward devaluation would result in a drop of burst number taking place only after the contact with the devalued reward. To test this prediction, we compared the difference in the within-session time course of burst number in response to high (10%) versus low (2%) concentration sucrose solutions, either in a condition of reward devaluation (exposure to 2% after daily 10%), or in a condition which does not involve changes in the reward value (two groups of subjects each repeatedly exposed to only one of the two concentrations). Reward devaluation resulted in a within-session decrement of the burst number, with the response rate dropping only after the contact with the devalued reward, as predicted. This response pattern was reliably observed only in subjects at their first devaluation experience. In contrast, exposure of separate groups of animals to the two different concentrations yielded lower levels of burst number in the low concentration group apparent since the beginning of the session, as previously observed with dopamine D1-like receptor blockade. These results show that the analysis of burst number, but not of burst size, reveals a specific activation pattern in response to reward devaluation, which differs from the pattern observed comparing the response to two different sucrose concentrations in separate groups of subjects, i.e. in a condition not involving reward devaluation. Finally, the characterisation of the experimental measures of the analysis of licking microstructure in behaviourally (and psychologically) meaningful functional terms, might be relevant for the investigation of the mechanisms underlying behavioural activation and the related evaluation processes.

Rationale We recently suggested that dopamine on D1-like receptors is involved in the activation of goal-directed responses and the level of response activation is “reboosted” on the basis of an evaluation process involving D2-like receptors assessing “response efficacy”. A main piece of evidence in support of this hypothesis was the observation of an “extinction mimicry” effect in the time course of licking bursts after dopamine D2-like receptor blockade in rats licking for sucrose. Objectives The aim of this study was to determine whether the pattern of licking observed with sucrose as a reward could be reproduced in rats licking for a different reward (0.9 % NaCl). Materials and methods We investigated the effects of the dopamine D1-like receptor antagonist SCH 23390 (0.01–0.04 mg/kg) and of the dopamine D2-like receptor antagonist raclopride (0.025–0.25 mg/kg) on the microstructure of licking for a 0.9 % NaCl solution in 12-h water-deprived rats in 30-min sessions. Results As previously observed with sucrose as a reward, raclopride reduced the size of licking bursts and produced on the burst number time course an “extinction mimicry” effect, while SCH 23390 reduced licking exclusively by reducing burst number. Conclusions These results are consistent with the proposed hypothesis and provide support to the use of the study of licking microstructure as a valid model not only for the investigation of the mechanisms governing ingestive behaviour but also for the investigation of the mechanisms underlying behavioural activation and the related evaluation processes.

Rationale Clozapine and the “atypical” antipsychotics are less prone than neuroleptics to induce extrapyramidal motor effects, worsening of the negative symptoms of schizophrenia and dysphoria. This is paralleled by preclinical evidence showing reduced suppression of behaviours aimed at the pursuit of reward, with increased measures of reward efficacy. Serotonin 5-HT2 receptors seem to play a role in determining this profile. Objective We investigated the effects of clozapine on the microstructure of ingestive behaviour, which might reveal behavioural dimensions, such as reward evaluation and behavioural activation, which might be relevant in explaining its atypical profile. Moreover, we investigated the possibility that coadministration of the typical antipsychotic haloperidol and the 5-HT2A/2C receptor antagonist ritanserin might mimic clozapine effects. Materials and methods The effects of clozapine (0.5, 1 and 5 mg/kg) and of the coadministration of haloperidol (0.05 mg/kg) and ritanserin (0.5 and 3 mg/kg) have been examined on the microstructure of licking for a 10% sucrose solution in rats. Results Clozapine failed to affect whole ingestion as revealed by the lack of effect on lick number. However, it increased reward evaluation at the dose of 1 mg/kg, as revealed by increased mean bout size. Haloperidol resulted in a decreased bout size. Ritanserin failed to exert any effects either alone or when coadministered with haloperidol. Conclusion The ability of clozapine to increase reward evaluation might contribute to explain its atypical profile both in the clinical setting and in preclinical studies. These results suggest that 5-HT2A/2C receptors are not involved in the observed effect.