Ethanol drinking at adulthood is sensitive to S1-R antagonism and is promoted by binge ethanol self-administration at adolescence.

BACKGROUND: Binge drinking at adolescence is a risk factor for problematic alcohol (ethanol) consumption later in life, yet the murine studies that modelled this phenomenon via ethanol self-administration have provided mixed findings. Antagonism of the sigma-1 receptor (S1-R) system at adolescence modulates ethanol's motivational effects and intake. It is still unknown, however, whether this antagonism would protect against enhanced ethanol intake at adulthood after adolescent binge ethanol exposure. METHODS: Exp. 1 and 2 tested adults male or female Wistar rats -exposed or not to ethanol self-administration at adolescence (postnatal days 31-49; nine 2-hour sessions of access to 8-10% ethanol)- for ethanol intake using 24-h two-bottle choice test (Exp. 1) or time restricted, single-bottle, tests (Exp. 2). Experiments 2-5 evaluated, in adolescent or adult rats, the effects of the S1-R antagonist S1RA on ethanol intake and on ethanol-induced conditioned taste or place aversion. Ancillary tests (e.g., novel object recognition, ethanol-induced locomotor activity) were also conducted. RESULTS: Adolescent ethanol exposure promoted ethanol consumption at both the restricted, single-bottle, and at the two-bottle choice tests conducted at adulthood. S1RA administration reduced ethanol intake at adulthood and facilitated the development of ethanol-induced taste (but not place) aversion. CONCLUSIONS: S1RA holds promise for lessening ethanol intake after chronic and substantial ethanol exposure in adolescence that results in heightened ethanol exposure at adulthood. This putative protective effect of S1-R antagonism may relate to S1RA exacerbating the aversive effects of this drug.

Binging from Food to Alcohol: A Sequential Interaction Between Binging Behaviors in Male Wistar Rats.

The development of excessive alcohol (ethanol) and/or highly palatable food self-administration is an essential task to elucidate the neurobiological mechanisms that underlie these behaviors. Previous work has highlighted that ethanol self-administration is modulated by both the induction of aversive states (i.e., stress or frustration) and by the concurrent availability of appetitive stimuli (e.g., food). In our protocol, rats are food deprived for three days until they reach 82%-85% of their ad libitum weight. After that, rats are exposed daily for 10 days to a brief binge or control eating experience with highly sugary and palatable food (i.e., the ingestion of 11.66 and 0.97 kcal/3 min, respectively), which is followed by a two-bottle-choice test (ethanol vs. water) in their home cages for 90 min. This model induces robust binge eating, which is followed by a selective increase in ethanol self-administration. Therefore, this protocol allows to study: a) behavioral and neurobiological factors related to binge eating, b) different stages of alcohol use, and c) interactions between the latter and other addictive-like behaviors, like binge eating.

Folate administration ameliorates neurobehavioral effects of prenatal ethanol exposure.

Background: Prenatal ethanol exposure (PEE) induces heightened ethanol intake at adolescence in preclinical studies. Ethanol intake alters the absorption of folate, a methyl-group donor critical for numerous cellular functions. The prenatal administration of folate is, therefore, a promising approach to reduce the effects of PEE.Objectives: Experiment 1 determined if prenatal folate modulated the effects of PEE on ethanol intake, anxiety-like response, and exploratory behaviors (Experiment 1) in Wistar rats. Experiment 2 assessed, in rats not given PEE, if postnatal folate reversed effects of ethanol exposure at postnatal days 28-42. Experiment 3 assessed if folate altered blood ethanol levels (BELs).Methods: Experiment 1 involved 242 (125 male) adolescent Wistar rats derived from dams given folate (20 mg/kg, gestational days - GD- 13-20) + ethanol (2.0 g/kg, GD 17-20), ethanol, or vehicle only at pregnancy. Experiment 2 involved 29 male adolescents administered vehicle or ethanol doses co-administered or not with folate. In Experiment 3 twelve adult females were tested for BELs after folate administration. These tests were applied: intake tests, light dark box (LDB), elevated plus maze, open field and concentric square field.Results: PEE heightened ethanol intake (η2 ps = 0.06-07) and induced hyperactivity and a reduced latency to exit the white area of the LDB (η2 ps = 0.12-17). These effects were partially inhibited by folate (p > .05). Rats exposed to ethanol exposure at adolescence exhibited reduced motor activity (η2 p = .17), regardless of folate treatment. Folate did not affect BELs.Conclusion: Folate administration should be considered as a preventive or acute treatment to attenuate the neurobehavioral effects of PEE.

Binge eating promotes ethanol self-administration in female rats with a history of intermittent ethanol exposure at adolescence.

BACKGROUND: Ethanol drinking begins during adolescence and, particularly when occurs in a binge-like pattern, exerts lingering adverse consequences. Pre-clinical studies indicate that intermittent ethanol exposure (IEA, a model of repeated ethanol intoxication), or binge eating (BE) can increase subsequent ethanol consumption. It is unknown if the promoting effects of BE upon ethanol drinking are found in female rats and are modulated by IEA at adolescence. This study assessed interactive effects between IEA and BE, upon ethanol drinking. METHODS: Female Wistar rats were given 4.0 g/kg ethanol, every other day from postnatal day 25-45. At adulthood, they were exposed to sessions in which a brief offering of a sizeable portion of highly palatable sugary pills was followed by a 120-min exposure to an ethanol bottle. RESULTS: Exploratory activity and recognition memory was not affected by the IEA. Glutathione peroxidase and catalase activity, and lipid peroxidation (measured in blood and brain at the end of the procedure) were not significantly affected by IEA or BE exposure. BE alone had a mild promoting effect on ethanol ingestion. Those rats that underwent IEA and BE, however, exhibited heightened and sustained ethanol self-administration (average of 2.12 g/kg/120 min, vs 1.15 g/kg/120 min of the other groups), that persisted throughout the BE sessions. IEA and a history of BE also promoted ethanol intake or preference in a two-bottle endpoint test. CONCLUSION: The study suggests that exposure to IEA exerts, when followed by BE at adulthood, promoting effects upon ethanol intake, particularly at concentrations ≥ 6%.

Administration of the sigma-1 receptor agonist PRE-084 at emerging adulthood, but not at early adolescence, attenuated ethanol-induced conditioned taste aversion in female rats.

Ethanol-induced conditioned taste aversion (CTA) is greater in late adolescence or young adulthood than in early adolescence. The role of the sigma receptor system in this age-related difference has not been extensively explored, particularly in female rats. This study assessed the effects of the activation of sigma-1 receptors (S1-R), via the selective S1-R agonist PRE-084, on ethanol-induced CTA at early or at terminal adolescence/emerging adulthood (28 or 56 days-old at the beginning of the procedures, respectively) in female Wistar rats. The modulation of binge-like ethanol intake by PRE-084 was assessed at terminal adolescence. S1-R activation at the acquisition of ethanol-induced CTA attenuated such learning at terminal but not at early adolescence. PRE-084 did not significantly affect ethanol binge drinking in the terminal adolescents. These results highlight the role of S1-R in ethanol-induced CTA and suggest that differential functionality of this transmitter system may underlie age-specific sensitivities to the aversive effects of ethanol.

Ventral hippocampus lesions and allocentric spatial memory in the radial maze: Anterograde and retrograde deficits.

Although the dorsal hippocampus (DHip) has been clearly implicated in spatial learning and memory, there is currently debate as to whether the ventral hippocampus (VHip) is also necessary in allocentric-based navigation tasks. To differentiate between these two subregions of the hippocampal dorsoventral axis, we examined the effect of neurotoxic lesions to the DHip and VHip in different learning situations, using a four-arm plus-shaped maze. In experiment 1 a spatial reference memory task was used, with results showing an acquisition deficit in DHip-lesioned rats but perfect learning in VHip-lesioned rats. However, in experiment 2 an acquisition deficit was found in VHip-lesioned rats using a doubly marked training protocol. In this case the position of the goal arm during training was marked simultaneously by the extramaze constellation of stimuli around the maze and an intramaze cue. The main results indicated that DHip and VHip groups presented significantly more allocentric errors in the probe test than the control rats. In experiments 3 and 4, animals with their brains still intact learned, respectively, a spatial reference memory task or a purely cue-guided navigation task, and DHip and VHip lesions were made 2-3 days after reaching learning criterion. Results indicated a profound retrograde deficit in both lesioned groups but only with regard to allocentric information. So, depending on the training protocol used, our results point to increased integration and cooperation throughout the hippocampal dorsoventral axis when allocentric learning and memory is involved. These data support the existence of a functional continuum from the dorsal to the ventral hippocampus.

Neurobehavioral and neurodevelopmental profiles of a heuristic genetic model of differential schizophrenia- and addiction-relevant features: The RHA vs. RLA rats.

The Roman High- (RHA) and Low-(RLA) avoidance rat lines/strains were generated through bidirectional selective breeding for rapid (RHA) vs. extremely poor (RLA) two-way active avoidance acquisition. Compared with RLAs and other rat strains/stocks, RHAs are characterized by increased impulsivity, deficits in social behavior, novelty-induced hyper-locomotion, impaired attentional/cognitive abilities, vulnerability to psychostimulant sensitization and drug addiction. RHA rats also exhibit decreased function of the prefrontal cortex (PFC) and hippocampus, increased functional activity of the mesolimbic dopamine system and a dramatic deficit of central metabotropic glutamate-2 (mGlu2) receptors (due to a stop codon mutation at cysteine 407 in Grm2 -cys407*-), along with increased density of 5-HT2A receptors in the PFC, alterations of several synaptic markers and increased density of pyramidal "thin" (immature) dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats, and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. RHA rats represent a promising heuristic model of neurodevelopmental schizophrenia-relevant features and comorbidity with drug addiction vulnerability.

Caloric Restriction in Group-Housed Mice: Littermate and Sex Influence on Behavioral and Hormonal Data.

Much of the research done on aging, oxidative stress, anxiety, and cognitive and social behavior in rodents has focused on caloric restriction (CR). This often involves several days of single housing, which can cause numerous logistical problems, as well as cognitive and social dysfunctions. Previous results in our laboratory showed the viability of long-term CR in grouped rats. Our research has studied the possibility of CR in grouped female and male littermates and unrelated CB6F1/J (C57BL/6J × BALBc/J hybrid strain) mice, measuring: (i) possible differences in body mass proportions between mice in ad libitum and CR conditions (at 70% of ad libitum), (ii) aggressive behavior, using the number of pushes and chasing behavior time as an indicator and social behavior using the time under the feeder as indicator, and (iii) difference in serum adrenocorticotropic hormone (ACTH) concentrations (stress biomarker), under ad libitum and CR conditions. Results showed the impossibility of implementing CR in unrelated male mice. In all other groups, CR was possible, with a less aggressive behavior (measured only with the number of pushes) observed in the unrelated female mice under CR conditions. In that sense, the ACTH levels measured on the last day of CR showed no difference in stress levels. These results indicate that implementantion of long-term CR in mice can be optimized technically and also related to their well-being by grouping animals, in particular, related mice.

Sigma-1 antagonism inhibits binge ethanol drinking at adolescence.

BACKGROUND: Ethanol use during adolescence is a significant health problem, yet the pharmacological treatments to reduce adolescent binge drinking are scarce. The present study assessed, in male and female adolescent Wistar rats, if the sigma-1 receptor (S1-R) antagonists S1RA or BD-1063 disrupted ethanol drinking. METHODS: Three times a week, for two weeks, the rats received the S1-R antagonists. Thirty min later they were exposed, for 2 h, to a bottle of 8% or 10 % v/v ethanol. A 24 h, two-bottle, ethanol intake test was conducted after termination of these procedures. A subset of these rats was tested for recognition memory via the novel object recognition test. RESULTS: The rats given 64 mg/kg S1RA drank, in each binge session, significantly less than vehicle counterparts. Male rats given 4 or 16 mg/kg S1RA drank significantly less than those given 0 mg/kg in session 3 or in session 1 and 2, respectively; whereas female rats given 4 or 16 mg/kg drank significantly less than females given 0 mg/kg in session 2-5 or in sessions 2-6, respectively. Administration of 32 mg/kg, but not of 2 or 8 mg/kg, BD-1063 suppressed, across sessions, ethanol drinking. S1-R antagonism reduced absolute ethanol drinking at the two-bottle choice post-test. Recognition memory was not affected by the ethanol exposure. CONCLUSIONS: The results indicate that S1-R antagonists may be promising targets to prevent increases in ethanol intake at adolescence. The persistent effect of S1-R antagonism in free-choice drinking suggests that modulation of the S1-R is altering plastic effects associated with ethanol exposure.

Binge-Like, Naloxone-Sensitive, Voluntary Ethanol Intake at Adolescence Is Greater Than at Adulthood, but Does Not Exacerbate Subsequent Two-Bottle Choice Drinking.

The present study assessed the effects of ethanol exposure during adolescence or adulthood. We exposed Wistar rats, males or females, to self-administered 8-10% (v/v) ethanol (BINGE group) during the first 2 h of the dark cycle, three times a week (Monday, Wednesday, and Friday) during postnatal days (PDs) 32-54 or 72-94 (adolescent and adults, respectively). During this period, controls were only handled, and a third (IP) condition was given ethanol intraperitoneal administrations, three times a week (Monday, Wednesday, and Friday), at doses that matched those self-administered by the BINGE group. The rats were tested for ethanol intake and preference in a two-bottle (24 h long) choice test, shortly before (PD 30 or 70) and shortly after (PD 56 or 96) exposure to the binge or intraperitoneal protocol; and then tested for free-choice drinking during late adulthood (PDs 120-139) in intermittent two-bottle intake tests. Binge drinking was significantly greater in adolescents vs. adults, and was blocked by naloxone (5.0 mg/kg) administered immediately before the binge session. Mean blood ethanol levels (mg/dl) at termination of binge session 3 were 60.82 ± 22.39. Ethanol exposure at adolescence, but not at adulthood, significantly reduced exploration of an open field-like chamber and significantly increased shelter-seeking behavior in the multivariate concentric square field. The rats that had been initially exposed to ethanol at adolescence drank, during the intake tests conducted at adulthood, significantly more than those that had their first experience with ethanol at adulthood, an effect that was similar among BINGE, IP and control groups. The study indicates that binge ethanol drinking is greater in adolescent that in adults and is associated with heightened ethanol intake at adulthood. Preventing alcohol access to adolescents should reduce the likelihood of problematic alcohol use or alcohol-related consequences.

GLP1 Receptor Agonist and SGLT2 Inhibitor Combination: An Effective Approach in Real-world Clinical Practice.

PURPOSE: The aim of this study was to evaluate the effectiveness and safety of combination therapy with a sodium-glucose cotransporter-2 (SGLT2) inhibitor and a glucagon-like peptide-1 receptor agonist (GLP1RA) in patients with inadequately controlled type 2 diabetes. METHODS: A retrospective search of electronic prescriptions of patients undergoing GLP1RA and SGLT2 inhibitor combination therapy was conducted. Once the patients had been identified, demographic data, blood and urine analyses (glycosylated hemoglobin [HbA1c], glucose, renal function, albuminuria, lipid profile, liver enzymes, and uric acid), physical examination (weight, body mass index, and blood pressure), and adverse effects were obtained from their electronic clinical records according to each of the following 3 periods: before the initiation of the combination, the first visit after initiation, and the last available visit. The influence of the duration of diabetes and the drug combination sequence on the effectiveness of the treatment was also analyzed. Statistical analysis was performed with SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). Quantitative variables are presented as mean and SD and were compared by using the Student t test, one-way ANOVA, or repeated measures ANOVA with Bonferroni correction. Categorical variables are expressed as percentages and were compared by using the χ2 test. RESULTS: A total of 212 patients were included, with women accounting for 52.4%. The mean age (SD) of the population was 61.5 (9.6) years. A significant reduction in HbA1c (-12 mmol/mol [-1.1%]) was observed with combined therapy (P < 0.001). The target of HbA1c <53 mmol/mol (<7%) was achieved in 42% of the participants. Mean weight loss was -3.5 kg, and almost 40% of the patients attained the weight loss goal of ≥5% (P < 0.001 in all analyses). Transaminase levels and renal parameters also improved. These benefits persisted over time and bore no relation to the evolution of diabetes. Simultaneous initiation of a combination of a GLP1RA and SGLT2 inhibitor led to faster weight loss and a greater decrease in HbA1c than when they are used sequentially; however, the long-term benefits in terms of metabolic control were similar. Adverse events were rare, and a tendency for a reduced insulin dose was observed. IMPLICATIONS: The findings of this study reveal the combined benefits of a GLP1RA and SGLT2 inhibitor in real-world clinical practice. In general, the combined treatment was well tolerated, and few adverse events were detected.

Frustration Tolerance and Personality Traits in Patients With Substance Use Disorders.

Previous research has suggested the prevalence of certain personality traits, some of which are related to a disorganized attachment, in substance abuse disorders. Further, frustration tolerance (FT) has been proposed as an important factor in addiction, both at the inception-following the "self-medication" hypothesis-and regarding treatment compliance. In turn, an inadequate response to frustrating events has been also associated with a disrupted attachment. Our goal is to explore the mediational role of FT in the relationship between personality traits and two different treatments for substance addiction: therapeutic community (TC) and ambulatory treatment (AT). Eighty-four subjects with substance abuse disorder were recruited in total (22 female), including 46 volunteers (13 female) in TC and 38 (9 female) in AT. They were assessed with Rosenzweig's test for FT and the Millon Clinical Multiaxial Inventory-III (MCMI-III) test to evaluate personality factors. By comparing with a control sample (335 volunteers, 268 female), we found that FT was lower in patients. Between therapeutic groups, FT was significantly lower in TC. Depressive, antisocial, sadistic, negativistic, schizotypal, borderline, paranoid, anxiety, dysthymia, alcohol use, drug use, posttraumatic stress disorder (PTSD), thought disorder, and delusional disorder traits were suggestive of pathology in the clinical samples and were significantly different between control, AT, and TC groups. Further, anxiety and PTSD traits were higher in TC than in AT. A mediational analysis revealed that the effect of anxiety and PTSD scales on therapeutic group was partially mediated by FT. In conclusion, FT and its interplay with personality traits commonly related to disorganized attachment (anxiety and PTSD) might be important factors to consider within therapeutic programs for persons with substance addiction.

Lateral habenula lesions disrupt appetitive extinction, but do not affect voluntary alcohol consumption.

This study analyzed the effects of LHb lesions on appetitive extinction and alcohol consumption. Eighteen male Wistar rats received neurochemical lesions of the LHb (quinolinic acid) and 12 received a vehicle infusion (PBS). In a runway instrumental task, rats received acquisition (12 pellets/trial, 6 trials/session, 10 sessions) and extinction training (5 sessions). In a consummatory task, rats had daily access to 32% sucrose (5 min, 10 sessions) followed by access to water (5 sessions). Then, animals received 2 h preference tests with escalating alcohol concentrations (2%-24%), followed by two 24 h preference tests with 24% alcohol. Relative to Shams, LHb lesions delayed extinction, as indicated by lower response latencies (instrumental task) and higher fluid consumption (consummatory task). LHb lesions did not affect alcohol consumption regardless of alcohol concentration or test duration. The LHb modulates appetitive extinction and needs to be considered as part of the brain circuit underlying reward loss.

Consummatory Successive Negative Contrast in Rats.

Using animal models in addiction and pain research is pivotal to unravel new pathways and mechanisms for the treatment of these disorders. Reward devaluation through a consummatory successive negative contrast (cSNC) task has shown the ability to reduce physical pain sensitivity (hypoalgesia) and increase oral ethanol consumption in rats. The procedure is based on exposing the experimental animals to a 32% sucrose solution during several sessions (preshift sessions) followed by a devaluation to 4% sucrose during the next few sessions (postshift sessions). The cSNC effect can be monitored by comparing the experimental group to an unshifted control that had access to 4% sucrose throughout the entire experiment (preshift and postshift sessions). The cSNC phenomenon is defined by lower consumption of sucrose in the downshifted group than in the unshifted group during postshfit sessions.

Reward loss and the basolateral amygdala: A function in reward comparisons.

The neural circuitry underlying behavior in reward loss situations is poorly understood. We considered two such situations: reward devaluation (from large to small rewards) and reward omission (from large rewards to no rewards). There is evidence that the central nucleus of the amygdala (CeA) plays a role in the negative emotion accompanying reward loss. However, little is known about the function of the basolateral nucleus (BLA) in reward loss. Two hypotheses of BLA function in reward loss, negative emotion and reward comparisons, were tested in an experiment involving pretraining excitotoxic BLA lesions followed by training in four tasks: consummatory successive negative contrast (cSNC), autoshaping (AS) acquisition and extinction, anticipatory negative contrast (ANC), and open field testing (OF). Cell counts in the BLA (but not in the CeA) were significantly lower in animals with lesions vs. shams. BLA lesions eliminated cSNC and ANC, and accelerated extinction of lever pressing in AS. BLA lesions had no effect on OF testing: higher activity in the periphery than in the central area. This pattern of results provides support for the hypothesis that BLA neurons are important for reward comparison. The three affected tasks (cSNC, ANC, and AS extinction) involve reward comparisons. However, ANC does not seem to involve negative emotions and it was affected, whereas OF activity is known to involve negative emotion, but it was not affected. It is hypothesized that a circuit involving the thalamus, insular cortex, and BLA is critically involved in the mechanism comparing current and expected rewards.

Caloric restriction in grouped rats: aggregate influence on behavioural and hormonal data.

The majority of studies in short- and middle-term caloric restriction (CR) have been primarily focused on physiological parameters, improvements in aging, modulation of oxidative stress, and long-term negative effects on cognitive functions. However, single-housing associated with CR may pose many logistical problems. Thus, it is necessary to study the effects of CR under conditions in which animals are group-housed. The aims of this study were to (i) observe the possible differences in the proportion of the weights and social behaviour under ad libitum and CR (at 70%) conditions; (ii) examine the eventual inequalities in the proportion of the weights and social behaviour (the time spent eating under the feeder as an indicator of dominance and empathy, and the number of 'pushes' as an indicator of aggressiveness) in sibling and non-sibling rats under CR conditions; and (iii) compare the concentrations of corticosterone (stress biomarker) in serum under ad libitum and CR conditions. The results indicated the effectiveness of CR in different groups independent of the relationship between the rats. No extreme changes in weight were observed in the CR rats. Behavioural observations also indicated the differences in the total time spent under the feeder and in the number of pushes (higher in both cases for the sibling rats). However, no significant differences in corticosterone levels were observed. Our results suggest the viability of group-housing rats during long periods of CR maintenance.

Hypoalgesia Induced by Reward Devaluation in Rats.

Reduced sensitivity to physical pain (hypoalgesia) has been reported after events involving reward devaluation. Reward devaluation was implemented in a consummatory successive negative contrast (cSNC) task. Food-deprived Wistar rats had access to 32% sucrose during 16 sessions followed by access to 4% sucrose during 3 additional sessions. An unshifted control group had access to 4% sucrose throughout the 19 sessions. Pain sensitivity was measured using von Frey filaments (Experiment 1) and Hargreaves thermal stimuli (Experiment 2) in pretraining baseline, 5 min, and 300 min after either the first (session 17) or second (session 18) devaluation session in the cSNC situation. Sucrose consumption was lower in downshifted groups relative to unshifted groups during postshift sessions-the cSNC effect. Hypoalgesia was observed in downshifted groups relative to unshifted controls when pain sensitivity was assessed 5 min after either the first or second devaluation session, regardless of the pain sensitivity test used. Both pain sensitivity tests yielded evidence of hypoalgesia 300 min after the second downshift session, but not 300 min after the first devaluation session. Whereas hypoalgesia was previously shown only after the second devaluation session, here we report evidence of hypoalgesia after both the first and second devaluation sessions using mechanical and thermal nociceptive stimuli. Moreover, the hypoalgesia observed 300 min after the second devaluation session in both experiments provides unique evidence of the effects of reward loss on sensitivity to physical pain 5 hours after the loss episode. The underlying neurobehavioral mechanisms remain to be identified.

Dorsomedial striatum lesions affect adjustment to reward uncertainty, but not to reward devaluation or omission.

The dorsomedial striatum (DMS) has been implicated in the acquisition of reward representations, a proposal leading to the hypothesis that it should play a role in situations involving reward loss. We report the results of an experiment in which the effects of DMS excitotoxic lesions were tested in consummatory successive negative contrast (reward devaluation), autoshaping training with partial vs. continuous reinforcement (reward uncertainty), and appetitive extinction (reward omission). Animals with DMS lesions exhibited reduced lever pressing responding, but enhanced goal entries, during partial reinforcement training in autoshaping. However, they showed normal negative contrast, acquisition under continuous reinforcement (CR), appetitive extinction, and response facilitation in early extinction trials. Open-field testing also indicated normal motor behavior. Thus, DMS lesions selectively affected the behavioral adjustment to a situation involving reward uncertainty, producing a behavioral reorganization according to which goal tracking (goal entries) became predominant at the expense of sign tracking (lever pressing). This pattern of results shows that the function of the DMS in situations involving reward loss is not general, but restricted to reward uncertainty. We suggest that a nonassociative, drive-related process induced by reward uncertainty requires normal output from DMS neurons.

Latent inhibition of conditioned taste aversion in rats with excitotoxic dorsal hippocampal lesions.

The hippocampus plays crucial roles for the acquisition of latent inhibition in different associative learning procedures, such as fear conditioning. However, the involvement of the hippocampus in the latent inhibition of conditioned taste aversion (CTA) is uncertain. Because different subregions of the hippocampus are associated with distinct functions, it is possible that specific regions of this structure are selectively involved in this learning. To explore the relationship between the dorsal hippocampal region and the latent inhibition of CTA, we analyzed the behavioral effects of excitotoxic lesions of the dorsal hippocampus vs. sham lesions in this paradigm. The results provide no evidence that the latent inhibition of CTA is compromised in rats with excitotoxic dorsal hippocampal lesions. The differential involvement of specific hippocampal regions in the latent inhibition of other associative learning paradigms is briefly discussed.

Hiperlipidemia familiar combinada: documento de consenso / Familial combined hyperlipidemia: consensus document

La hiperlipidemia familiar combinada (HFC) es un trastorno muy frecuente asociado a enfermedad coronaria prematura. Se transmite de forma autosómica dominante, aunque no existe un gen único asociado al trastorno. El diagnóstico se realiza mediante criterios clínicos, y son importantes la variabilidad del fenotipo lipídico y la historia familiar de hiperlipidemia. Es frecuente la asociación con diabetes mellitus tipo 2, hipertensión arterial y obesidad central. Los pacientes con HFC se consideran de riesgo cardiovascular alto y el objetivo terapéutico es un colesterol-LDL < 100 mg/dl, y < 70 mg/dl en presencia de enfermedad cardiovascular establecida o diabetes mellitus. Los pacientes con HFC requieren tratamiento con estatinas potentes y, a veces, tratamiento combinado. La identificación y el manejo de otros factores de riesgo cardiovascular, como la diabetes y la hipertensión, son fundamentales para reducir la carga de enfermedad cardiovascular. Este documento proporciona recomendaciones para el diagnóstico y el tratamiento integral de los pacientes con HFC especialmente dirigidas a médicos de atención primaria (AU)

Familial combined hyperlipidemia (FCH) is a frequent disorder associated with premature coronary artery disease. It is transmitted in an autosomal dominant manner, although there is not a unique gene involved. The diagnosis is performed using clinical criteria, and variability in lipid phenotype and family history of hyperlipidemia are necessaries. Frequently, the disorder is associated with type 2 diabetes mellitus, arterial hypertension and central obesity. Patients with FCH are considered as high cardiovascular risk and the lipid target is an LDL-cholesterol < 100 mg/dL, and < 70 mg/dL if cardiovascular disease or type 2 diabetes are present. Patients with FCH require lipid lowering treatment using potent statins and sometimes, combined lipid-lowering treatment. Identification and management of other cardiovascular risk factors as type 2 diabetes and hypertension are fundamental to reduce cardiovascular disease burden. This document gives recommendations for the diagnosis and global treatment of patients with FCH directed to specialists and general practitioners (AU)