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Palatable food and drugs of abuse activate common neurobiological pathways and numerous studies suggest that fat consumption increases vulnerability to drug abuse. In addition, preclinical reports show that palatable food may relieve craving for drugs, showing that an ad libitum access to a high-fat diet (HFD) can reduce cocaine-induced reinstatement. The main aim of the present study was to evaluate the effect of a limited and intermittent exposure to HFD administered during the extinction and reinstatement processes of a cocaine-induced conditioned place preference (CPP). Male and female mice underwent the 10 mg/kg cocaine CPP. From post-conditioning onwards, animals were divided into four groups: SD (standard diet); HFD-MWF with 2-h access to the HFD on Mondays, Wednesdays, and Fridays; HFD-24h, with 1-h access every day; and HFD-Ext with 1-h access to the HFD before each extinction session. Our results showed that all HFD administrations blocked reinstatement in males, while only the HFD-MWF was able to inhibit reinstatement in females. In addition, HFD-Ext males needed fewer sessions to extinguish the preference, which suggests that administration of fat before being exposed to the environmental cues is effective to extinguish drug-related memories. HFD did not affect Oprμ gene expression but increased CB1r gene expression in the striatum in HFD-Ext males. These results support that palatable food could act as an alternative reward to cocaine, accelerating extinction and blocking reinstatement, these effects being sex specific.

Eating is necessary for survival, but it is also one of the great pleasures enjoyed by human beings. Research to date shows that palatable food can be rewarding in a similar way to drugs of abuse, indicating considerable comorbidity between eating disorders and substance-use disorders. Analysis of the common characteristics of both types of disorder has led to a new wave of studies proposing a Gateway Theory of food as a vulnerability factor that modulates the development of drug addiction. The homeostatic and hedonic mechanisms of feeding overlap with some of the mechanisms implicated in drug abuse and their interaction plays a crucial role in the development of drug addiction. Studies in animal models have shown how palatable food sensitizes the reward circuit and makes individuals more sensitive to other substances of abuse, such as cocaine or alcohol. However, when palatable food is administered continuously as a model of obesity, the consequences are different, and studies provide controversial data. In the present review, we will cover the main homeostatic and hedonic mechanisms that regulate palatable food intake behavior and will explain, using animal models, how different types of diet and their intake patterns have direct consequences on the rewarding effects of psychostimulants and ethanol.

Prepulse inhibition (PPI) of the startle reflex is a measure of sensory-motor synchronization. A deficit in PPI has been observed in psychiatric patients, especially those with schizophrenia and vulnerable subjects, since the neural bases of this disorder are also involved in the regulation of PPI. Recently, we have reported that baseline PPI levels in mice can predict their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. Mice with a low PPI presented a lower sensitivity to the conditioned rewarding effects of cocaine; however, once they acquired conditioned preference with a higher dose of the drug, a more persistent associative effect of cocaine with respect to environmental cues was evident in these animals when compared with High-PPI mice. Therefore, we proposed that the PPI paradigm can determine subjects with a higher vulnerability to the effects of cocaine. Developing locomotor sensitization after pre-exposure to cocaine is considered an indicator of transitioning from recreational use to a compulsive consumption of the drug. Thus, the aim of the present study was to evaluate whether subjects with a low PPI display a higher locomotor sensitization induced by cocaine. First, male and female OF1 mice were classified as High- or Low-PPI according to their baseline PPI levels. Subsequently, the motor effects induced by an acute dose of cocaine (Experiments 1 and 2) and the development of locomotor sensitization induced by pre-exposure to this drug (Experiments 3 and 4) were recorded using two apparatuses (Ethovision and actimeter). Low-PPI mice presented low sensitivity to the motor effects of an acute dose of cocaine, but a high increase of activity after repeated administration of the drug, thus suggesting a great developed behavioral sensitization. Differences after pretreatment with cocaine vs. saline were more pronounced among Low-PPI subjects than among High-PPI animals. These results endorse our hypothesis that the PPI paradigm can detect subjects who are more likely to display behaviors induced by cocaine and which can increase the risk of developing a cocaine use disorder. Herein, we further discuss whether a PPI deficit can be considered an endophenotype for cocaine use disorder.

Psychiatric eating disorders (ED) and substance use disorder (SUD) are frequent comorbidities and negatively affect evaluation, treatment, and prognosis of both pathologies. The aim of the present study was to determine the prevalence of eating disorders amongst patients seeking treatment for SUD, mainly alcohol, cocaine, and cannabis, and the modulating role of impulsivity and the presence of the eating restriction disorder. We employed the following evaluation instruments: the Barratt impulsivity scale, the eating disorder inventory (EDI), and the Valencia Addiction to Eating Restriction Questionnaire (CVAR). The results showed that patients with a SUD had higher levels of impulsivity and higher restriction scores. In terms of eating disorders, patients with SUD had a higher prevalence than the control group, with women presenting significantly higher scores than men. These results confirm that eating disorders have a very high prevalence in the population with addictions; especially, women present eating disorders that are more serious and higher impulsivity rates.

The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body’s metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders.

Background Substance use disorders and social stress are currently associated with changes in the immune system response by which they induce a proinflammatory state in neurons and glial cells that eventually modulates the reward system. Aims The aim of the present work was to assess the role of the immune TLR4 (Toll-like receptors 4) and its signaling response in the increased contextual reinforcing effects of cocaine and reinforcing effects of ethanol (EtOH) induced by social defeat (SD) stress. Methods Adult male C57BL/6 J wild-type (WT) mice and mice deficient in TLR4 (TLR4-KO) were assigned to experimental groups according to stress condition (exploration or SD). Three weeks after the last SD, conditioned place preference (CPP) was induced by a subthreshold cocaine dose (1 mg/kg), while another set underwent EtOH 6% operant self-administration (SA). Several inflammatory molecules were analyzed in the hippocampus and the striatum. Results SD induced higher vulnerability to the conditioned rewarding effects of cocaine only in defeated WT mice. Similarly, defeated WT mice exhibited higher 6% EtOH consumption, an effect that was not observed in the defeated TLR4-KO group. However, the motivation to obtain the drug was observed in both genotypes of defeated animals. Notably, a significant upregulation of the protein proinflammatory markers NFkBp-p65, IL-1β, IL-17 A and COX-2 were observed only in the defeated WT mice, but not in their defeated TLR4-KO counterparts. Conclusions These results suggest that TLR4 receptors mediate the neuroinflammatory response underlying the increase in the rewarding effects of cocaine and EtOH induced by social stress.

Social interaction is known to be the main source of stress in human beings, which explains the translational importance of this research in animals. Evidence reported over the last decade has revealed that, when exposed to social defeat experiences (brief episodes of social confrontations during adolescence and adulthood), the rodent brain undergoes remodeling and functional modifications, which in turn lead to an increase in the rewarding and reinstating effects of different drugs of abuse. The mechanisms by which social stress cause changes in the brain and behavior are unknown, and so the objective of this review is to contemplate how social defeat stress induces longlasting consequences that modify the reward system. First of all, we will describe the most characteristic results of the short-and longterm consequences of social defeat stress on the rewarding effects of drugs of abuse such as psychostimulants and alcohol. Secondly, and throughout the review, we will carefully assess the neurobiological mechanisms underlying these effects, including changes in the dopaminergic system, corticotrophin releasing factor signaling, epigenetic modifications and the neuroinflammatory response. To conclude, we will consider the advantages and disadvantages and the translational value of the social defeat stress model, and will discuss challenges and future directions.

This study employs an oral operant conditioning paradigm to evaluate the effects of repeated social defeat during adolescence on the reinforcing and motivational actions of ethanol in adult OF1 mice. Social interaction, emotional and cognitive behavioral aspects were also analyzed, and real-time polymerase chain reaction (PCR) experiments were performed to study gene expression changes in the mesocorticolimbic and hypothalamus-hypophysis-adrenal (HHA) axis. Social defeat did not alter anxiety-like behavior in the elevated plus maze or cognitive performance in the passive avoidance and Hebb-Williams tests. A social interaction test revealed depression-like symptoms and social subordination behavior in defeated OF1 mice. Interestingly, social defeat in adolescence significantly increased the number of effective responses, ethanol consumption values and motivation to drink. Finally, real-time PCR analyses revealed that social defeat significantly increased tyrosine hydroxylase and corticotropin-releasing hormone in the ventral tegmental area and paraventricular nucleus, respectively. In contrast, mu-opioid receptor gene expression was decreased in the nucleus accumbens of socially defeated mice. In summary, these findings suggest that exposure to social defeat during adolescence increases vulnerability to the rewarding effects of ethanol without affecting emotional or cognitive performance. The gene expression alterations we have observed in the mesocorticolimbic and HHA axis systems of defeated mice could be related with their increased ethanol consumption. These results endorse future research into pharmacological strategies that modulate these systems for the treatment of social stress-related alcohol consumption problems.

Psychiatric disorders constitute one of the main causes of disability worldwide. During the past years, considerable research has been conducted on the genetic architecture of such diseases, although little understanding of their etiology has been achieved. The difficulty to access up-to-date, relevant genotype-phenotype information has hampered the application of this wealth of knowledge to translational research and clinical practice in order to improve diagnosis and treatment of psychiatric patients. PsyGeNET (http://www.psygenet.org/) has been developed with the aim of supporting research on the genetic architecture of psychiatric diseases, by providing integrated and structured accessibility to their genotype-phenotype association data, together with analysis and visualization tools. In this article, we describe the protocol developed for the sustainable update of this knowledge resource. It includes the recruitment of a team of domain experts in order to perform the curation of the data extracted by text mining. Annotation guidelines and a web-based annotation tool were developed to support the curators' tasks. A curation workflow was designed including a pilot phase and two rounds of curation and analysis phases. Negative evidence from the literature on gene-disease associ- ations (GDAs) was taken into account in the curation process. We report the results of the application of this workflow to the curation of GDAs for PsyGeNET, including the analysis of the inter-annotator agreement and suggest this model as a suitable approach for the sustainable development and update of knowledge resources. Database URL: http://www.psygenet.org. PsyGeNET corpus: http://www.psygenet.org/ds/PsyGeNET/results/psygenetCorpus.tar We received support from ISCIII-FEDER (PI13/00082, CP10/00524, CPII16/00026), IMI-JU under grants agreements no. 115191 (Open PHACTS)] and no. 115372 (EMIF), resources of which are composed of financial contribution from the EU-FP7 (FP7/2007-2013) and EFPIA companies in kind contribution, and the EU H2020 Programme 2014-2020 under grant agreements no. 634143 (MedBioinformatics) and no. 676559 (Elixir-Excelerate). The Research Programme on Biomedical Informatics (GRIB) is a member of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001/0023, of the PE I + D+i 2013-2016, funded by ISCIII and FEDER. MRA, SMR and MCBG are supported RD16/0017/0007; OV, FF and MT are supported by RD16/0017/0010; and AS and FJP are supported by RD16/0017/0001, by Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA-Retics-ISCIII). AGS acknowledges financial support from the Spanish Ministry of Economy and Competitiveness, through the 'María de Maeztu' Programme for Units of Excellence in R&D (MDM-2014-0370). Funding for open access: EU H2020 Programme 2014-2020 under grant agreements no. 634143 (MedBioinformatics).