Inhibition of Nitric Oxide Synthesis Prevents the Effects of Intermittent Social Defeat on Cocaine-Induced Conditioned Place Preference in Male Mice.

We have previously observed that mice exposed to social defeat stress are more sensitive to cocaine in the conditioned place preference (CPP) paradigm. In this context, it has been suggested that the nitric oxide (NO) pathway plays a role in the effects of stress. The present study evaluates the role of a neuronal NO synthase (nNOS) inhibitor (7-nitroindazole, 7-NI) in the short- and long-term behavioural effects of intermittent social defeat (ISD). Four groups of mice were employed for the study: a control group and three stressed groups, one treated with vehicle and two treated with 7-NI (7.25 or 12.5 mg/kg). After the last episode of defeat, mice were tested in the elevated plus maze (EPM), social interaction, object recognition and tail suspension tests. Three weeks later, mice were conditioned with cocaine (1 mg/kg). Stressed mice, irrespective of the treatment received, showed anxiety in the EPM, presented a deficit of social interaction and spent less time immobile in the tail suspension test. However, only stressed mice treated with vehicle developed CPP. Thus, although 7-NI did not modify the short-term behavioural effects of ISD, it prevented ISD-induced potentiation of the rewarding properties of cocaine in adulthood. These results support a specific role of nNOS in the effects of social stress on drug reward.

Behavioural traits related with resilience or vulnerability to the development of cocaine-induced conditioned place preference after exposure of female mice to vicarious social defeat.

Exposure to stress induced by intermittent repeated social defeat (IRSD) increases vulnerability to the development of cocaine-induced conditioned place preference (CPP) among male mice; however, some defeated mice are resilient to these effects of stress. In the present study we evaluated the effects of vicarious IRSD (VIRSD) in female mice and explored behavioural traits that are potentially predictive of resilience. C57BL/6 female mice (n = 28) were exposed to VIRSD, which consisted of the animals witnessing a short experience of social defeat by a male mouse on postnatal day (PND) 47, 50, 53 and 56. The control group (n = 10) was not exposed to stress. Blood samples were collected on PND 47 and 56 for corticosterone and interleukin-6 determinations. On PND 57-58, female mice performed several behavioural tests (elevated plus maze, hole-board, object recognition, social interaction, TST and splash tests). Three weeks later, the effects of cocaine (1.5 mg/kg) on the CPP paradigm were assessed. VIRSD decreased corticosterone levels (on PND 56), increased interleukin-6 levels, enhanced novelty-seeking, improved recognition memory and induced anxiety- and depression-like symptoms. Control and VIRSD female mice did not acquire CPP, although some stressed individuals with certain behavioural traits - including a high novelty-seeking profile or the development of depression-like behaviour in the splash test shortly after VIRSD - acquired cocaine CPP. Our results confirm that some behavioural traits of female mice are associated with vulnerability or resilience to the long-term effects of social stress on cocaine reward, as previously observed in males.

Behavioral Traits Associated With Resilience to the Effects of Repeated Social Defeat on Cocaine-Induced Conditioned Place Preference in Mice.

The relationship between stress and drug use is well demonstrated. Stress-induced by repeated social defeat (RSD) enhances the conditioned place preference (CPP) induced by cocaine in mice. The phenomenon of resilience understood as the ability of subjects to overcome the negative effects of stress is the focus of increasing interest. Our aim is to characterize the behavior of resilient animals with respect to the effects of RSD on the CPP induced by cocaine. To this end, 25 male C57BL/6 mice were exposed to stress by RSD during late adolescence, while other 15 male mice did not undergo stress (controls). On the 2 days following the last defeat, all the animals carried out the elevated plus maze (EPM) and Hole Board, Social Interaction, Tail Suspension and Splash tests. Three weeks later, all the animals performed the CPP paradigm with a low dose of cocaine (1 mg/kg). Exposure to RSD decreased all measurements related to the open arms of the EPM. It also reduced social interaction, immobility in the tail suspension test (TST) and grooming in the splash test. RSD exposure also increased the sensitivity of the mice to the rewarding effects of cocaine, since only defeated animals acquired CPP. Several behavioral traits were related to resilience to the potentiating effect of RSD on cocaine CPP. Mice that showed less submission during defeat episodes, a lower percentage of time in the open arms of the EPM, low novelty-seeking, high social interaction, greater immobility in the TST and a higher frequency of grooming were those that were resilient to the long-term effects of social defeat on cocaine reward since they behaved like controls and did not develop CPP. These results suggest that the behavioral profile of resilient defeated mice is characterized by an active coping response during episodes of defeat, a greater concern for potential dangers, less reactivity in a situation of inevitable moderate stress and fewer depressive-like symptoms after stress. Determining the neurobehavioral substrates of resilience is the first step towards developing behavioral or pharmacological interventions that increase resilience in individuals at a high risk of suffering from stress.

Improvement of Main Cognitive Functions in Patients with Alzheimer's Disease after Treatment with Coconut Oil Enriched Mediterranean Diet: A Pilot Study.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder (mainly in women), and new therapies are needed. In this way, ketone bodies are a direct source of cellular energy and can be obtained from coconut oil, postulating that coconut oil could be a new non-pharmacological alternative in AD patients. OBJECTIVE: The aim of this study is to detect changes in the main cognitive functions of patients with AD after following a coconut oil enriched Mediterranean diet, and to determine whether there are differences in function of stage or sex. METHODS: A prospective, longitudinal, qualitative, analytic, experimental study was carried out in 44 patients with AD, who were randomly divided into two homogenous groups of 22 patients each: an experimental group of patients who followed a coconut oil enriched Mediterranean diet for 21 days and a control group. In order to determine the cognitive changes after the intervention, we carried out the 7 Minute Screen, which analyses temporal orientation, visuospatial and visuoconstructive abilities, and semantic and episodic memory. RESULTS: After intervention with coconut oil, improvements in episodic, temporal orientation, and semantic memory were observed, and it seems that the positive effect is more evident in women with mild-moderate state, although other improvements in males and severe state were also shown. CONCLUSIONS: The isocaloric coconut oil enriched Mediterranean diet seems to improve cognitive functions in patients with AD, with differences according to patient sex and degree of severity of the disease, although more studies in this line are needed.

Increased ethanol consumption after interruption of fat bingeing.

There is a marked comorbidity between alcohol abuse and eating disorders, especially in the young population. We have previously reported that bingeing on fat during adolescence increases the rewarding effects of ethanol (EtOH). The aim of the present work was to study if vulnerability to EtOH persists after cessation of binge eating. OF1 mice binged on fat (HFB: high-fat binge) during adolescence (PND 25-43) and were tested for 15 days after the last access to HFB (on PND 59) using the self-administration paradigm, the conditioned place preference (CPP) and locomotor sensitization to ethanol. Our results showed that after 15 days of cessation of fat ingestion, mice increased their consumption of ethanol and showed greater motivation to obtain ethanol. On the other hand, no effects were observed in the CPP, while an increased locomotor response to ethanol was detected. The present results confirm and extend our previous study demonstrating that the compulsive intake of fat induces long-lasting effects on the reward system that lead to an increased consumption of EtOH.

Dopamine D2 receptors mediate the increase in reinstatement of the conditioned rewarding effects of cocaine induced by acute social defeat.

Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D1- and D2-like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1mg/kg or 25mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on the CPP induced by 3mg/kg of cocaine with or without a stress experience. Mice exposed to ASD showed an increase in reinstatement of the conditioned reinforcing effects of cocaine that was blocked by all of the dopamine receptor antagonists. Blockade of dopamine D2-like receptors with raclopride specifically prevented the effects of stress without affecting the rewarding properties of cocaine. However, SCH23390 inhibited cocaine-induced preference in the control groups and even induced aversion in defeated mice conditioned with the lower dose of cocaine. Moreover, the lowest dose of SCH23390 blocked the rewarding effects of 3mg/kg of cocaine-induced CPP. Our results confirm that the dopamine D2 receptor is involved in the short-term effects of ASD on the rewarding effects of cocaine. The dopamine D1 receptor is clearly involved in the rewarding effects of cocaine, but its role in the effects of ASD remains to be demonstrated.

Pharmacological modulation of protein kinases as a new approach to treat addiction to cocaine and opiates.

Drug addiction shares brain mechanisms and molecular substrates with learning and memory processes, such as the stimulation of glutamate receptors and their downstream signalling pathways. In the present work we provide an up-to-date review of studies that have demonstrated the implication of the main memory-related calcium-dependent protein kinases in opiate and cocaine addiction. The effects of these drugs of abuse in different animal models of drug reward, dependence and addiction are altered by manipulation of the mitogen-activated protein kinase (MAPK) family, particularly extracellular signal regulated kinase (ERK), calcium/calmodulin-dependent kinase II (CaMKII), the protein kinase C (PKC) family (including PKMζ), cAMP-dependent protein kinase A (PKA), cGMP-dependent protein kinase G (PKG), the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target mammalian target of Rapamycin (mTOR), cyclin-dependent kinase 5 (Cdk5), heat-shock proteins (Hsp) and other enzymes and proteins. Research suggests that drugs of abuse induce dependence and addiction by modifying the signalling pathways that involve these memory-related protein kinases, and supports the idea that drug addiction is an excessive aberrant learning disorder in which the maladaptive memory of drug-associated cues maintains compulsive drug use and contributes to relapse. Moreover, the studies we review offer new pharmacological strategies to treat opiate and cocaine dependence based on the manipulation of these protein kinases. In particular, disruption of reconsolidation of drug-related memories may have a high therapeutic value in the treatment of drug addiction.

Preclinical evidence of new opioid modulators for the treatment of addiction.

IMPORTANCE OF THE FIELD: Addiction to opiates is one of the most severe forms of substance dependence, and despite a variety of pharmacological approaches to treat it, relapse is observed in a high percentage of subjects. New pharmacological compounds are necessary to improve the outcome of treatments and reduce adverse side effects. Moreover, drugs that act on the opioid system can also be of benefit in the treatment of alcohol or cocaine addiction. AREA COVERED BY THIS REVIEW: Recent preclinical studies of pharmacological agents for the treatment of opiate addiction (2008 to the present date). WHAT THE READER WILL GAIN: The reader will be informed of the latest drugs shown in animal models to modify dependence on opiates and the reinforcing effects of these drugs. In addition, reports of the latest studies to test these compounds in models of other drug addictions are reviewed. TAKE HOME MESSAGE: The classic clinical pharmacotherapy for opiate dependence, involving mu-opioid receptor agonists or antagonists, has not yielded a high success rate in humans. In pharmacotherapy for opioid dependence, new options are emerging and different pharmacological strategies are now being tested.

Effect of adolescent exposure to WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference.

The present study employs a conditioned place preference procedure (CPP) to examine the effects of exposure to the cannabinoid agonist WIN 55212-2 (WIN) (0.1 and 0.5mg/kg) during adolescence on the reinforcing properties of +/-3,4-methylenedioxymetamphetamine hydrochloride (MDMA) (1.25 and 2.5mg/kg) in mice. On postnatal day (PD) 27, animals received a daily injection of the assigned treatment on 5 consecutive days, and three days later the place conditioning procedure was initiated (PD 35). The results suggest that pre-exposure to cannabinoids strengthens the properties of MDMA and favors reinstatement of the craving for the drug, which endorses the gateway hypothesis.

Effects of extended cocaine conditioning in the reinstatement of place preference.

Rats allowed extended access to cocaine self-administration develop a number of symptoms of addiction, such as greater susceptibility to drug-induced relapse. Using the conditioned place preference (CPP), the number of conditioning training sessions was increased in order to augment exposure to contextual cues associated with the effects of a drug. Mice were conditioned with a steady dose of 6 or 25 mg/kg of cocaine for 4, 8, 12, 16, 20 or 40 days. Weekly sessions of extinction followed the establishment of preference, after which a priming dose of cocaine was administered to reinstate the extinguished preference. The magnitude of the place preference effect was equal in all groups, independently of the number of conditioning sessions. The persistence of the place preference was not related with the number of sessions. Higher responsiveness to reinstatement of the extinguished preference occurred only with an intermediate number of conditioning sessions. In this way, the relation between the number of training sessions and vulnerability to relapse appeared to follow an inverted U-shaped function. Our results suggest that increasing the number of conditioning sessions from 12 to up to 16, without increasing the amount of drug administered, can be of great use in the study of vulnerability to relapse.