Present and Future Pharmacological Treatments for Opioid Addiction

When treating opioid addiction, multidisciplinary treatment is highly recommended, but pharmacotherapy plays a key role. Although the ideal goal is to achieve complete abstinence, an elevated percentage of opioid addicts requires maintenance substitution therapy. In the first section of this chapter, we will focus on the current pharmacological interventions to treat opioid addiction, such as methadone, buprenorphine, and naltrexone. Thanks to these medications, people are able to go back to their normal lives, by preventing withdrawal symptoms, reducing craving, and increasing their adherence to psychotherapy. In the second section, based on the evidence that addiction induces neuroadaptive changes in several neurotransmission systems, we focus on the wide range of possible pharmacological developments at the preclinical and clinical levels, which in recent years have increased considerably

Diet, drugs, and the brain : are ultra-processed foods a gateway to addiction?

Foods that are rich in fats and sugars are pleasurable because they stimulate our reward circuits, the same circuits that are activated by drugs. In a context in which unhealthy diets and drug abuse are common from adolescence, it is important to investigate their consequences. This article reviews the relationship between especially tasty food, our brain?s reward system, and drug use. Studies with animal models have proven that an intermittent high-fat diet during adolescence increases the consumption of cocaine and ethanol. Moreover, recent research has shown the fundamental role of the diet in the development and treatment of addictions

Effect of Voluntary Wheel-Running Exercise on the Endocrine and Inflammatory Response to Social Stress: Conditioned Rewarding Effects of Cocaine

The present paper evaluates the effect of physical activity on the increase of the conditioned rewarding effects of cocaine induced by intermittent social stress and on the neuroinflammatory response that contributes to the enhancement of drug response. For that purpose, three studies were designed in which social stress was induced in different samples of mice through a social-defeat protocol; the mice underwent an increase of physical activity by different modalities of voluntary wheel running (continuous and intermittent access). The results showed that continuous access to running wheels prior to stress enhanced the establishment of cocaine place preference, whereas an intermittent access exerted a protective effect. Wheel running contingent to cocaine administration prevented the development of conditioned preference, and if applied during the extinction of drug memories, it exerted a dual effect depending on the stress background of the animal. Our biological analysis revealed that increased sensitivity to cocaine may be related to the fact that wheel running promotes inflammation though the increase of IL-6 and BDNF levels. Together, these results highlight that physical exercise deeply impacts the organism’s response to stress and cocaine, and these effects should be taken into consideration in the design of a physical intervention

Oxytocin signaling as a target to block social defeat-induced increases in drug abuse reward

There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual’s vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature regarding the effects of OXT in different stages of the addiction cycle. The current literature affirms that a well-functioning oxytocinergic system has protective effects such as the modulation of the initial response to drugs of abuse, the attenuation of the development of dependence, the blunting of drug reinstatement and a general anti-stress effect. However, this system is dysregulated if there is continuous drug use or chronic exposure to stress. In this context, OXT is emerging as a promising pharmacotherapy to restore its natural beneficial effects in the organism and to help rebalance the functions of the addicted brain

Resilience to social defeat stress in adolescent male mice

Adverse social experiences during adolescence are associated with the appearance of mental illness in adulthood. Social defeat (SD) is an ethologically valid murine model to study the consequences of social stress. In adolescent mice, SD induces depressive-like behaviors, increased anxiety and potentiates the reinforcing effects of cocaine and alcohol. However, not all mice exposed to SD will be susceptible to these effects. Adult mice resilient to the effects of SD show a consistent phenotype being resilient to depressive-like behaviors and to the increase in cocaine and alcohol consumption. The aim of the present study was to characterize the resilient phenotype to depressive-like behaviors and increase cocaine and ethanol rewarding effects of mice socially defeated during adolescence. To that end, adolescent mice were exposed to repeated SD, and 24 h after the last encounter, they underwent a social interaction test (SIT) in order to evaluate depressive-like behaviors. Cocaine-induced reward conditioning and ethanol intake was evaluated in two different sets of mice 3 weeks after the last SD using cocaine-induced conditioned place preference (CPP) and oral ethanol self-administration (SA). The neuroinflammation response was measured at the end of the experimental procedure by measuring striatal and cortical levels of IL-6 and CX3CL1. The results confirmed that a comparable percentage of adolescent mice develop resilience to depressive-like behaviors to that observed in adult mice. However, increased anxiety was more severe in resilient mice. Likewise, an increased preference for an ineffective dose of cocaine and an increased ethanol consumption was observed in resilient mice compared to controls. The increase in IL-6 and CX3CL1 was mainly observed in the striatum of susceptible mice compared to that of control mice. Our results confirm that, contrary to prior assumptions in adults, responses to SD stress are more complex and singular in adolescents, and caution should be taken for the correct interpretation and translation of those phenotypes

Ethanol intake in male mice exposed to social defeat: Environmental enrichment potentiates resilience

Large preclinical evidence shows that exposure to social defeat (SD) increases vulnerability to drug abuse, increasing the consumption of ethanol. However, not all subjects are equally affected by the changes induced by stress. Previous reports have evidenced that the resilient phenotype to depressive-like behaviors after SD is associated with the resistant phenotype to cocaine-increased rewarding effects and the smaller neuro- inflammatory response. The aim of the present study was to further clarify whether the resilient profile to depressive-like behavior also predicts a protection against the increase in ethanol intake induced by SD. The neuroinflammatory profile was studied after the end of the oral ethanol self-administration (SA) procedure, measuring levels of the pro-inflammatory cytokine IL-6 and the chemokine CX3CL1 or fractalkine in the striatum and prefrontal cortex. Previous studies have shown that environmental enrichment (EE) is an effective mecha- nism to dimish the detrimental effects of social stress. In a second study, we aimed to evaluate if EE housing before exposure to SD could potentiate resilience. Our results showed that mice with a phenotype susceptible to SD-induced depressive-like behaviors showed increased ethanol consumption and increased neuroinflammatory signaling. In contrast, despite the lack of effect on depressive-like behaviors, defeated mice previously housed under EE conditions did not show an increase in ethanol SA or an increase in immune response. To sum up, the resilient phenotype to SD develops at different levels, such as depressive-like behaviors, ethanol consumption and the neuroinflammatory response. Our results also point to the protective role of EE in potentiating resilience to SD effects

Acute and mid-term outcomes of transvenous implant of a new left ventricular quadripolar lead versus bipolar leads for cardiac resynchronization therapy: Results from a single-center prospective database

Background: The purpose of this study was to evaluate the feasibility of the use of a quadripolar left ventricular (LV) lead for cardiac resynchronization therapy and to compare its acute and mid-term outcomes with those obtained with bipolar leads. Cardiac resynchronization exhibits a high incidence of problems involving the LV lead when conventional leads are used, and these problems may be minimized by using multipolar leads. Methods: We gathered clinical, implant, and follow-up data at 3 and 9 months from 21 consecutive patients in whom a quadripolar (Group Q) or bipolar (Group B) lead was used for a biventricular defibrillator implant. Results: The leads were successfully implanted in all of the patients. In Group B, more than one lead was used in 20% (p = 0.048) of cases. There were no clinical differences or differences in the implant parameters between the two groups except for the radiation dose, which was greater in group B (p = 0.035). The incidence of problems related to the LV lead during follow-up was higher in group B, but the difference was not significant (42.9% vs. 23.8%, p = 0.326). The use of more than one LV lead was the only variable that was significantly associated with lead-related problems during follow-up (p = 0.03; OR = 10.8; 95% CI 1.07–108.61). Conclusions: The quadripolar lead was associated with excellent implantation success rates and mid-term performance. The multi-programmability capabilities of quadripolar leads facilitated the achievement of implant goals and helped to reduce problems during the implant and follow-up. (Cardiol J 2012; 19, 5: 470-478

Voluntary wheel running protects against the increase in ethanol consumption induced by social stress in mice

Previous studies have shown that exposure to social defeat (SD), a model of social stress, produces a long-term increase in the consumption of ethanol, most likely through an increase in the neuroinflammation response. The aim of the present study was to evaluate whether exposure to physical activity in the form of voluntary wheel running (VWR) could block the increase in ethanol consumption and the neuroinflammatory response induced by social stress. Mice were exposed to either 4 sessions of repeated social defeat (RSD) or a non-stressful experience. During the whole procedure, half of the mice were exposed to controlled physical activity, being allowed 1 h access to a low-profile running wheel three times a week. Three weeks after the last RSD, animals started the oral self-administration (SA) of ethanol (6% EtOH) procedure. Biological samples were taken four hours after the first and the fourth RSD, 3 weeks after the last RSD, and after the SA procedure. Brain tissue (striatum) was used to determine protein levels of the chemokines fractalkine (CX3CL1) and SDF-1 (CXCL12). RSD induced an increase in ethanol consumption and caused greater motivation to obtain ethanol. The striatal levels of CX3CL1 and CXCL12 were also increased after the last RSD. VWR was able to reverse the increase in ethanol intake induced by social stress and the neuroinflammatory response. In conclusion, our results suggest that VWR could be a promising tool to prevent and reduce the detrimental effects induced by social stress

Effect of the CB1 cannabinoid agonist WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference in mice

<p>Abstract</p> <p>Background</p> <p>Numerous reports indicate that MDMA users consume other psychoactive drugs, among which cannabis is one of the most common. The aim of the present study was to evaluate, using the conditioned place preference, the effect of the cannabinoid agonist WIN 55,212-2 on the rewarding effects of MDMA in mice.</p> <p>Methods</p> <p>In the first experiment adolescent mice were initially conditioned with 1.25, 2.5 or 5 mg/kg of MDMA or 0.1 or 0.5 mg/kg of WIN and subsequently with both drugs. Reinstatement of the extinguished preference by priming doses was performed in the groups that showed CPP. In the second experiment, animals were conditioned with 2.5 or 5 mg/kg of MDMA and, after extinction, reinstatement of the preference was induced by 0.5 or 0.1 mg/kg of WIN.</p> <p>Results</p> <p>A low dose of WIN 55212-2 (0.1 mg/kg) increased the rewarding effects of low doses of MDMA (1.25 mg/kg), although a decrease in the preference induced by MDMA (5 and 2.5 mg/kg) was observed when the dose of WIN 55212-2 was raised (0.5 mg/kg). The CB1 antagonist SR 141716 also increased the rewarding effects of the lowest MDMA dose and did not block the effects of WIN. Animals treated with the highest WIN dose plus a non-neurotoxic dose of MDMA exhibited decreases of striatal DA and serotonin in the cortex. On the other hand, WIN 55212-2-induced CPP was reinstated by priming injections of MDMA, although WIN did not reinstate the MDMA-induced CPP.</p> <p>Conclusions</p> <p>These results confirm that the cannabinoid system plays a role in the rewarding effects of MDMA and highlights the risks that sporadic drug use can pose in terms of relapse to dependence. Finally, the potential neuroprotective action of cannabinoids is not supported by our data; on the contrary, they are evidence of the potential neurotoxic effect of said drugs when administered with MDMA.</p

The Association between a MAOB Variable Number Tandem Repeat Polymorphism and Cocaine and Opiate Addictions in Polyconsumers

Genetic analysis of the association between alcohol, cocaine, and opiate addiction and variable number tandem repeat (VNTR) polymorphisms in monoamine oxidase B (MAOB) and serotonergic 5-hydroxytryptamine (serotonin) receptor 1B and 2C (HTR1B 21 and HTR2C) pathway genes was performed in a sample of 302 polyconsumers. Our genetic association analysis revealed a significant association between a 184 base pair (bp) VNTR polymorphism in the MAOB gene and addiction to cocaine and opiates. This work highlights new genetic marker associations in cocaine and opiate polyconsumer addictions. These data help to clarify and quantify the complex role of genetics in addictive disorders, as well as their future contribution to the prevention (genetic counselling), diagnosis (genetic diagnosis of vulnerability), and treatment (pharmacogenomics) of these disorders.This research was funded by Centro Superior de Investigación en Salud Pública (CSISP), Spain (grant number CS2003-05-05); Valencian Reginal Government Department of Health, Spain (grant number T4591000); and Research Foundation of the Hospital Provincial de Castellón (Ref. CAF 15-049 and 21-026)