Chapter 12 - Neuroscience of opiates for addiction medicine: From stress-responsive systems to behavior

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Abstract

Opiate addiction, similarly to addiction to other psychoactive drugs, is chronic relapsing brain disease caused by drug-induced short-term and long-term neuroadaptations at the molecular, cellular, and behavioral levels. Preclinical research in laboratory animals has found important interactions between opiate exposure and stress-responsive systems. In this review, we will discuss the dysregulation of several stress-responsive systems in opiate addiction: vasopressin and its receptor system, endogenous opioid systems (including proopiomelanocortin/mu opioid receptor and dynorphin/kappa opioid receptor), orexin and its receptor system, and the hypothalamic–pituitary–adrenal axis. A more complete understanding of how opiates alter these stress systems, through further laboratory-based studies, is required to identify novel and effective pharmacological targets for the long-term treatment of heroin addiction.

Introduction

Opiate addiction is a major global public health problem, and there is still a need for alternative medications that could enhance the effectiveness of existing treatments (e.g., methadone maintenance treatment) in reducing opiate abuse, manage withdrawal, and prevent relapse. Addiction to heroin, a potent agonist at opioid receptors, is often characterized by a drug user's initial use resulting in tolerance and eventually severe withdrawal symptoms during periods of abstinence. The reward pathways and withdrawal symptoms, and the desire to avoid them often result in relapse and reescalation of drug use. The length of time a person spends in each of the different developing stages of opiate addiction varies by individual; stress plays a major role in initiation, maintenance, and withdrawal, and elevates drug craving (Koob and Kreek, 2007).

Recent studies in laboratory animals have implicated the dysregulation of several brain stress-responsive systems and hypothalamic–pituitary–adrenal (HPA) axis in the acquisition of opiate self-administration behaviors and progression toward opiate dependence. For example, environmental stressors modulate the effects of drugs on the acquisition of drug self-administration behavior, locomotor activity, and reinstatement of self-administration after extinction (e.g., Breese et al., 2011, Heilig et al., 2010, Koob and Kreek, 2007, Schank et al., 2012, Shalev et al., 2010, Sinha et al., 2011, Spanagel et al., 2014). Atypical stress responsivity is one of the critical factors influencing individual vulnerability to drug relapse. This review will discuss the roles of four important systems to current addiction research.

The arginine vasopressin (AVP) system has been studied in neuroendocrinology and drug addiction. The HPA axis in rodents is directly influenced by the AVP system. This neuropeptide system is profoundly altered by opiates in rodent models, which is discussed in detail in this review. Of interest is the impact of drugs of abuse, such as heroin, alcohol, and cocaine, on AVP and V1b (AVP type 1b receptor) system and their potential roles in taking and seeking behaviors. Specific brain areas such as the medial amygdala, paraventricular nucleus (PVN) of the hypothalamus, and anterior pituitary will be discussed as well as the functions of AVP and its V1b receptors which have been identified and elucidated.

The endogenous opioid systems include the proopiomelanocortin (POMC)/mu opioid receptor (MOP-r) and dynorphin/kappa opioid receptor (KOP-r) systems. The new data on potential roles of POMC and dynorphin in opiate-related seeking behaviors and the control of the HPA axis will be discussed herein as the second topic.

The third is the stress-responsive orexin (or hypocretin) system. Most of the lateral hypothalamic orexin neurons coexpress dynorphin. Orexin has actions in reward-related areas of the brain, such as the nucleus accumbens (NAc) and ventral tegmental area (VTA) with implications in rewarding and addictive-like behaviors.

Finally, there is substantial evidence demonstrating that opiates alter the HPA axis, and in turn the abnormal HPA activity may contribute to the development of opiate addiction and relapse to drug use. In our discussion of the four systems, we will provide an overview of recent research on opiate addiction, with specific emphasis on preclinical laboratory-based research to elucidate the neurobiology of opiate addiction.

Section snippets

AVP and V1b Systems

The two central G protein-coupled AVP receptor subtypes V1a and V1b are highly expressed in the rat extended amygdala. The V1b receptors are expressed prominently in the amygdala, hypothalamus, hippocampus, and anterior pituitary. Recent studies suggest that increased AVP neuronal activity in the amygdala represents a step in the neurobiology of stress-related behaviors in rodent models: (a) acute stress increases extracellular AVP levels in the rat amygdala (Wigger et al., 2004) and (b)

POMC Systems

The POMC gene encodes a prohormone expressed at significant levels in the pituitary or specific brain regions. Cell-specific posttranslational processing of the POMC prohormone generates a variety of biologically active peptides. In the pituitary, anterior lobe corticotrophs release ACTH, whereas intermediate lobe melanotrophs further process POMC to produce N-acetylated forms of α-melanocyte-stimulating hormone and β-endorphin. In the brain, a specialized population of neurons in the

Orexin and Its Receptors

The orexins are expressed in the lateral hypothalamus, perifornical area, and dorsomedial hypothalamus, with extensive projections in the brain (de Lecea et al., 1998). Orexin A acts at orexin type 1 and 2 receptors (OX1R and OX2R), and orexin B acts on OX2R exclusively. Hypothalamic orexins are involved in the regulation of sleep–wakefulness, arousal, feeding, and stress. Orexin receptor blockade in the VTA after acute morphine administration, for example, attenuated an increase in

HPA Axis

It has been reported that stress-induced elevation of HPA activity predicts relapse to drug use and amounts of subsequent use (e.g., Sinha et al., 2006). Vulnerability to drug abuse is enhanced by stress, and the HPA response to stress seems one of the critical factors influencing individual vulnerability to drug abuse. The HPA axis is a well-studied stress-responsive system in animals and humans. Stress, triggered by internal or external stimuli, increases corticotropin-releasing factor (CRF)

Conclusion and Future Directions

As shown in this review, there has been substantial progress in understanding how exposure to drug of abuse interacts with stress-responsive brain systems in order to regulate addictive behaviors. The endogenous opioid systems (including POMC/MOP-r and dynorphin/KOP-r systems) clearly play a major role in heroin addiction, and specific gene alterations may contribute to stress responsivity and may affect vulnerability to develop heroin addiction and to relapse. Other stress-responsive systems

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