The endogenous opioid system: A common substrate in drug addiction

Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits that involve several neurotransmitters. One of the neurochemical systems that plays a pivotal role in different aspects of addiction is the endogenous opioid system (EOS). Opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within these reward circuits. Chronic exposure to the different prototypical drugs of abuse, including opioids, alcohol, nicotine, psychostimulants and cannabinoids has been reported to produce significant alterations within the EOS, which seem to play an important role in the development of the addictive process. In this review, we will describe the adaptive changes produced by different drugs of abuse on the EOS, and the current knowledge about the contribution of each component of this neurobiological system to their addictive properties.     

Monoamine transporters and psychostimulant addiction

Psychostimulants are a broadly defined class of drugs that stimulate the central and peripheral nervous systems as their primary pharmacological effect. The abuse liability of psychostimulants is well established and represents a significant public health concern. An extensive literature documents the critical importance of monoamines (dopamine, serotonin and norepinephrine) in the behavioral pharmacology and addictive properties of psychostimulants. In particular, the dopamine transporter plays a primary role in the reinforcing and behavioral-stimulant effects of psychostimulants in animals and humans. Moreover, both serotonin and norepinephrine systems can reliably modulate the neurochemical and behavioral effects of psychostimulants. However, there is a growing body of evidence that highlights complex interactions among additional neurotransmitter systems. Cortical glutamatergic systems provide important regulation of dopamine function, and inhibitory amino acid gamma-aminobutyric acid (GABA) systems can modulate basal dopamine and glutamate release. Repeated exposure to psychostimulants can lead to robust and enduring changes in neurobiological substrates, including monoamines, and corresponding changes in sensitivity to acute drug effects on neurochemistry and behavior. Significant advances in the understanding of neurobiological mechanisms underlying psychostimulant abuse and dependence have guided pharmacological treatment strategies to improve clinical outcome. In particular, functional agonist treatments may be used effectively to stabilize monoamine neurochemistry, influence behavior and lead to long-term abstinence. However, additional clinical studies are required in order to identify safe and efficacious pharmacotherapies.     

精神兴奋剂的强化作用和成瘾的神经生物学

多巴胺转运体一直被认为是苯丙胺类精神兴奋剂增强多巴胺突触传递的主要分子靶点。本综述结合本实验室及其他实验室的结果,讨论说明这类毒品还可以通过改变多巴胺能神经元的放电模式,来影响动作电位依赖性的多巴胺释放。证据提示,在兴奋剂强化效应中,动作电位依赖性的多巴胺释放比多巴胺转运体所介导的多巴胺浓度的升高更为重要。这很有可能是因为前者在时程上具有特定的变化模式,携带着来自不同脑区、经多巴胺能神经元整合、处理过的突触信息。     

Biological basis of sex differences in drug abuse: preclinical and clinical studies

The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review, we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men; thus, different prevention and treatment strategies may be required. Similar sex differences in drug sensitivity and self-administration have been reported in laboratory animal studies. Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, opiates, and nicotine during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse). Male and female animals differ in their behavioral, neurological, and pharmacological responses to drugs. Although the role of sex in the mechanisms of drug action remains unclear, preclinical and clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse. Future research is necessary to provide information on how to design more effective drug abuse treatment programs and resources that are sex specific. Electronic Publication     

Flupenthixol as a potential pharmacotreatment of alcohol and cocaine abuse/dependence.

Preclinical and clinical studies suggest that the mesolimbic dopamine system plays a major role in mediating the reinforcing effects of drugs of abuse, including alcohol and psychostimulants, and that pharmacological blockade of dopamine D1 and/or D2 receptors may reduce intake of these drugs, as well as relapse rates. The neuroleptic flupenthixol, which has dopamine D1 and D2 receptor antagonist properties and which may be given intramuscularly in order to improve compliance, has been studied as a possible anti-craving drug in substance abuse disorders. Flupenthixol has been shown to attenuate the discriminative stimulus effects of psychostimulants, as well as their intake in animal models of drug abuse. In addition, the compound was found to reduce alcohol intake in a rat model of alcoholism, but the 'anti-alcohol' effect appeared to be only weakly selective and nonspecific. Clinically, the drug has been studied in alcoholics, cocaine addicts and in patients with comorbid psychiatric disorders. Although the data base is still limited and a number of recent trials have not been completely analyzed, these studies suggest that flupenthixol may be useful in decreasing cocaine consumption. Recent studies in alcoholism, however, have shown disappointing results. A number of pilot studies suggest that probably the most promising area may be the treatment of substance abuse/dependence in patients with comorbid psychiatric disorders. Future studies should focus on dosing issues, the differentiation between short- and long-term effects and the identification of subgroups of patients with particular psychopathology.     

The importance of the adenosine A(2A) receptor-dopamine D(2) receptor interaction in drug addiction

Drug addiction is a serious brain disorder with somatic, psychological, psychiatric, socio-economic and legal implications in the developed world. Illegal (e.g., psychostimulants, opioids, cannabinoids) and legal (alcohol, nicotine) drugs of abuse create a complex behavioral pattern composed of drug intake, withdrawal, seeking and relapse. One of the hallmarks of drugs that are abused by humans is that they have different mechanisms of action to increase dopamine (DA) neurotransmission within the mesolimbic circuitry of the brain and indirectly activate DA receptors. Among the DA receptors, D(2) receptors are linked to drug abuse and addiction because their function has been proven to be correlated with drug reinforcement and relapses. The recognition that D(2) receptors exist not only as homomers but also can form heteromers, such as with the adenosine (A)(2A) receptor, that are pharmacologically and functionally distinct from their constituent receptors, has significantly expanded the range of potential drug targets and provided new avenues for drug design in the search for novel drug addiction therapies. The aim of this review is to bring current focus on A(2A) receptors, their physiology and pharmacology in the central nervous system, and to discuss the therapeutic relevance of these receptors to drug addiction. We concentrate on the contribution of A(2A) receptors to the effects of different classes of drugs of abuse examined in preclinical behavioral experiments carried out with pharmacological and genetic tools. The consequences of chronic drug treatment on A(2A) receptor-assigned functions in preclinical studies are also presented. Finally, the neurochemical mechanism of the interaction between A(2A) receptors and drugs of abuse in the context of the heteromeric A(2A)-D(2) receptor complex is discussed. Taken together, a significant amount of experimental analyses provide evidence that targeting A(2A) receptors may offer innovative translational strategies for combating drug addiction.     

Volatile Solvents as Drugs of Abuse: Focus on the Cortico-Mesolimbic Circuitry

Volatile solvents such as those found in fuels, paints, and thinners are found throughout the world and are used in a variety of industrial applications. However, these compounds are also often intentionally inhaled at high concentrations to produce intoxication. While solvent use has been recognized as a potential drug problem for many years, research on the sites and mechanisms of action of these compounds lags behind that of other drugs of abuse. In this review, we first discuss the epidemiology of voluntary solvent use throughout the world and then consider what is known about their basic pharmacology and how this may explain their use as drugs of abuse. We next present data from preclinical and clinical studies indicating that these substances induce common addiction sequelae such as dependence, withdrawal, and cognitive impairments. We describe how toluene, the most commonly studied psychoactive volatile solvent, alters synaptic transmission in key brain circuits such as the mesolimbic dopamine system and medial prefrontal cortex (mPFC) that are thought to underlie addiction pathology. Finally, we make the case that activity in mPFC circuits is a critical regulator of the mesolimbic dopamine system''s ability to respond to volatile solvents like toluene. Overall, this review provides evidence that volatile solvents have high abuse liability because of their selective effects on critical nodes of the addiction neurocircuitry, and underscores the need for more research into how these compounds induce adaptations in neural circuits that underlie addiction pathology.     

From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use?

Addictive drugs can profoundly affect social behaviour both acutely and in the long-term. Effects range from the artificial sociability imbued by various intoxicating agents to the depressed and socially withdrawn state frequently observed in chronic drug users. Understanding such effects is of great potential significance in addiction neurobiology. In this review we focus on the 'social neuropeptide' oxytocin and its possible role in acute and long-term effects of commonly used drugs. Oxytocin regulates social affiliation and social recognition in many species and modulates anxiety, mood and aggression. Recent evidence suggests that popular party drugs such as MDMA and gamma-hydroxybutyrate (GHB) may preferentially activate brain oxytocin systems to produce their characteristic prosocial and prosexual effects. Oxytocin interacts with the mesolimbic dopamine system to facilitate sexual and social behaviour, and this oxytocin-dopamine interaction may also influence the acquisition and expression of drug-seeking behaviour. An increasing body of evidence from animal models suggests that even brief exposure to drugs such as MDMA, cannabinoids, methamphetamine and phencyclidine can cause long lasting deficits in social behaviour. We discuss preliminary evidence that these adverse effects may reflect long-term neuroadaptations in brain oxytocin systems. Laboratory studies and preliminary clinical studies also indicate that raising brain oxytocin levels may ameliorate acute drug withdrawal symptoms. It is concluded that oxytocin may play an important, yet largely unexplored, role in drug addiction. Greater understanding of this role may ultimately lead to novel therapeutics for addiction that can improve mood and facilitate the recovery of persons with drug use disorders.     

The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction?

Dopamine-containing neurons originating in the ventral tegmental area project primarily to the nucleus accumbens and the prefrontal cortex, forming the mesolimbic and mesocortical systems, respectively. Virtually every drug of abuse influences dopamine-mediated neurotransmission by affecting directly or indirectly the activity of these cells. Amphetamine and cocaine, in addition to opioids and nicotine, induce short- and long-term modifications of firing in the dopamine-containing neurons of the ventral mesencephalon. Although exposure to psychostimulants mainly depresses neuronal activity, nicotine and morphine enhance neuronal activity. However, under particular conditions, these drugs could cause different changes of firing. In this article, we propose that changes in the activity of dopamine-containing neurons are related to the processes of addiction. Therefore, we suggest that both the modulation of dopamine release in the extracellular space and transient or enduring changes in the firing of dopamine-containing neurons could be associated with important features of drugs of abuse.     

Determining the region-specific contributions of 5-HT receptors to the psychostimulant effects of cocaine

Cocaine is a drug of abuse that has complex neurochemical and behavioural profiles. When it became evident that models that involve only dopamine do not fully explain the complex effects of cocaine on behaviour, the focus of research expanded to include the 5-hydroxytryptamine (5-HT) system in the brain. The 5-HT system comprises several subtypes of 5-HT receptors, which contribute differentially to the various behavioural effects of cocaine. In this article, we describe which subtypes regulate behaviours that are related to cocaine addiction and how they might provide new therapeutic approaches. Numerous subpopulations of each 5-HT receptor can be distinguished according to their location in the brain. We also discuss how these subpopulations relate to the effects of 5-HT-receptor stimulation at the systemic level. These insights provide a new receptor-based approach for understanding the 5-HT mechanisms that subserve the actions of cocaine and possible pharmacotherapies against cocaine addiction.     

Behavioural effects of acute and repeated cocaine treatments: a comparative study in sensitisation-prone RHA rats and their sensitisation-resistant RLA counterparts

Rationale Dopamine (DA) transmission is critically involved in the motor effects of psychostimulants and opiates, as well as in the augmentation of these effects resulting from repeated drug administration—a process termed behavioural sensitisation. The latter is known to play a central role in the development and maintenance of drug addiction as well as in the high frequency of relapse observed in drug addicts following detoxification. The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for extreme performances in the acquisition of avoidant behaviour has generated two phenotypes that differ in the functional properties of the mesocortical and mesolimbic DA systems and in their behavioural and neurochemical responses to the acute administration of psychostimulants and opiates. More recently, we showed that repeated morphine or amphetamine injections induce behavioural sensitisation in RHA, but not RLA, rats.Objective To further characterize the differences in the susceptibility to develop psychostimulant sensitisation between the Roman lines, we evaluated the behavioural effects of acute cocaine (5 and 10 mg kg^–1, i.p.) 1 day before and 8 days after repeated administration of saline (2 ml kg^–1, i.p.) or cocaine (10 mg kg^–1, i.p. for 14 consecutive days).Results We show that repeated cocaine administration elicits augmented behavioural responses to both challenge doses of the same drug only in RHA rats.Conclusions The Roman lines represent a useful model to investigate how, and to what extent, the genetic make-up influences the neural substrates of individual vulnerability to addiction.     

A differential activation of dopamine output in the shell and core of the nucleus accumbens is associated with the motor responses to addictive drugs: a brain dialysis study in Roman high- and low-avoidance rats

Addictive substances like morphine and psychostimulants induce a preferential increase in dopamine (DA) output in the nucleus accumbens (NAC), a major terminal field of the mesolimbic dopaminergic projection. Two subregions of the NAC, the dorsolateral core and the ventromedial shell, are thought to subserve different functions related to the reinforcing properties of natural and drug rewards. The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats, respectively, for rapid vs. extremely poor active avoidance acquisition in a shuttle-box has resulted in two phenotypes that differ in their behavioural and neurochemical responses to addictive drugs. We used brain dialysis to assess whether such differences in the responsiveness to drugs of abuse are related to differences in mesolimbic DA neuron function. In RHA rats, morphine, cocaine, and amphetamine caused a larger increase in DA efflux in the NAC shell vs. the NAC core, whereas the profile for the drug-induced increases in DA output was almost completely superimposable in the NAC shell and NAC core of RLA rats. Moreover, morphine, cocaine, and amphetamine caused a larger increment in basal DA output in the NAC shell of RHA rats vs. the NAC shell of RLA rats. These drugs also elicited a more robust increase in locomotion, rearing, sniffing, and grooming in RHA than in RLA rats. These results demonstrate that genetically determined differences in the functional properties of DA neurons projecting to the NAC shell may critically influence the behavioural response patterns to addictive drugs that distinguish the Roman lines.     

Pre- and postsynaptic dopamine mechanisms after repeated nicotine: effects of adrenalectomy

The reinforcing properties of nicotine may be related to its ability to release dopamine in the nucleus accumbens and to increase locomotor activity in experimental animals. Both these effects are sensitized following repeated drug exposure, a phenomenon that may underlie important aspects of addiction. Adrenal steroids may be involved both in positive reinforcement and in sensitization. Adrenalectomy hampers, e.g., the induction of locomotor sensitization to nicotine, and cross-sensitization between stress and psychostimulants may develop. Here, the effect of adrenalectomy on postsynaptic and presynaptic changes of the mesolimbic dopamine system in association with nicotine sensitization was examined. Adrenalectomy or sham-operated rats received daily nicotine (0.4 mg/kg s.c.) or vehicle for 15 days, after which the locomotor responses to nicotine (0.2 mg/kg s.c.) and the dopamine D1/D2 receptor agonist apomorphine (1.0 mg/kg s.c. or 100 microM in the nucleus accumbens by reversed microdialysis) were recorded. In addition, accumbal dopamine output was monitored by in vivo microdialysis after nicotine challenge. Sham/nicotine animals showed a sensitized locomotor response to systemic and local apomorphine compared to all other groups, including the adrenalectomized/nicotine group. Nicotine increased accumbal dopamine output in all animals. In contrast, nicotine induced a pronounced increase in locomotor activity in the sham/nicotine animals compared to the other vehicle group and the adrenalectomized animals. These results indicate that adrenal steroids are involved in the induction of the postsynaptic component of nicotine sensitization, whereas their involvement in tentative presynaptic changes remains unclear.     

Pharmacological determinants of the reinforcing effects of psychostimulants: relation to agonist substitution treatment

Illicit use of psychostimulants, such as cocaine and methamphetamine, continues to pose a significant public health concern. On the basis of the relative success at treating opiate and tobacco users with agonist substitution treatments, this strategy has been pursued in the search for a pharmacotherapy for psychostimulant addiction. The reinforcing effects of drugs are central to their abuse liability; therefore, gaining a better understanding of the factors that determine the reinforcing effects of psychostimulants should inform the development of an effective treatment. Although the reinforcing effects of drugs are known to be multiply determined, the author's dissertation research focused on pharmacological factors. This review presents results from that research as well as findings reported in the extant literature, suggesting that the reinforcing effects of psychostimulant drugs are determined both by their pharmacodynamic and pharmacokinetic profiles. There is evidence to support the conclusion that affinity for dopamine transporters appears to be of critical importance, whereas serotonin transporters seem to serve a modulatory function. A more rapid rate of onset may enhance a drug's reinforcing effects, but a drug with a slow onset can still maintain self-administration. A drug's duration of action may only influence the rate but not the strength of responding that is maintained. Slow-onset, long-acting monoamine transporter ligands can be expected to have reinforcing effects and therefore abuse liability, which has implications for the use of these drugs as pharmacotherapies. Nonetheless, on the basis of promising preclinical and clinical findings, this appears to represent a viable treatment strategy.     

Reward and Abuse of Opiates

Abstract: The dependence creating properties of drugs are mediated by structures in the brain. The mesolimbic system seems to play a crucial role in the behaviourally reinforcing effects of opiates and other drugs of abuse. The significance of dopamine in opiate reinforcement is still a matter of debate, in spite of the large number of studies on this subject. Dopamine appears to be involved in conditioning processes and in drug self-administration behaviour only once it has been established. Neuropeptides, centrally active fragments of hormones, may play a role in the individual vulnerability for the development of drug dependence. Administration of a number of wellknown neuropeptides attenuates the acquisition of drug self-administration behaviour. The virtues and flaws of some widely used animal models for drug dependence are discussed.     

Reward and abuse of opiates.

The dependence creating properties of drugs are mediated by structures in the brain. The mesolimbic system seems to play a crucial role in the behaviourally reinforcing effects of opiates and other drugs of abuse. The significance of dopamine in opiate reinforcement is still a matter of debate, in spite of the large number of studies on this subject. Dopamine appears to be involved in conditioning processes and in drug self-administration behaviour only once it has been established. Neuropeptides, centrally active fragments of hormones, may play a role in the individual vulnerability for the development of drug dependence. Administration of a number of wellknown neuropeptides attenuates the acquisition of drug self-administration behaviour. The virtues and flaws of some widely used animal models for drug dependence are discussed.     

The neurobiological bases for the pharmacotherapy of nicotine addiction

Nicotine, the major psychoactive agent present in tobacco, acts as a potent addictive drug both in humans and laboratory animals, whose locomotor activity is also stimulated. A large body of evidence indicates that the locomotor activation and the reinforcing effects of nicotine may be related to its stimulatory effects on the mesolimbic dopaminergic function. Thus, it is now well established that nicotine can increase in vivo DA outflow in the nucleus accumbens and the corpus striatum. The stimulatory effect of nicotine on DA release most probably results from its ability to excite the neuronal firing rate and to increase the bursting activity of DA neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), and from its stimulatory action on DA terminals in the corpus striatum and the nucleus accumbens. The neurochemical data are consistent with neuroanatomical findings showing the presence of nicotinic acetylcholine receptors (nAChRs) in the SNc, the VTA, and in projection areas of the central dopaminergic system such as the corpus striatum and the nucleus accumbens. Several lines of evidence indicate that the reinforcing properties of drugs of abuse, including nicotine, can be affected by a number of transmitter systems which may act by modulating central dopaminergic function. In this paper, the neurobiological mechanisms underlying nicotine addiction will be reviewed, and the possible strategies for new pharmacological treatments of nicotine dependence will be examined.     

The orphan receptor GPR3 modulates the early phases of cocaine reinforcement

BACKGROUND AND PURPOSE The modulatory activity of the orphan receptor GPR3 in the brain has been related to the control of emotional behaviours. Limbic structures that express GPR3 have been associated with the effects of drug abuse. EXPERIMENTAL APPROACH The role of GPR3 in different cocaine-elicited behaviours including locomotor activity, behavioural sensitization, conditioned place preference (CPP) and intravenous self-administration was evaluated in Gpr3-/- mice and their Gpr3+/+ littermates. Cocaine-induced dopamine release in the nucleus accumbens was also evaluated to elucidate the effect of Gpr3 deletion on extracellular levels of dopamine. KEY RESULTS Gpr3-/- mice exhibited higher rewarding responses in the CPP paradigm. Gpr3-/- mice self-administered more cocaine, especially during the first days of training. No differences were found between genotypes regarding behavioural sensitization and the maximal effort required to obtain a cocaine infusion. Non-contingent priming injections of cocaine before operant training eliminated enhanced cocaine self-administration in Gpr3-/- mice. Extracellular levels of dopamine in the nucleus accumbens induced by cocaine did not differ between genotypes. CONCLUSIONS AND IMPLICATIONS The increased responsiveness of Gpr3-/- mice to the acute locomotor effects of cocaine and the inconsistency to further increase this effect reflected an 'already maximally sensitized' basal state. Enhanced responsiveness of Gpr3-/- mice to cocaine reward and to early phases of reinforcement suggests that an initial alteration increased vulnerability to this type of drug abuse. Overall, altered signalling pathways of GPR3 could contribute to the neurobiological substrate involved in developing addiction to cocaine.     

Overview of the progress in drug dependence studies--mainly focussing on psychic dependence]

The technical term 'drug dependence' was officially adopted by WHO's Expert Committee on Addiction in 1964. Until this, to describe a state of dependence, terms such as 'poisoning', 'habit', 'ism', and 'addiction' had been used from time to time. Until the 1950's, investigators were mainly focussed on the phenomena of physical dependence. However, once the concept of psychic dependence had been introduced, behavioral and neuropharmacological studies on the modes of drug action that produce psychic dependence were activated and have progressed in the last two decades, and among the points clarified by these studies are the following: 1. The critical drug properties that produce psychic dependence are those of rewarding subjective and reinforcing effects of drugs but these effects are not the properties that produce physical dependence, although the development of physical dependence on particular drugs such as opiates may substantially enhance craving for the drugs. 2. The mesolimbic and mesocortical dopamine systems in the brain and also the N. Accumbens play a primary or at least a partial role in producing the subjective and reinforcing effects of major dependence-producing drugs such as cocaine, opiates, barbiturates, benzodiazepines, and ethanol. 3. Many drugs such as naltrexone, methadone, and some dopamine antagonists and serotonin reuptake inhibitors or antagonists were found to be effective in the pharmacotherapy of the dependence on opiates, cocaine, or ethanol.