Pharmacotherapy For Drug Addiction Research Articles

Pharmacological treatments for opiate and alcohol addiction: A historical perspective of the last 50 years

Addiction pharmacotherapy aims to prevent drug abstinence symptoms, reduce drug craving and relapse, and normalize physiologic functions disrupted by chronic use of the drug. During the last 50 years, there has been an enormous revolution in pharmacotherapy for drug addiction. From abstinence as practically the only treatment option available, there are now multiple drugs on the market that have proved their efficacy in treating opiate and alcohol disorders. The present review will focus on the pharmacological treatments of the drugs whose consumption most affects individuals and society: alcohol and opiates. We will review the drugs most widely prescribed to prevent relapse and maintain abstinence, as well as those designed to reduce the consumption of short-acting drugs (e.g. maintenance therapies) since the 1960s. Methadone and buprenorphine are the most widely used maintenance therapies for opiate addicts, although new pharmacological depot systems of naltrexone are showing promising results. For alcohol use disorders, acamprosate, nalmefene and naltrexone are replacing disulfiram prescriptions, and a wide variety of new products are currently under study. The number of new pharmacological targets already on clinical trials and the advanced new ways to administer classic therapies can improve the success rate of the pharmacotherapy for opioid and alcohol addiction.

The neurocircuitry involved in oxytocin modulation of methamphetamine addiction.

The role of oxytocin in attenuating the abuse of licit and illicit drugs, including the psychostimulant methamphetamine, has been examined with increased ferocity in recent years. This is largely driven by the potential application of oxytocin as a pharmacotherapy. However, the neural mechanisms by which oxytocin modulates methamphetamine abuse are not well understood. Recent research identified an important role for the accumbens core and subthalamic nucleus in this process, which likely involves an interaction with dopamine, glutamate, GABA, and vasopressin. In addition to providing an overview of methamphetamine, the endogenous oxytocin system, and the effects of exogenous oxytocin on drug abuse, we propose a neural circuit through which exogenous oxytocin modulates methamphetamine abuse, focusing on its interaction with neurochemicals within the accumbens core and subthalamic nucleus. A growing understanding of exogenous oxytocin effects at a neurochemical and neurobiological level will assist in its evaluation as a pharmacotherapy for drug addiction.

The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: A systematic review.

Drug addiction is a serious illness with deleterious functional and social consequences for both the affected individuals, their families, and society at large. In spite of the abundant research on substance dependence, there are few effective treatments for this disease. Given the crucial role of the endogenous opioid system in the development and maintenance of substance abuse disorders, this review focuses on the opioidergic system and examines the role of opioidergic genes in the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addiction. Scopus (all databases) and Pubmed were systematically searched with no language or year restrictions, up to July 2014, for studies that focused on the relationship between polymorphisms of opioidergic genes and the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addictions. Selected search terms were opioid, gene, polymorphism, drug therapy, substance abuse, and response. The genetic variability of μ-, δ- and κ-opioid receptors genes OPRM1, OPRD1, and OPRK1 modulates the efficacy of opioid antagonist treatments such as naltrexone and methadone, as well as the cocaine vaccine. Despite the number of promising reports, data from additional cohorts are needed to substantiate these findings. Gene variant profiling could help predict treatment response and assist in developing effective treatments for alcohol, opioid, and cocaine addiction.

The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: A systematic review

The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: A systematic review

Effects of the cannabinoid CB1 receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine-seeking behavior in rats

BackgroundCannabinoid CB1 receptors play an essential role in drug addiction. Given the side effect profiles of orthosteric CB1 antagonism, new strategies have been attempted to modulate this target, such as CB1 receptor allosteric modulation. However, the effect of CB1 allosteric modulation in drug addiction is unknown. The present study examined the effects of the CB1 receptor allosteric modulator ORG27569 on the reinstatement of cocaine- and methamphetamine-seeking behavior in rats. MethodsRats were trained to self-administer 0.75mg/kg cocaine or 0.05mg/kg methamphetamine in 2-h daily sessions for 14 days which was followed by 7 days of extinction sessions in which rats responded on the levers with no programmed consequences. On reinstatement test sessions, rats were administered ORG27569 (1.0, 3.2, 5.6mg/kg, i.p.) or SR141716A (3.2mg/kg, i.p.) 10min prior to re-exposure to cocaine- or methamphetamine-paired cues or a priming injection of cocaine (10mg/kg, i.p.) or methamphetamine (1mg/kg, i.p.). ResultsBoth cues and a priming injection of cocaine or methamphetamine significantly reinstated the extinguished active lever responding. Pretreatment with ORG27569 resulted in a dose-related attenuation of both cue- and drug-induced reinstatement of cocaine- and methamphetamine-seeking behavior. SR141716A also exhibited similar inhibitory action on reinstatement of drug-seeking behavior. ConclusionNegative allosteric modulation of CB1 receptors can produce similar functional antagonism as orthosteric CB1 receptor antagonists on reinstatement of drug-seeking behavior. Thus, ORG27569 or other negative allosteric modulators deserve further study as potentially effective pharmacotherapy for drug addiction.

The role of metabotropic glutamate receptor 7 (mGluR7) in drug dependence

The successful pharmacotherapy for drug addiction is a challenge for pharmacology in XXI century. We still do not have any registered medication for cocaine by FDA, alcohol therapies are not enough successful. High hopes concern metabotropic glutamate 7 receptor as a target for pharmacotherapy development of drug dependence. It is well documented the role of the mGluR7 in rewarding and motivational effects of cocaine and alcohol. The mGluR7 allosteric agonist AMN082 and antagonist MMPIP have become new tools in preclinical studies. AMN082 attenuated cocaine-enhanced electrical Brain Stimulation Reward (eBSR) in rats decreased cocaine self-administration, too, probably by counteracting cocaine-induced inhibition of the ventral pallidal GABA release. The mGluR7 activation reduced alcohol intake and preference in rats. The mGluR7 receptors take part in reinstatement of drug-seeking behavior after abstinence. The investigations showed that AMN082 suppressed cocaine-induced reinstatement of self-administrated rats via mGluR2/3 mechanism. It was mentioned also that mGluR7 allosteric agonist inhibited reinstatement of ethanol-induced CPP. Moreover, activation of the mGluR7 receptor exhibits less adverse reaction in comparison to other mGluRs and may give a promise for further development of drug dependence therapies in humans. However, some nonspecific effects of the mGluR7 in ethanol addiction have been recognized, so there are further investigations needed to explain the mechanisms of the mGluR7 action in rewarding and motivational effects of drugs.

The Nociceptin/Orphanin FQ Receptor (NOP) as a Target for Drug Abuse Medications

Several studies show that the nociceptin receptor NOP plays a role in the regulation of reward and motivation pathways related to substance abuse. Administration of the NOP's natural peptide ligand, Nociceptin/Orphanin FQ (N/OFQ) or synthetic agonist Ro 64-6198 has been shown to block rewarding effects of cocaine, morphine, amphetamines and alcohol, in various behavioral models of drug reward and reinforcement, such as conditioned place preference and drug self-administration. Administration of N/OFQ has been shown to reduce drug-stimulated levels of dopamine in mesolimbic pathways. The NOP-N/OFQ system has been particularly well examined in the development of alcohol abuse in animal models. Furthermore, the efficacy of the mixed-action opioid buprenorphine, in attenuating alcohol consumption in human addicts and in alcohol-preferring animal models, at higher doses, has been attributed to its partial agonist activity at the NOP receptor. These studies suggest that NOP receptor agonists may have potential as drug abuse medications. However, the pathophysiology of addiction is complex and drug addiction pharmacotherapy needs to address the various phases of substance addiction (craving, withdrawal, relapse). Further studies are needed to clearly establish how NOP agonists may attenuate the drug addiction process and provide therapeutic benefit. Addiction to multiple abused drugs (polydrug addiction) is now commonplace and presents a treatment challenge, given the limited pharmacotherapies currently approved. Polydrug addiction may not be adequately treated by a single agent with a single mechanism of action. As with the case of buprenorphine, a mixed-action profile of NOP/opioid activity may provide a more effective drug to treat addiction to various abused substances and/or polydrug addiction.

Impact of Genetic Variability in Nicotinic Acetylcholine Receptors on Nicotine Addiction and Smoking Cessation Treatment

Nicotine dependence (ND) is one of the world's leading causes of preventable death. Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the world. Evidence for a genetic influence on smoking behaviour and ND has prompted a search for susceptibility genes. Evidence has recently accumulated that single nucleotide polymorphisms (SNPs) in the genetic region encoding the nicotinic acetylcholine receptor (nAChR) subunits α6, α5, α3, and β4 are associated with smoking and ND. Brain nAChR are a heterogeneous family of ion channels expressed in the various parts of the brain. A number of studies suggest that brain nAChR are critical targets for the development of pharmacotherapy for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Additionally, we will provide an overview of the three major pharmacotherapies for smoking cessation (which have demonstrated efficacy) such as: nicotine replacement therapy (NRT), bupropion, and varenicline. An appreciation of the complexity of nAChR and their regulation will be necessary for the development of nAChR modulators as potential pharmacotherapy for drug addiction. Prevention strategies should be tailored to carriers of SNPs located on chromosome 15q and that are strongly associated with nicotine dependence and risk of lung cancer.

Neuronal Nicotinic Receptors as Brain Targets for Pharmacotherapy of Drug Addiction

Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the United States and the rest of the world. Accumulated evidence indicates that brain nicotinic acetylcholine receptors (nAChRs) are a heterogenous family of ion channels expressed in the various parts of the brain. A growing body of preclinical studies suggests that brain nAChRs are critical targets for the development of pharmacotherapies for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Furthermore, we will discuss the role of nAChRs in mediating nicotine-induced addictive behavior in animal models. Additionally, we will provide an overview of the effects of nicotine and nicotinic compounds on the mesolimbic dopamine system, part of the reinforcement/reward circuitry of the brain, as an example of the neurochemical basis of nicotine addiction and other drug addictions. An appreciation of the complexity of nicotinic receptors and their regulation will be necessary for the development of nicotinic receptor modulators as potential pharmacotherapy for drug addiction.

Selective Antagonism at Dopamine D3 Receptors as a Target for Drug Addiction Pharmacotherapy: A Review of Preclinical Evidence

The focal distribution of the dopamine (DA) D(3) receptor in brain regions implicated in emotional and cognitive functions has made this target a main focus of drug discovery efforts. This paper will review the most recent lines of research in support of the use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D(3) receptor in the rodent and human brain; (2) changes in expression of the DA D(3) receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D(3) receptor antagonists in preclinical paradigms assessing the behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine, and heroin. This manuscript, however, will not review the effects of nonselective DA D(2)/D(3) receptor antagonists or partial D(3) receptor agonists. Growing evidence suggests that selective DA D(3) receptor antagonists do not affect the primary reinforcing effects of drugs of abuse, but rather seem to regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. In addition, selective antagonism at DA D(3) receptors appears to disrupt significantly the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior. These preclinical findings will be discussed in the context of translational research relevant to the design of early clinical trials and hypothesis testing in humans.

Lobeline, a potential pharmacotherapy for drug addiction, binds to μ opioid receptors and diminishes the effects of opioid receptor agonists

Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of lobeline and the endogenous opioid system. In guinea pig brain homogenates, lobeline displaced ( K i = 0.74 μM) the binding of [ 3H]DAMGO [(D-Ala 2, N-ME-Phe 4, Gly 5-ol)-enkephalin]. In a functional assay system comprised of MOR-1 μ opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, lobeline had no effect on the resting current, but maximally inhibited (IC 50 = 1.1 μM) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, lobeline-evoked [ 3H]overflow from rat striatal slices preloaded with [ 3H]dopamine was not blocked by naltrexone. Importantly, concentrations of lobeline (0.1–0.3 μM) that did not have intrinsic activity attenuated (∼50%) morphine-evoked [ 3H]overflow. Overall, the results suggest that lobeline functions as a μ opioid receptor antagonist. The ability of lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and lobeline could be investigated as a treatment for opiate addiction.