1,721,015 research outputs found
Transition from 'model-based' to 'model-free' behavioral control in addiction: Involvement of the orbitofrontal cortex and dorsolateral striatum
No full textEffect of repeated administrations of heroin, naltrexone, methadone, and alcohol on morphine glucuronidation in the rat
No full textRationale: Heroin is rapidly metabolized to morphine that in turn is transformed in morphine-3-glucuronide (M3G), an inactive metabolite, and morphine-6-glucuronide (M6G), a potent mu-opioid receptor (MOR) agonist. We have found that heroin addicts exhibit higher M6G/M3G ratios relative to morphine-treated control subjects. We have also shown that heroin-treated rats exhibit measurable levels of M6G (which is usually undetectable in this species) and reduced levels of M3G. Objective: We investigated the role of MOR in these effects of heroin, by examining the effects of methadone, a MOR agonist, and of naltrexone, a MOR antagonist, on morphine glucuronidation. We also investigated the effects of alcohol, which is known to alter drug metabolism and is frequently coabused by heroin addicts. Methods: Morphine glucuronidation was studied in liver microsomes obtained from rats exposed daily for 10 days to saline, heroin (10 mg/kg, i.p.), naltrexone (20-40 mg/kg, i.p.), heroin + naltrexone (10 mg/kg + 20-40 mg/kg, i.p.), methadone (5-20 mg/kg, i.p.), or 10% ethanol. Results: Heroin induced the synthesis of M6G and decreased the synthesis of M3G. Naltrexone exhibited intrinsic modulatory activity on morphine glucuronidation, increasing the synthesis of M3G via a low-affinity/ high-capacity reaction characterized by positive cooperativity. The rate of M3G synthesis in the heroin + naltrexone groups was not different from that of the naltrexone groups. Methadone and ethanol induced a modest increase in M3G synthesis and had no effect on M6G synthesis. Conclusion: The effects of heroin on morphine glucuronidation are not shared by methadone or alcohol (two drugs that figure prominently in the natural history of heroin addiction) and do not appear to depend on the activation of MOR
What have positron emission tomography and 'Zippy' told us about the neuropharmacology of drug addiction?
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Animal models of drug relapse and craving: From drug priming-induced reinstatement to incubation of craving after voluntary abstinence
No full textHigh rates of relapse to drug use during abstinence is a defining feature of drug addiction. In abstinent drug users, drug relapse is often precipitated by acute exposure to the self-administered drug, drug-associated cues, stress, as well as by short-term and protracted withdrawal symptoms. In this review, we discuss different animal models that have been used to study behavioral and neuropharmacological mechanisms of these relapse-related phenomena. In the first part, we discuss relapse models in which abstinence is achieved through extinction training, including the established reinstatement model, as well as the reacquisition and resurgence models. In the second part, we discuss recent animal models in which drug relapse is assessed after either forced abstinence (e.g., the incubation of drug craving model) or voluntary (self-imposed) abstinence achieved either by introducing adverse consequences to ongoing drug self-administration (e.g., punishment) or by an alternative nondrug reward using a discrete choice (drug vs. palatable food) procedure. We conclude by briefly discussing the potential implications of the recent developments of animal models of drug relapse after voluntary abstinence to the development of medications for relapse prevention
Incubation of methamphetamine but not heroin craving after voluntary abstinence in male and female rats
No full textWe recently introduced an animal model of incubation of methamphetamine craving after choice-based voluntary abstinence in male rats. Here we studied the generality of this phenomenon to (1) female rats, and (2) male and female rats with a history of heroin self-administration. We first trained rats to self-administer palatable food pellets for 6 days (6 h per day) for either methamphetamine (0.1 mg/kg/infusion) or heroin (0.1 mg/kg/infusion) for 12 days (6 h/day). We then assessed relapse to drug seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent either voluntary abstinence (achieved via a discrete choice procedure between drug and palatable food; 20 trials/day) or home-cage forced abstinence. We found no sex differences in methamphetamine self-administration or in the strong preference for the palatable food over methamphetamine during the choice-based voluntary abstinence. In both sexes, methamphetamine seeking in the relapse tests was higher after 21 days of either voluntary or forced abstinence than after 1 day (incubation of methamphetamine craving). We also found no sex differences in heroin self-administration or the strong preference for the palatable food over heroin during the choice-based voluntary abstinence. However, male and female rats with a history of heroin self-administration showed incubation of heroin craving after forced but not voluntary abstinence. Our results show that incubation of methamphetamine craving after voluntary abstinence generalizes to female rats. Unexpectedly, prolonged voluntary abstinence prevented the emergence of incubation of heroin craving in both sexes
Modeling the role of environment in addiction
No full textThe aim of this review is to provide an overview of the main types of animal models used to investigate the modulatory role of environment on drug addiction. The environment can alter the responsiveness to addictive drugs in at least three major ways. First, adverse life experiences can make an individual more vulnerable to develop drug addiction or to relapse into drug seeking. Second, neutral environmental cues can acquire, through Pavlovian conditioning, the ability to trigger drug seeking even after long periods of abstinence. Third, the environment immediately surrounding drug taking can alter the behavioral, subjective, and rewarding effects of a given drug, thus influencing the propensity to use the same drug again. We have focused in particular on the results obtained using an animal model we have developed to study the latter type of drug-environment interaction. (C) 2007 Elsevier Inc. All rights reserved
Highly impulsive rats: Modelling an endophenotype to determine the neurobiological, genetic and environmental mechanisms of addiction
No full textImpulsivity describes the tendency of an individual to act prematurely without foresight and is associated with a number of neuropsychiatric co-morbidities, including drug addiction. As such, there is increasing interest in the neurobiological mechanisms of impulsivity, as well as the genetic and environmental influences that govern the expression of this behaviour. Tests used on rodent models of impulsivity share strong parallels with tasks used to assess this trait in humans, and studies in both suggest a crucial role of monoaminergic corticostriatal systems in the expression of this behavioural trait. Furthermore, rodent models have enabled investigation of the causal relationship between drug abuse and impulsivity. Here, we review the use of rodent models of impulsivity for investigating the mechanisms involved in this trait, and how these mechanisms could contribute to the pathogenesis of addiction
Effect of novel allosteric modulators of metabotropic glutamate receptors on drug self-administration and relapse: a review of preclinical studies and their clinical implications
No full textResults from preclinical rodent studies during the last 20 years implicated glutamate neurotransmission in different
brain regions in drug self-administration and rodent models of relapse. These results, along with evidence for druginduced
neuroadaptations in glutamatergic neurons and receptors, suggested that addiction might be treatable by
medications that inhibit glutamatergic responses to drugs of abuse, drug-associated cues, and stressors. This idea is
supported by findings in rodent and primate models that drug self-administration and relapse are reduced by systemic
injections of antagonists of ionotropic glutamate receptors or metabotropic glutamate receptors (mGluRs) or
orthosteric agonists of mGluR2/3. However, these compounds have not advanced to clinical use because of potential
side effects and other factors. This state of affairs has led to the development of positive allosteric modulators (PAMs)
and negative allosteric modulators (NAMs) of mGluRs. PAMs and NAMs of mGluRs, either of which can inhibit evoked
glutamate release, may be suitable for testing in humans. We reviewed results from recent studies of systemically
injected PAMs and NAMs of mGluRs in rodents and monkeys, focusing on whether they reduce drug selfadministration,
reinstatement of drug seeking, and incubation of drug craving. We also review results from rat
studies in which PAMs or NAMs of mGluRs were injected intracranially to reduce drug self-administration and
reinstatement. We conclude that PAMs and NAMs of mGluRs should be considered for clinical trials
Applications of positron emission tomography in animal models of neurological and neuropsychiatric disorders
No full textPositron emission tomography (PET) provides dynamic images of the biodistribution of radioactive tracers in the brain. Through application of the principles of compartmental analysis, tracer uptake can be quantified in terms of specific physiological processes such as cerebral blood flow, cerebral metabolic rate, and the availability of receptors in brain. Whereas early PET studies in animal models of brain diseases were hampered by the limited spatial resolution of PET instruments, dedicated small-animal instruments now provide molecular images of rodent brain with resolution approaching 1 mm, the theoretic limit of the method. Major applications of PET for brain research have consisted of studies of animal models of neurological disorders, notably Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD), stroke, epilepsy and traumatic brain injury; these studies have particularly benefited from selective neurochemical lesion models (PD), and also transgenic rodent models (AD, HD). Due to their complex and uncertain pathophysiologies, corresponding models of neuropsychiatric disorders have proven more difficult to establish. Historically, there has been an emphasis on PET studies of dopamine transmission, as assessed with a range of tracers targeting dopamine synthesis, plasma membrane transporters, and receptor binding sites. However, notable recent breakthroughs in molecular imaging include the development of greatly improved tracers for subtypes of serotonin, cannabinoid, and metabotropic glutamate receptors, as well as noradrenaline transporters, amyloid-β and neuroinflammatory changes. This article reviews the considerable recent progress in preclinical PET and discusses applications relevant to a number of neurological and neuropsychiatric disorders in humans
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