the Circuit Blocking Reward



  • the Circuit Blocking Reward
  • Reward system
  • Background
  • Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome ( RDS). Apr 19, Post-use dysphoria then comes to dominate reward circuit hedonic .. a sufficient intensity so as to totally block the rewarding properties of the. The reward system is a group of neural structures responsible for incentive salience associative . There are several explanations as to why the mesolimbic dopamine pathway is central to circuits mediating reward. First . Berridge discovered that blocking dopamine systems did not seem to change the positive reaction to.

    the Circuit Blocking Reward

    Specifically it was shown [ 28 , 29 ] in transfected kidney cells and expressed in Spodoptera frugiperda insect cells that stimulation of DA receptors by the pure D2 receptor agonist Bromocriptine resulted in proliferation of D2 receptors over a 14 day period. In the same study it was shown that administration of a DA antagonist caused the proliferation of D2 antagonist receptors as well.

    These two independent effects suggest that environmental manipulation in spite of genetic antecedents will result in receptor proliferation. This can best be explained by the understanding that agonist activity involves the stimulation of the mRNA that is involved in transcription.

    This fact becomes very important when coupled with the findings that an increase in substance seeking is due to a paucity of DA D2 receptors [ 24 , 25 ].

    Therefore, if low D2 receptors equate to increased craving behavior then an increase in D2 receptors should result in attenuation of craving behavior. Most recent examples of pharmaceuticals that block DA release and or receptor activation include Acomplia Rimonabant , the cannabinoid CB1 receptor blocker and possibly Gabapentin.

    While there are numerous studies supporting the therapeutic benefits of Acomplia as an anti-craving drug the long term adverse effects resulted in a recent rejection by the United States Federal Drug Administration FDA.

    Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. Christensen et al [ 31 ] did a meta-analysis of all published randomized controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent Rimonabant. They collected data from four double-blind, randomized controlled trials including participants that compared 20 mg per day Rimonabant with placebo.

    Patients given Rimonabant had a 4. Patients given Rimonabant were 2. Their findings suggest that 20 mg per day of Rimonabant increases the risk of adverse psychiatric events — i. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with Rimonabant, these researchers recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions. Concerning this report, we propose that the negative effects on mood are due to the continued blockade of naturally required DA release at the NAc.

    Gabapentin is used for the treatment of seizures, anxiety and neuropathic pain. It has been proposed that Gabapentin may be useful in the treatment of cocaine dependence. However, clinical trials with Gabapentin have shown conflicting results, while preclinical studies are sparse.

    In one study, Peng et al [ 32 ] investigated the effects of Gabapentin on intravenous cocaine self-administration and cocaine-triggered reinstatement of drug-seeking behavior, as well as on cocaine-enhanced DA in the NAc. At the doses tested, it has no effect in the addiction-related animal behavioral models. Based on our current theoretical model we are opposed to the use of Gabapentin to treat substance seeking behavior especially in long term care.

    Summary of completed clinical studies with nutraceutical supplementation: Chen et al [ 39 ] with permission Elsevier. Perfumi M, Mattioli L. Chromium salts — This has been added to the formula to enhance insulin sensitivity and resultant brain concentration of serotonin.

    Many vitamins and minerals serve as co-factors in neurotransmitter synthesis. They also serve to restore general balance, vitality and well-being to the RDS patient who typically is in a state of poor nutritional health. The utilization of GABA is limited due to its polar nature and ability to cross the blood brain barrier. Glutamate is used in a low level only to prevent over-inhibition of enkephalin breakdown and subsequent inhibition of GABAergic spiny neurons of the substantia nigra.

    Other more recent published clinical trials include:. In a one year open trial consisting of patients moderate to severe alcoholics utilization of both Oral and IV forms of Synaptamine resulted in significant reduction in cravings; reduced depression, reduced anxiety; reduced anger; reduced fatigue; reduced lack of energy, and reduced crisis [ 36 ].

    In a one year open trial consisting of 76 patients severe poly drug addicts utilization of oral forms of Synaptamine resulted in significant attenuation of drug cravings; reduced relapse; reduced stress; reduced depression; reduced anger; and increased energy. In a one year cross sectional open trial study of 24 unscreened individuals utilization of oral Synaptamine variant resulted in the following benefits: In a subset of 27 individuals out of self-identified obese subjects geneotyped for polymorphisms of the DRD2 gene and of those carrying the T aq A1 allele had a significant Pearson correlation with days on treatment compared to the A2 carriers.

    For the DRD2A1 carriers the number of days on Synaptamine Complex variant changed according to geneotyping a total of five candidate genes was compared to only 52 days in A2 probands suggesting that DRD2 genotype can predict treatment compliance [ 76 ].

    The result of utilizing this natural dopaminergic activating approach over time should lead to neuronal DA release at the NAc, potentiating a proliferation of D2 receptors [ 28 , 29 ]. It is noteworthy that animal gene therapy utilizing cDNA vectors of the DRD2gene implanted into the NAc results in decrease alcohol craving behavior [ 49 ].

    We are cognizant that the dopaminergic activation approach should be utilized to treat not only alcohol, cocaine and nicotine cravings, but glucose craving as well. Thus the coupling of genetic antecedents and nutrition may be a very viable alternative approach for the treatment of obesity. Obesity-related medical conditions are the second leading cause of death in the U. Classified as a chronic disease in , the understanding of obesity and its causes and effects has been further elucidated through additional research into the genetic and biologic factors influencing this deadly disease.

    What used to be understood as primarily a behavioral problem of overeating and under-exercising has only contributed to continued increases in the rates of obesity despite increases in dieting, exercise and the understanding of genes [ 50 ]. Successful strategies to induce sustainable fat loss and manage obesity effectively have been elusive.

    For the most part, the tactics employed have not been multi-faceted, multi-system approaches, but have been characterized by one-dimensional metabolic approaches e.

    Recent evidence indicates a much more complex and multidimensional syndrome, characterized by the simultaneous breakdown of many facets of metabolism exacerbated or limited by the predispositions of inherited genetic traits [ 51 , 52 ]. There is significant evidence to substantiate the existence of RDS as a new paradigm shift in the understanding of Obesity [ 53 ]. Specifically, there are genetic links to the various roles of catecholaminergic-influenced pathways in aberrant substance seeking behavior, in particular cravings for carbohydrates [ 14 , 50 , 53 , 54 ].

    We propose that these various neurological factors involved in the etiology of obesity, regulated by genetic predispositions, are a subtype of RDS. There is growing evidence to support the augmentation of precursor amino acid therapy and enkephalinase and COMT inhibition leading to enhanced levels of neurotransmitters: We are proposing potential mechanisms herein, along with the rationale for utilizing this multifaceted approach to attenuate the pleiotropic defaults in obesity as well as other addictions including alcohol, cocaine and nicotine.

    In this regard, preliminary testing for the first time seems to support a combination of neurotransmitter precursor amino acids, enkephalinase inhibition, and catecholamine 0-methyl-transferase C. Components of a nutrigenomic formula are modified based on the identification of specific gene polymorphisms resulting from genomic testing and the determination of correct dosage levels to promote successful and sustainable results in improved body recomposition [ 55 , 56 ]. In summary, the impact of biomics technology and the DNA directed nutraceutical targeting of the brain reward circuitry may provide a customized approach to prevent and treat high risk individuals who are carriers of a genetic predisposition to obesity and related RDS behaviors.

    While over genes have been associated with obesity, we believe that selective candidate genes could provide useful information. Thus, we present the necessity of exploiting systems biology and "omics" [ 34 ]. Addiction is conceptualized as a cycle of decreased function of brain reward systems and recruitment of antireward systems that progressively worsen, resulting in the compulsive use of drugs.

    This concept is similar to our concept of RDS which is counter to the normal homeostatic limitation of reward function.

    According to Koob and La Moal [ 57 ] "counteradaptive processes, such as opponent processes that are part of the normal homeostatic limitation of reward function, fail to return within the normal homeostatic range and are hypothesized to repeatedly drive the allostatic state. Excessive drug taking thus results in not only the short-term amelioration of the reward deficit but also suppression of the antireward system.

    However, in the long term, there is worsening of the underlying neurochemical dysregulations that ultimately form an allostatic state decreased dopamine and opioid peptide function, increased corticotropin-releasing factor activity. This allostatic state is hypothesized to be reflected in a chronic deviation of reward set point that is fueled not only by dysregulation of reward circuits per se but also by recruitment of brain and hormonal stress responses. Vulnerability to addiction may involve genetic comorbidity i.

    DRD2 gene A1 allele etc. Moreover, others have described relapse in specific terms emphasizing the importance of dopaminergic function. These researchers have used positron emission tomography to investigate in humans the role of dopamine DA and the brain circuits it regulates in these processes.

    They have shown that increases in DA are associated with the subjective reports of drug reinforcement corroborating the relevance of drug-induced DA increases in the rewarding effects of drugs in humans. During withdrawal they have shown significant reductions in DA D2 receptors and in DA release in drug abusers.

    They have supported the original RDS concept [ 27 ] by postulating that this hypodopaminergic state would result in a decreased sensitivity to natural reinforcers, perpetuating the use of the drug as a means to compensate for this deficit and contributing to the anhedonia and dysphoria seen during withdrawal.

    Because the D2 reductions are associated with decreased activity in the anterior cingulate gyrus and in the orbitofrontal cortex they postulate that this is one of the mechanisms by which DA disruption leads to compulsive drug administration and the lack of control over drug intake in the drug-addicted individual.

    This is supported by studies showing that during craving these frontal regions become hyperactive in proportion to the intensity of the craving. Therefore, Volkow et al [ 58 ] postulate that dopamine contributes to addiction by disrupting the frontal cortical circuits that regulate motivation, drive, and self-control. In fact, being carriers of specific polymorphisms of the dopaminergic system places these individuals, both children and adults, at high risk for RDS behaviors i.

    The linking of ADHD and obesity via a dopaminergic mechanism has also been proposed by others [ 61 , 62 ]. There is strong evidence indicating that dopamine dysregulation is very important in the pathophysiology of ADHD, as well as in the mechanism of the therapeutic action of stimulant drugs. With regard to therapeutic implications, recent studies indicate that methylphenidate MPH , a drug widely used for ADHD, reduced overall energy intake with a selective reduction in dietary fat [ 61 ].

    The findings are consistent with a reward deficiency model [ 34 ] of obesity whereby low brain dopamine predicts overeating and obesity, and administering agents that increase dopamine results in reduced feeding behavior.

    The obesity epidemic has focused attention on obesity's health consequences beyond cardio-vascular disease and diabetes. Detailed consideration suggests that dopaminergic changes in the prefrontal cortex among individuals with the ADHD subtype Attention Deficit Disorder ADD may increase their risk for obesity.

    Thus, individuals and populations with a high prevalence of hypodopaminergic genes may experience higher rates of obesity in the presence of abundant food [ 62 ]. From an evolutionary perspective, Campbell and Eisenberg [ 62 ] suggest that alterations in the dopamine system appear to affect a wide range of behavioral phenotypes. They suggest that recent evolutionary changes in the dopamine receptor genes selected to increase cognitive and behavioral flexibility may now be associated with attention problems and increased food consumption in an obesity gene environment.

    With this said we must consider these results with caution, especially in terms of in vivo studies by Chen et al [ 63 ] showing a down-regulation of D2 receptor density following a 6 day infusion of the D2 agonist quinpirole [ 64 ]. Interestingly, continuous infusion of quinpirole caused a significant down-regulation of striatal D2 dopamine receptors without significantly changing the density of D1 receptors. This was accompanied by a decrease in the level of D2 receptor messenger RNA in the striatum as measured by northern blotting.

    The down-regulation of dopamine receptors was selective for D2 dopamine receptors. Moreover, continuous treatment with quinpirole resulted in a significant increase in striatal mu opioid receptor levels without significant change in the delta opioid receptors. This treatment also induced a significant decrease in proenkephalin messenger RNA in the striatum. Taken together, these results suggest that the down-regulation of D2 dopamine receptor and D2 receptor messenger RNA is the result of the persistent stimulation of D2 receptors and that the up-regulation of mu opioid receptors may be a compensatory response to a decreased biosynthesis of enkephalin.

    While this appears at first sight to contradict our suggestion, we theorize that the difference in continuous stimulation by a slow more physiological and natural release of DA, as proposed herein, will result in a proliferation in D2 receptors as seen in the in vitro studies [ 28 , 29 ] and documented by the consistent anti-craving effects observed in clinical trials [ 18 , 34 - 49 ].

    It is noteworthy that diminished DA receptors are not inevitably associated with depression or addictive behaviors.

    In fact, while the lower incidence of Parkinson's disease PD among smokers may be explained by a protective effect of cigarette smoke, or by a tendency to avoid addictive behaviors among future PD cases, this does not hold true for alcoholism.

    Hernan et al [ 64 ] conducted an indirect test of the latter hypothesis by comparing the incidence of PD between alcoholics and nonalcoholics in the General Practice Research Database of the United Kingdom.

    Their case-control study included 1, cases and 10, matched controls. Overall, they did not find a lower incidence of PD among alcoholics compared with nonalcoholics odds ratio: However, the contrary made be true.

    In Parkinson's disease, dopamine dysregulation syndrome DDS is characterized by severe dopamine addiction and behavioral disorders such as manic psychosis, hypersexuality, pathological gambling, and mood swings or Reward Deficiency Syndrome, as reported by Linazaroso et al [ 65 ].

    In this regard, Witjas et al [ 66 ] describe the case of 2 young parkinsonian patients suffering from disabling motor fluctuations and dyskinesia associated with severe DDS. In addition to alleviating the motor disability in both patients, subthalamic nucleus STN deep brain stimulation greatly reduced the behavioral disorders as well as completely abolishing the addiction to dopaminergic treatment.

    According to the authors [ 66 ], dopaminergic addiction in patients with Parkinson's disease therefore does not constitute an obstacle to high-frequency STN stimulation, and this treatment may even cure the addiction. These findings related to Parkinson's disease partly support our proposal herein.

    There is an abundance of studies showing that acute blockade of DA receptors will result in an attenuation of substance seeking as in the case observed for the Cannabinoid CB1 receptor antagonist, Rimonabant, which neuronal blocks DA-release [ 67 ]. This and other work has prompted Berridge [ 68 ] to rethink the role of DA as a so called "well-being substance". According to Berridge there are three competing explanatory categories: Does it instead meadiate learned predictions of future reward, and stamp in associative links learning?

    Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli 'wanting'? In this regard, recent evidence indicates that dopamine is not needed for new learning, and is not sufficient to mediate learning directly by causing teaching or prediction signals.

    By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal 'wanting', and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short-circuit and sensitize the dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals.

    In short, dopamine's contribution appears to be chiefly to cause 'wanting' for hedonic rewards, more than 'liking' or learning for those rewards. Interestingly, Alcaro et al [ 69 ] agree with Berridge's view by suggesting that the rewarding properties of drugs of abuse are, in part, caused by the activation of the "SEEKING" disposition, ranging from appetitive drive to persistent craving depending on the intensity of the affect.

    The implications of such a view for understanding addiction are considered, with particular emphasis on factors predisposing individuals to develop compulsive drug seeking behaviors. In our view this predisposition is genetic and involves among other candidate genes the DRD2 gene.

    Statistical analysis revealed a significant association between the DRD2 TaqI A genotypes and "Eros" a loving style characterized by a tendency to develop intense emotional experiences based on physical attraction to the partner , thus supporting hedonism as a "wanting" or "SEEKING" phenomena.

    Exploiting this view one might argue that the "reward center" be simplified and termed "the well-being system". In brief, the site of the brain where one experiences feelings of well being is the mesolimbic system. This part of the brain has been termed the "reward center".

    The chemical messages include serotonin, enkephalins, GABA and dopamine, all working in concert to provide a net release of DA at the NAc a region in the mesolimbic system. It is well known that genes control the synthesis, vesicular storage, metabolism, receptor formation and catabolism of neurotransmitters. The polymorphic versions of these genes have certain variations, which could lead to an impairment of the neurochemical events involved in the neuronal release of DA.

    The cascade of these neuronal events has been termed "Brain Reward Cascade". A breakdown of this cascade will ultimately lead to a dysregulation and dysfunction of DA. Since DA has been established as the "pleasure molecule" and the "anti-stress molecule," any reduction in function could lead to reward deficiency and resultant aberrant substance seeking behavior.

    Our physiology is motivationally programmed to drink, eat, have sex and desire pleasurable experiences. Impairment of the mechanisms involved in these natural processes leads to multiple impulsive, compulsive and addictive behaviors governed by genetic polymorphic antecedents. While there are a plethora of genetic variations at the level of mesolimbic activity, polymorphisms of the serotonergic-2A receptor 5-HTT2a , dopamine D2 receptor DRD2 and catechol-o-methyl-transferase COMT genes predispose individuals to excessive cravings and resultant aberrant behaviors.

    An umbrella term to describe common genetic antecedents of multiple impulsive, compulsive and addictive behaviors is RDS. Acute utilization of these substances induces a feeling of well being. But unfortunately, sustained and prolonged abuse leads to a toxic pseudo feeling of well being resulting in tolerance and disease or discomfort. Thus, low DA receptor levels consequent on carrying the DRD2 A1 allelic genotype result in excessive cravings and consequential behavior, whereas normal or high DA receptors levels result in low craving-induced behavior.

    Experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents.

    In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression, causing proliferation of D2 receptors. This molecular finding serves as the basis for inducing DA release naturally, also causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human.

    This proliferation of D2 receptors will in turn induce the attenuation of craving behavior. In fact, as mentioned earlier, this has been proven with work showing DNA-directed overexpression a form of gene therapy of the DRD2 receptors and significant reduction in alcohol craving-induced behavior in animals [ 50 ].

    Support for the impulsive nature of individuals possessing dopaminergic gene variants is derived from a recent article suggesting that variants in the COMT gene predicts impulsive choice behavior, and may shed light on treatment targets [ 71 ].

    A new but emerging concept provides a more comprehensive understanding of reward behaviors and the role of DA. In fact, interfering with accumbens DA appears partially to dissociate the process of primary reinforcement from processes regulating instrumental response initiation, maintenance and selection [ 72 ]. The fact that DA in the accumbens is involved with seeking maintenance suggests that activating the DA system over long periods of time rather than blocking DA receptors should result in attenuation of substance seeking behavior.

    It is noteworthy that assessment of 42 studies led to the conclusion that short-term administration of naltrexone significantly reduced the relapse rate, but was not associated with modification in the abstinence rate, suggesting the need for additional approaches [ 74 ].

    We therefore suggest further that the biochemical and molecular changes that take place in dopaminergic and enkephalinergic systems following continuous neutraceutical treatment with dopamine agonists may underlie the mechanisms by which certain dopamine-mediated behaviors may be influenced. It is our intention to perform micro-dialysis studies showing that precursor amino acid therapy and enkephalinase inhibition induce DA release at the nucleus accumbens of both animals and humans, as well to perform additional clinical trials using nutrigenomic principles [ 76 , 77 ].

    Finally our concept is supported by other work involving glutamate neurotoxicity. Preincubation with the D2 type dopamine agonists provides neuroprotection against glutamate neurotoxicity and the protective effects blocked by a D2 antagonist, indicating that D2 agonists provide protection mediated not only by the inhibition of dopamine turnover, but also via D2 type dopamine receptor [ 78 ].

    While we caution interpretation our laboratory is encouraged that long -term dopaminergic agonistic therapy seems warranted. The authors would like to thank LifeGen, Inc. National Center for Biotechnology Information , U. Theor Biol Med Model. Published online Nov Author information Article notes Copyright and License information Disclaimer. Received Apr 19; Accepted Nov This article has been cited by other articles in PMC. Abstract Background and hypothesis Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach.

    Background It is well known that brain reward circuitry is regulated by neurotransmitter interactions and net release of the substance Dopamine DA in the Nucleus accumbens NAc [ 1 ]. Brain reward cascade explanation While dopamine DA is critical to maintain normalization of natural rewards, the neuronal release of DA into NAc synaptic sites is somewhat complex.

    Open in a separate window. RDS and genetic antecedents Understanding the brain reward cascade provides insight into the development of a blue-print for unlocking certain candidate genes and polymorphisms that could impact the brain in a negative manor. Role of dopamine agonists in proliferation of D2 receptors Studies in vitro have shown that constant stimulation of DA receptors by agonists result in proliferation of Dopamine D2 receptors coupled to G proteins.

    Traditional anti-craving treatments block dopamine activity at the brain reward centers Most recent examples of pharmaceuticals that block DA release and or receptor activation include Acomplia Rimonabant , the cannabinoid CB1 receptor blocker and possibly Gabapentin.

    Table 1 Summary of completed clinical studies with nutraceutical supplementation: Improvement of inpatient treatment of the alcoholic as a function of neuronutrient restoration: Blum K, Trachtenberg MC. Neurogenic deficits caused by alcoholism: The second neural circuit mediating stress-triggered relapse to drug-seeking behavior originates in the central nucleus of the amygdala and projects to the bed nucleus of the stria terminalis.

    This neural circuit uses corticotrophin-releasing factor CRF as its major neurotransmitter. Relapse to drug-seeking behavior triggered by environmental cues previously paired with drinking or drugging also appears to involve two separate neural circuits in the brain - one originating in the ventral subiculum of the hipppocampus and one originating in the basolateral complex of the amygdala.

    Both such circuits use glutamate as their major neurotransmiiter. In a pioneering series of experiments, Gardner and colleagues showed that discrete low-level electrical stimulation of these circuits triggers relapse to drug-seeking behavior, and demonstrated that these relapse circuits are glutamaterically mediated [ , ]. Knowing the exact neural circuits involved in mediating relapse to drug-seeking behavior, and their respective neurotransmitters, opens up the distinct possibility of being able to develop anti-craving and anti-relapse medication using medication development strategies that are highly targeted on specific neurobiological substrates of relapse [ — ].

    In , Grimm and colleagues described a compelling phenomenon at the laboratory animal level - that relapse vulnerability to drug-seeking behavior incubates grows more intense with the mere passage of time [ ]. Once stable drug-taking is established, the animals are returned to their home cages, where they simply wait for varying amounts of time days, weeks, months.

    Importantly, nothing is done to the animals during this waiting period. They are not re-exposed to drug nor to stress nor to any drug-associated environmental cues, nor are they exposed to deliberate extinction of the drug-taking habit. Then, on test day, they are returned to the test chamber in which they originally acquired the drug-taking habit and allowed access to the manipulandum typically, a wall-mounted lever or a nose-poke detector device that originally activated the infusion pump to deliver the drug.

    They are then tested for drug-seeking behavior lever-pressing, nose-poking in the absence extinction testing or presence cue-triggered testing of the environmental cues originally associated with the drug-taking behavior. This remarkable increase in vulnerability to relapse to drug-seeking behavior with the mere passage of time is considered to be an animal model of the extreme fragility of control over relapse vulnerability, and the increase in this vulnerability with the passage of time that is so frequently reported by human addicts.

    The same researchers subsequently found that this incubation of craving phenomenon corresponds to a post-cocaine time-dependent increase in brain-derived neurotrophic factor BDNF protein levels within the mesolimbic dopaminergic reward and relapse circuits - specifically in the nucleus accumbens and amygdala [ ]. This research group also explored the role of the amygdaloid extracellular signal-regulated kinase ERK signaling pathway in this incubation [ ].

    Cocaine seeking induced by exposure to cocaine cues was substantially higher after 30 days of cocaine withdrawal than after 1 day. Exposure to these cues increased ERK phosphorylation in the central, but not the basolateral, amygdala after 30 days of cocaine withdrawal, but not after 1 day. After 30 days of incubation of cocaine craving, inhibition of central but not basolateral amygdaloid ERK phosphorylation produced an inhibition of cocaine-seeking behavior.

    After 1 day of withdrawal, stimulation of central amygdaloid ERK phosphorylation increased cocaine-seeking behavior. All of this suggests that incubation of cocaine craving is mediated by time-dependent increases in the responsiveness of the central amygdaloid ERK pathway to cocaine cues. Central amygdaloid glutamate is also involved [ ]. As the amygdala is critical to cue-triggered relapse [ ] and the nucleus accumbens to drug- and stress-triggered relapse [ , , , ], these findings are important.

    They are especially important in the context of synaptic remodeling. Addiction obviously involves learning stimulus-reward learning being an important substrate in the acquisition of addiction; stimulus-response learning being an important substrate in relapse responding.

    Beginning with the pioneering neuropsychological work of Hebb in the s [ ], it has been widely appreciated that the neural substrate of learning must involve synaptic remodeling. In recent decades it has come to be appreciated that two important mechanistic substrates of synaptic remodeling are long-term potentiation LTP and long-term depression LTD [ ].

    LTP and LTD have been demonstrated to be produced by addictive drugs in precisely those brain loci implicated in reward and relapse - nucleus accumbens [ — ], amygdala [ , ], and hippocampus [ — ].

    As a neuronal trophic factor, BDNF may be involved in - indeed, may be an underlying mechanism for - the synaptic remodeling in the nucleus accumbens, amygdala, and hippocampus that may underlie the incubation of craving phenomenon and, by extension, the development of increased vulnerability to relapse among human addicts. Furthermore, such synaptic remodeling may underlie the very transition to the unregulated and compulsive drug-seeking behavior that characterizes addiction, inasmuch as this transition is associated with impaired glutamate receptor-dependent brain LTD [ ].

    If this be true, an entirely new strategy for anti-addiction, anti-craving, anti-relapse medication development could emerge - medications that target BDNF-mediated synaptic remodeling in the nucleus accumbens, amygdala and hippocampus. Of course, such medication development need not be mutually exclusive to anti-craving and anti-relapse medication development predicated on other neural mechanistic strategies - e.

    From all of the above, it may be appreciated that a number of important phenomena are often confused, even among medical and other professionals who deal routinely with drug addiction and with patients impacted by it. It is important to disentangle these phenomena. Second, abusive drug-seeking and drug-taking behavior becomes, with time, habit-driven rather than reward-driven.

    This transition arguably defines the onset of addictive drug-seeking behavior, and is arguably referable to a transition of the neural locus of control over drug-seeking behavior from the ventral tegmental-ventral neostriatal axis medial ventral tegmental area and nucleus accumbens to a more dorsolateral overlying set of neural loop circuits involving the substantia nigra and dorsolateral neostriatum.

    Third, addiction and physical dependence are different phenomena - the first referable to forebrain mesolimbic and mesostriatal reward-related and habit-related circuitry; the second referable to neural loci in the vicinity of the midbrain locus coeruleus and the dorsal mesencephalon. Some drugs are addictive without producing physical dependence; other drugs produce physical dependence without being addictive.

    Fourth, opiate- or cannabinoid-induced analgesia are distinct phenomena - having nothing to do with opiate-induced or cannabinoid-induced addictive drug-taking behavior. Opiate-induced analgesia is referable to action on neural mechanisms on peripheral nociceptive neurons, spinal cord dorsal horn pain-gates, dorsal root ganglia, brain-stem tegmental spinothalamic and neospinothalamic pain relay nuclei, and the periaqueductal gray matter of the brain-stem.

    Cannabinoid-induced analgesia is referable to action on neural mechanisms on peripheral nociceptive neurons, spinal cord dorsal horn pain-gates, dorsal root ganglia, and brain-stem tegmental spinothalamic and neospinothalamic pain relay nuclei.

    Importantly, appropriate medical use of opiates or cannabinoids for the treatment of pain carries extremely low risk of inducing addiction see further discussion below.

    Far too many physicians and other health care professionals have uncritically accepted the false allegation that opiate addiction can be induced by medically appropriate long-term treatment of pain with opiates [ ]. This leads to medical malpractice and the ethically unacceptable undertreatment of pain in millions of suffering patients.

    Equally unacceptably, this misconception permeates the law-enforcement, judicial, and legislative branches of government - with many egregious consequences. It also permeates ordinary society, causing many pain patients to refuse medically appropriate indeed, often essential treatment of pain - with often horrible consequences for quality of life.

    The truth of the matter is that, although some chronic pain patients are at risk for addiction, they are a very small percentage of the total number of chronic pain patients. Reliable evidence exists to support the contention that appropriate medical treatment of pain with opiates does not incur a risk of addiction in the vast majority of pain patients. First, chronic pain inhibits opiate-seeking behavior in animal models [ , ].

    Third, chronic pain inhibits reward signaling through the ventral tegmental area-nucleus accumbens reward circuitry, as assessed using the electrical brain-stimulation reward animal model [ , ]. Fourth, chronic pain inhibits the development of opiate-induced physical dependence [ , ].

    At present, a number of effective pharmacotherapies exist for the treatment of drug addiction. The opiate agonist methadone has been shown to be effective for opiate addiction [ , ], as has the partial opiate agonist buprenorphine [ — ]. Even heroin itself has been used successfully as a maintenance pharmacotherapy for opiate addiction [ ]. For highly motivated individuals with a strong desire to achieve abstinence from the opiate-taking habit, the long-acting opiate antagonist naltrexone has proven effective [ , ].

    Naltrexone has also proven to be effective for some alcoholics wishing to quell alcohol cravings [ — ]. Acamprosate is also claimed to have effectiveness against alcohol addiction [ ], as is the GABA-B receptor agonist baclofen [ — ]. This work with baclofen in preclinical animal models of addiction suggests a broad potential clinical efficacy for baclofen in treating addiction at the human level, but thus far only preliminary studies on human patients have been undertaken with baclofen [ ].

    Nicotine replacement therapy e. Yet, none of the above-listed pharmacotherapies is effective for a majority of the patients for whom the therapy should produce clinical benefit, and with the possible exception of baclofen, none of the above therapies is broadly effective against multi-drug addiction. Thus, there is real need for further medication development in the field of addiction medicine.

    The fact that cocaine and other psychostimulants derive their addictive efficacies from inhibiting the synaptic reuptake of dopamine or by causing presynaptic release of dopamine in the reward-related and relapse-related nucleus accumbens makes the development of slow-onset long-acting dopamine transporter inhibitors for treatment of psychostimulant addiction rational [ — ].

    The fact that inhibition of medium spiny GABAergic neurons in the nucleus accumbens may constitute a final common pathway for addictive-drug-induced reward [ ] makes development of GABAergic agonist therapies rational. As noted above, extraordinary promise has been seen with the GABA-B receptor agonist baclofen in preclinical animal models [ — ], with some supporting evidence from preliminary human use [ — ].

    Similarly, considerable promise has been seen with the indirect GABA agonist gamma-vinyl GABA in preclinical animal models [ — ], again with some supporting evidence from preliminary human trials [ ]. The fact that cannabinoids activate, and endocannabinoids mediate, brain reward and brain relapse circuits and substrates [ , , , — ] provides a mechanistic rationale for the development of cannabinoid CB1 receptor antagonists as anti-addiction medications [ 40 , — ]. The facts that glutamate circuits innervate and modulate brain reward mechanisms [ — ], and that glutamatergic circuits mediate at least some forms of relapse to drug-seeking behavior [ , ], make the development of drugs acting on the glutamate circuitry of the brain attractive as potential anti-addiction medications [ 41 , — ].

    The fact that CRF is the neurotransmitter of one of the stress-triggered relapse circuits in the brain makes the development of anti-CRF medications attractive [ , — ]. Addiction medicine has made enormous strides in recent decades. Arguably, addiction medicine has animal models with face-validity, predictive-validity, and construct-validity that are as good or better than animal models in other medical specialties.

    More has been learned in the last few decades about the neurobiology of addiction, craving, and relapse than would have been thought possible when Olds and Milner first described the reward circuits of the brain in [ 6 ].

    These tremendous advances in knowledge bode well for the development of definitive therapies for an illness that is as old as recorded human history. Diagram of the brain-reward circuitry of the mammalian laboratory rat brain, with sites at which various addictive drugs act to enhance brain reward mechanisms and thus to produce drug-seeking behavior, drug-taking behavior, drug-craving, and relapse to drug-seeking behavior.

    After [ 1 ]. Enhancement of electrical brain-stimulation reward by an addictive drug nicotine and attenuation of that enhancement by a highly selective dopamine D3 receptor antagonist SBA.

    After [ 38 ]. Minute-by-minute measurements - using in vivo brain microdialysis - of extracellular nucleus accumbens dopamine in a laboratory rat voluntarily self-administering intravenous heroin.

    The thick dashed vertical lines indicate the start left thick dashed vertical line and end right thick dashed vertical line of availability of heroin. Thus, the animal appears to self-administer the addictive drug to enhance extracellular nucleus accumbens dopamine and to keep it within a preferred and elevated range — thus keeping hedonic tone enhanced over its normal basal state when unaffected by addictive drugs.

    After [ 49 , 50 ]. Intravenous cocaine self-administration in monkeys of differing social hierarchy status within the social group. The solid black circles indicate monkeys with low social status; the open circles indicate moneys with high social status. Low social status produces a dopamine deficit in the mesotelencephalic reward circuitry, and a proclivity to self-administer addictive drugs. After [ 77 ]. Initially, animals are allowed to freely self-administer intravenous cocaine in the presence of environmental cues that indicate the availability of cocaine.

    At the point indicated by the first vertical dashed line, the cue lights are turned off and saline is substituted for cocaine in the infusion apparatus. This causes immediate and robust relapse to intense levels of drug-seeking behavior although the infusion apparatus is filled with saline, as during the extinction and detoxification stage. After [ 37 ]. Incubation enhancement of drug-craving with the mere passage of time. Drug-seeking behavior measured as extinction responding.

    Drug-seeking behavior measured as cue-triggered relapse to drug seeking behavior. After [ ]. The author is indebted to Ms. Stacey Saunders for editorial assistance, and to Dr. Zheng-Xiong Xi for assistance with the figures. National Center for Biotechnology Information , U. Author manuscript; available in PMC Aug Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Adv Psychosom Med. See other articles in PMC that cite the published article.

    Addiction - An Ages-Old Medical and Societal Problem The abusive use of addictive drugs is a medical and societal problem as old as recorded human history. The Intense Nature of Brain-Stimulation Reward Electrical brain-stimulation reward is remarkable for the intensity of the reward and reinforcement produced [ 1 ]. Using Electrical Brain-Stimulation Reward to Assess the Degree of Reward Evoked by Addictive Drugs In the half-century since the initial discovery of the brain-stimulation reward phenomenon, a number of techniques have been developed to quantify the degree of reward enhancement produced by addictive drugs.

    Activation of Brain Reward Substrates by Direct Intracerebral Microinjection of Addictive Drugs Just as systemic injections of addictive drugs enhance brain reward substrates, so too does intracerebral microinjection. Open in a separate window. Genetic and Experiential Contributions to the Disease of Addiction As noted above, it is relatively easy to selectively breed laboratory animals for the behavioral phenotype of drug-seeking behavior the behavioral phenotype breeds true after about 15 generations in laboratory rodents.

    Contributions to Addiction Vulnerability at the Animal Level Considerable research has been devoted to identifying individual characteristics that predict high vulnerability to drug-seeking behavior in animals, with considerable success.

    Contributions to Addiction Vulnerability at the Human Level A wide variety of individual characteristics that predict high vulnerability to drug addiction at the human level have also been identified. Neurobiologically-Measured Aberrations in Brain Reward Function as Addiction Vulnerability Factors Volkow and colleagues have carried out positron emission tomography studies of dopaminergic function in brains of awake human subjects, using displacement of [ 11 C]raclopride as a measure of extracellular dopamine.

    The Natural Progression of the Disease of Addiction The disease of addiction is characterized by progressive stages. Addiction and Physical Dependence - Different Phenomena and Different Brain Substrates It is very important to realize that addiction and physical dependence are different phenomena with different underlying brain substrates [ 3 ]. Persistent Drug Craving and Relapse - The Real Clinical Problem in Addiction Any cigarette smoker who has tried to quit the smoking habit knows that the real clinical problem in addiction is persistent drug craving and relapse.

    Neuroanatomy and Neurochemistry of Brain Circuits Mediating Relapse By a variety of research strategems - including combining intracerebral microinjections or anatomically discrete intracerebral lesions with one of the animal relapse models outlined above - it has been possible to discover the brain circuits underlying relapse to drug-seeking behavior triggered by the three classical relapse triggers.

    Incubation of Craving - An Animal Model of the Extreme Fragility of Control Over Vulnerability to Relapse in Human Addicts In , Grimm and colleagues described a compelling phenomenon at the laboratory animal level - that relapse vulnerability to drug-seeking behavior incubates grows more intense with the mere passage of time [ ].

    The Disentanglement of Important Addiction-Related Phenomena From all of the above, it may be appreciated that a number of important phenomena are often confused, even among medical and other professionals who deal routinely with drug addiction and with patients impacted by it.

    A Final Comment Addiction medicine has made enormous strides in recent decades. Acknowledgments The author is indebted to Ms. What we have learned about addiction from animal models of drug self-administration.

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    Reward system

    The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic . which antagonizes ΔFosB- and other APmediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22– Apr 1, the brain's circuitry, a reprogramming of the reward system, and lasting, . For example, if the drug inhibits or blocks the activity of a particular. As noted earlier, substances of abuse affect the brain reward pathway, which is made .. By blocking the effects of adenosine, caffeine leads increased firing of.



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