Addictive States Research Articles

Mechanisms for the Regulation of State Changes in the Central Nervous System

Current work on central nervous system (CNS) mechanisms underlying behavior has expanded from consideration of specific sensory codes or motor controls to the analyses of global CNS states. These include states of arousal, alertness, attention, emotional states regarding emotion and motivation, and states of addiction, which carry great importance for medicine and public health. In this brief introduction, orderly neuroanatomical concepts of forebrain pathways regulating motivated behaviors are presented. Neuropeptides often coordinate large sets of responses associated with an individual behavioral state. Here, we emphasize some of the central roles for opioid peptides. We also mention a few outstanding unanswered questions related to this area of neuroscience.

Enhancement of endocannabinoid neurotransmission through CB1 cannabinoid receptors counteracts the reinforcing and psychostimulant effects of cocaine

Cannabinoids, in contrast to typical drugs of abuse, have been shown to exert complex effects on behavioural reinforcement and psychomotor function. We have shown that cannabinoid agonists lack reinforcing/rewarding properties in the intracranial self-stimulation (ICSS) paradigm and that the CB1 receptor (CB1R) agonist WIN55,212-2 attenuates the reward-facilitating actions of cocaine. We sought to determine the effects of the endocannabinoid neurotransmission enhancer AM-404 (1, 3, 10, 30 mg/kg) on the changes in ICSS threshold and locomotion elicited by cocaine and extend the study of the effects of WIN55,212-2 (0.3, 1, 3 mg/kg) on cocaine-induced hyperlocomotion. AM-404 did not exhibit reward-facilitating properties, and actually increased self-stimulation threshold at the highest dose. Cocaine significantly reduced self-stimulation threshold, without altering maximal rates of responding. AM-404 (10 mg/kg) attenuated this action of cocaine, an effect which was reversed by pretreatment with the selective CB1R antagonist SR141716A. WIN55,212-2 decreased locomotion at the two highest doses, an effect that was blocked by SR141716A; AM-404 had no effect on locomotion. Cocaine caused a significant, dose-dependent increase in locomotion, which was reduced by WIN55,212-2 and AM-404. SR141716A blocked the effects of WIN55,212-2 and AM-404 on cocaine-induced hyperlocomotion. SR141716A alone had no effect on ICSS threshold or locomotion. These results indicate that cannabinoids may interfere with brain reward systems responsible for the expression of acute reinforcing/rewarding properties of cocaine, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for the treatment of psychostimulant addiction and pathological states associated with psychomotor overexcitability.

Smokers' brains compute, but ignore, a fictive error signal in a sequential investment task

Addicted individuals pursue substances of abuse even in the clear presence of positive outcomes that may be foregone and negative outcomes that may occur. Computational models of addiction depict the addicted state as a feature of a valuation disease, where drug-induced reward prediction error signals steer decisions toward continued drug use. Related models admit the possibility that valuation and choice are also directed by 'fictive' outcomes (outcomes that have not been experienced) that possess their own detectable error signals. We hypothesize that, in addiction, anomalies in these fictive error signals contribute to the diminished influence of potential consequences. Using a simple investment game and functional magnetic resonance imaging in chronic cigarette smokers, we measured neural and behavioral responses to error signals derived from actual experience and from fictive outcomes. In nonsmokers, both fictive and experiential error signals predicted subjects' choices and possessed distinct neural correlates. In chronic smokers, choices were not guided by error signals derived from what might have happened, despite ongoing and robust neural correlates of these fictive errors. These data provide human neuroimaging support for computational models of addiction and suggest the addition of fictive learning signals to reinforcement learning accounts of drug dependence.

Evaluation of Effectiveness of Integrated Intervention Program in Improving Drug Addicts' Psychological Health

To investigate the social mental state of drug addicts in a compulsive drug abuse treatment center; evaluate the effectiveness of integrated program for the prevention of abuse relapse and improvement of drug addicts' psychological health. The study subjects were addicts from the Wuhan Compulsive Drug Abuse Treatment Center between October 2003 and June 2004, who satisfied the inclusion criteria. A non-randomized control-intervention study design was adopted. Volunteers willing to take part in intervention were put into the intervention group with their full awareness and willingness to prevent drug abuse relapse. The control group was composed of the addicts who were willing to prevent relapse and to be followed up after their discharge. The effectiveness of the integrated intervention program in promoting addicts' psychological health: before the intervention, the scores of Self-Rating Anxiety Scale (SAS), the positive and negative dimensionalities of Simple Coping Style Questionnaire (SCSQ) and Chinese Perceived Stress Scales (CPSS) had no significant differences between the intervention group and the control group. After the intervention, except that the SCSQ's positive dimensionality in the intervention group was significantly higher than that in the control group, other indices in the intervention group were lower. Before and after the intervention, the psychological health level in both the groups was lower than that in the normal population; there were significant differences between addicts and normal subjects in regards with all of the indices above. Drug abuse was associated closely with addicts' social mental factors. The integrated intervention program can alleviate anxiety and stress, reduce co-morbid mental disorders and effectively improve their coping style. In conclusion, the program can promote addicts' psychological health significantly.

CREB Modulates the Functional Output of Nucleus Accumbens Neurons: A CRITICAL ROLE OF N-METHYL-d-ASPARTATE GLUTAMATE RECEPTOR (NMDAR) RECEPTORS

Nucleus accumbens (NAc) medium spiny neurons cycle between two states, a functionally inactive downstate and a functionally active upstate. Here, we show that activation of the transcription factor cAMP-response element-binding protein (CREB), a common molecular response to several drugs of abuse, increases both duration of the upstate and action potential firing during the upstate. This effect of CREB is mediated by enhanced N-methyl-d-aspartate glutamate receptor (NMDAR) function: increased CREB activity increases both NMDAR-mediated synaptic currents and surface level of NMDARs, while inhibition of NMDARs abolishes the effect of CREB on upstate duration. Furthermore, mimicking the effect of CREB by pharmacological enhancement of NMDAR function in the NAc in vivo suppressed novelty- and cocaine-elicited locomotor activity. These findings suggest that by enhancing NMDAR-mediated synaptic transmission, CREB activation promotes the proportion of time NAc neurons spend in the upstate. This effect, along with the CREB enhancement of NAc membrane excitability (Dong, Y., Green, T., Saal, D., Marie, H., Neve, R., Nestler, E. J., and Malenka, R. C. (2006) Nat. Neurosci. 9, 475-477), may counteract drug-induced maladaptations in the NAc and thus ameliorate the addictive state.

Application of the Sensory Contact Model for Pharmacological Studies under Simulated Clinical Conditions

AbstractThe sensory contact model allows forming different psycho-pathological states (anxious depression, catalepsy, social withdrawal, pathological aggression, cognition disturbances, anhedonia, addictive states etc.) produced by repeated agonistic interactions in male mice and investigating the therapeutic and preventive properties of any drug as well as its efficiency under simulated clinical conditions. This approach can be useful for a better understanding of the drugs’ action in different stages of disease development in individuals. It is suggested that this behavioral approach and pharmacological designs may be applied for the screening of novel psychotropic drugs.

The Orbitofrontal Cortex, Impulsivity, and Addiction

The association between impulsivity and addiction is currently a topic of intense research interest. Investigations into the neurobiological basis of aspects of impulse control have revealed some striking parallels between the brain circuitry and neurochemical systems implicated in drug dependence and impulsive behavior. Both processes are heavily regulated by limbic corticostriatal circuits including the orbitofrontal cortex (OFC) and nucleus accumbens (NAC), and are modulated by dopamine (DA) and serotonin (5-HT). Hypoactivity within the OFC has been observed in recently abstinent cocaine users, and this is thought to contribute to the cognitive deficits associated with drug abuse, including impairments in impulse control. However, the neurobiological mechanisms underlying these functional and behavioral deficits are unclear. In parallel to observations made in the NAC, recent data indicate that chronic cocaine use also induces the transcription factor DeltaFosB in the OFC and that this plays a role in the cognitive sequelae of chronic cocaine administration. In particular, DeltaFosB appears to be involved in the development of tolerance to the disruptive effects of acute cocaine on impulsivity and motivation observed after repeated cocaine administration. Increased DeltaFosB also contributes to increased impulsivity during withdrawal from the drug. Both effects could be attributed to the up-regulation of local inhibitory processes in the OFC after over-expression of DeltaFosB and chronic cocaine treatment. Through integrating what is known of the interaction between addictive drugs and impulsivity at the neural, neurochemical, and molecular level, novel insight may be obtained into the multi-faceted regulation of the addicted state.

HIV risk behavior among injection drug users in Tehran, Iran

Iran faces parallel human immunodeficiency virus (HIV) and injection drug use epidemics; more than 62% of known HIV cases occur among injection drug users (IDU). We conducted a formative study of IDU in Tehran to explore risk behavior in the wake of the recent harm reduction efforts. Key informant interviews (n = 40), focus group discussions (nine groups of IDU, n = 66) and a review of existing published and unpublished literature were conducted. Participants included IDU, physicians, policy makers, police, IDU advocates and their families. IDU were diverse in gender, education, income and neighborhood of residence. Interviews were transcribed and analyzed using grounded theory. A typology of IDUs in Tehran, categorized according to self-defined networks as well as HIV risks, is presented. This categorization is based on the groups identified by IDUs, compared to those identified by other key informants, and on a secondary data review. Homeless, female, young IDU and users of a more potent form of heroin were identified as having increased risks for HIV. Participants described shortening transitions from smoked opium to injected opiates. Whereas a majority of participants considered needle sharing less common than previously, sharing continues in locations of group injection, and in states of withdrawal or severe addiction. System-wise barriers to harm reduction were discussed, and include the cost or stigma of purchasing needles from pharmacies, over-burdened clinics, irregular enforcement of laws protecting IDU and lack of efforts to address the sexual risks of IDU. This research is one of the first to describe a diversity of IDU, including women and higher socio-economic class individuals, in Tehran. While efforts in harm reduction in Iran to date have been notable, ongoing risks point to an urgent need for targeted, culturally acceptable interventions.

Homers regulate drug-induced neuroplasticity: Implications for addiction

Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

A Novel Molecule “Shati” Is Involved in Methamphetamine-Induced Hyperlocomotion, Sensitization, and Conditioned Place Preference

Drug addiction places an enormous burden on society through its repercussions on crime rate and healthcare. Repeated exposure to drugs of abuse causes cellular adaptations in specific neuronal populations that ultimately can lead to a state of addiction. In the present study, we have identified a novel molecule "shati" from the nucleus accumbens (NAc) of mice treated with methamphetamine (METH) using the PCR-select complementary DNA subtraction method. Moreover, we investigated whether shati is involved in METH-induced hyperlocomotion, sensitization, and conditioned place preference (CPP). METH induced expression of shati mRNA dose dependently via dopamine (DA) receptors. We prepared antibodies against shati and, using them, found shati to be expressed in neuronal cells of the mouse brain. Treatment with the shati antisense oligonucleotide (shati-AS), which significantly inhibited the expression of shati mRNA, enhanced the acute METH response, METH-induced behavioral sensitization, and CPP. Blockage of shati mRNA by shati-AS potentiated the METH-induced increase of DA overflow in the NAc and the METH-induced decrease in synaptosomal and vesicular DA uptake in the midbrain. These results suggest that a novel molecule shati is involved in the development of METH-induced hyperlocomotion, sensitization, and CPP. The functional roles of shati in METH-regulated behavioral alternations are likely to be mediated by its inhibitory effects on the METH-induced increase of DA overflow in the NAc and the METH-induced decrease in DA uptake in the midbrain.

The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine

Many central stimulating drugs have a pronounced stimulatory effect on striatal and cortical activity which is associated to enhanced function of mesencephalic dopaminergic neurons. Mesencephalic KCNQ (also termed K v7) potassium channels suppress the basal activity of dopaminergic neurons in the substantia nigra and ventral tegmental area. These regions have extensive dopaminergic projections to the striatum and cortex, and positive modulation of KCNQ channel function may therefore potentially reduce the reinforcing impact of central stimulating drugs. We studied the effects of the principal neuronal KCNQ channel opener, retigabine, in rats exposed acutely to cocaine, methylphenidate (dopamine reuptake inhibitors) or phencyclidine (PCP, a psychotomimetic NMDA receptor antagonist). Retigabine (≥ 1.0 mg/kg) inhibited cocaine, methylphenidate and PCP-stimulated locomotor activity. Also, retigabine reduced spontaneous locomotor activity. The inhibitory effect of retigabine on psychostimulant-induced locomotor activity was accompanied by a marked reduction in c-Fos expression, in particular the nucleus accumbens and primary motor cortex were responsive to retigabine pre-treatment. Notably, retigabine also reduced basal extracellular levels of striatal dopamine metabolites and partially prevented dopamine overflow in the striatum induced by dopamine reuptake blockade. In combination, these data suggest that retigabine reduces striatal and cortical excitability, thereby attenuating excitatory effects of central stimulating drugs in dopamine-rich areas of the rat forebrain. KCNQ channel openers may therefore be of potential relevance in the treatment of addiction states caused by abuse of psychostimulants.

Psychological mood state of opiate addicted women during pregnancy and postpartum in comparison to non-addicted healthy women

Opiate addiction has been widely documented to have a negative impact on pregnancy course and outcome. The unfavorable psychosocial situation of addicted women predispose for poor processing of the physiological and psychological demands of pregnancy. Thus the aim of our study was to investigate the psychological mood state of opiate addicts during pregnancy and postpartum in comparison to healthy women. In a case-controlled, prospective, longitudinal study, nine pregnant opiate addicts and nine healthy pregnant women matched by age, level of education and gestational age at birth were interviewed in the third trimester of pregnancy and postpartum. Standardized questionnaires and inventories for assessment of the general psychopathology and emotional state, the perceived self-efficacy expectancy, the psychosocial adaptation to pregnancy and the fear of delivery, respectively were applied. Addicted women achieved significantly higher scores in the test assessing general psychopathology and emotional state before delivery compared to abstinent women. Interestingly this difference was unverifiable postpartum. This study reaffirms the presumption of a disadvantageous psychological condition in pregnant opiate addicts in comparison to healthy pregnant women for the first time in a prospective case-control study design.

Mental Health and Addiction State of Ethnocultural/Racial Communities

Migration has become a common trend and an expected fact of life among the majority of underdeveloped and developing nations. Immigration exposes newcomers to a new experience, an acculturation. Acculturation is not always a successful process and may become stressful. Acculturative stress can manifest itself in different ways. Many researchers have suggested a connection between immigration and increased risk of developing mental health/addiction problems. Studies have shown that ethnocultural/racial groups have experienced difficulties in gaining access to mental health and addiction care services. This background paper is prepared to 1) discuss the mental health & addiction state of Ethnocultural/racial communities, and 2) offer working recommendations.

Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy

There has been considerable progress in the systemic treatment of cancer because of the rapid development and clinical application of molecular targeted agents. Although patients with a particular type and stage of cancer are often treated as a single group, more-specific therapy is being considered, as subsets of these patients who are more likely to benefit from treatment with particular agents are being identified. We previously introduced the concept of 'oncogene addiction' to explain how some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities are dependent on or 'addicted' to one or a few genes for both maintenance of the malignant phenotype and cell survival. Thus, reversal of only one or a few of these abnormalities can inhibit cancer cell growth and in some cases translate to improved survival rates. This review summarizes current experimental and clinical evidence for the concept of oncogene addiction and describes molecular mechanisms that may explain this phenomenon. In addition, we discuss how high-throughput screening methods, including gene-expression profiling and proteomics, and emerging methods for analyzing complex cellular networks can be used to identify the state of oncogene addiction, i.e. the 'Achilles' heel,' in specific cancers. Finally, we discuss the use of molecular targeted agents in combination with other anticancer agents as a strategy to optimize therapy and prevent disease recurrence.

Commentary on: Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance by Griffiths et al.

The study by Griffiths et al. is noteworthy both for the rigorousness of its design and execution, as well as the clarity of its results. It demonstrates that psilocybin can be safely studied in normal human beings who do not have a history of hallucinogenic drug use. As would be expected, during the psilocybin session participants showed perceptual changes and labile mood. It is striking that majority of the participants reported 2 months later that the psilocybininduced experience was personally very meaningful and spiritually significant. Indeed, most of them rated the psilocybin-induced experience as one of the top five most important experiences in their life. It is especially notable that participants reported that the drug produced positive changes in attitudes and behaviors well after the sessions, and these self-observations were consistent with ratings by friends and relatives. These participants were well-prepared for the psilocybin experience by an experienced monitor, who expressly stated that psilocybin might produce increased personal awareness and insight. However, it is clear that the effects of psilocybin were more than expectancy effects because the active drug control condition (40 mg of methylphenidate) did not produce similar effects on ratings of significance or on measures of spirituality, positive attitude, or behavior. The term psychedelic, when applied to drugs, implies that the drug experience is “mind-expanding.” The paper by Griffiths et al. illustrates the accuracy of this description for psilocybin, and I hope that this landmark paper will also be “field-expanding.” The report clearly demonstrates that we can objectively study the experiences reported by many to be profoundly spiritual and meaningful, and that we can investigate the long-term positive consequences for the individual’s attitudes and behavior. It will open the way to study the neural mechanisms responsible for these drugaltered states of consciousness. It is entirely conceivable that psychotropic agents that produce these experiences may have a role in the treatment of addictive states. Spirituality has long been a major component of the 12step approach to the treatment of alcoholism and other forms of drug addiction. Although the investigations of LSD for the treatment of alcoholism failed to show any clear-cut significant beneficial effects, the possibility that a spiritual experience, such as that reported in the present study, might be useful cannot be discounted. The set and setting in which the drug is administered may dramatically alter the drug experience. In the present study by Griffiths et al., the set was well-established for a positive experience by the preparatory sessions with the monitor, and the setting was one that was designed to produce an introspective state. This may be an important determinant of the experience and could well alter any possible therapeutic efficacy. The possibility of easing the ennui and anguish of impending death with agents such as psilocybin is also suggested in the study by Kast (1966) and those that are reviewed in the commentary of Professor Nichols. It is likely that psilocybin might have the same salutary effects. This is not an insignificant issue especially considering the large numbers of aging individuals in our society who may be in need of hospice care. In summary, I hope that this paper by Griffiths et al. renews interest in a fascinating and potentially useful class of psychotropic agents. The misuse of these substances that led to their control in Schedule I of the Controlled Substances Act cannot be allowed to continue to curtail their use as tools for understanding the neurobiology of Psychopharmacology DOI 10.1007/s00213-006-0460-x

Why Addiction Has a Chronic, Relapsing Course. The Neurobiology of Addiction

Approximately 200 million people in the United States have an addiction disorder that significantly disrupts employment, family relationships, financial stability, and personal health. As a result, addiction has become one of the most critical health care challenges presently facing the American health care system. Research in the last five years has provided substantial evidence that addiction is a neuro-biological condition rooted in genetic factors. During the addiction process neurologic changes occur that are responsible for tolerance, craving, and relapse. It appears that once addiction becomes chronic, the brain enters an addicted state that may be irreversible without pharmaceutical intervention. Such alterations in neurochemistry-rather than poor volitional control-account for why addiction is characterized by a chronic, relapsing-remitting course. This paper discusses (a) the neurobiological factors underlying the addiction process, (b) available pharmaceutical treatment, and (c) how recent research regarding the neurobiology of addiction affects occupational therapy's role in addiction rehabilitation. A case study follows that illustrates how occupational therapists can contribute to addiction intervention.

Changes in the Expression of G Protein-Coupled Receptor Kinases and β-Arrestins in Mouse Brain During Cannabinoid Tolerance: A Role for Ras-ERK Cascade

The focus of our study was to determine the role of G protein-coupled receptor kinases (GRKs) and beta-arrestins in agonist-induced CB1 receptor modulation during cannabinoid tolerance and their dependence from the extracellular signal-regulated kinase (ERK) cascade. In wild-type mice, chronic Delta9-tetrahydrocannabinol (THC) exposure significantly activated specific GRK and beta- arrestin subunits in all the considered brain areas (striatum, cerebellum, hippocampus, and prefrontal cortex), suggesting their involvement in the adaptive processes underlying CB1 receptor downregulation and desensitization. These events were ERK-dependent in the striatum and cerebellum, because they were prevented in the genetic (Ras-GRF1 knockout mice) and pharmacological (SL327-pretreated mice) models of ERK activation inhibition, whereas in the hippocampus and prefrontal cortex, they appeared to be mostly ERK-independent. In the latter areas, ERK activation after chronic THC increased the transcription factors cyclic adenosine monophosphate response element-binding protein and Fos B as well as a downstream protein known as brainderived neurotrophic factor. As a whole, our data suggest that in the striatum and cerebellum, THC-induced ERK activation could represent a key signaling event to initiate homologous desensitization of CB1 receptor, accounting for the development of tolerance to THC-induced hypolocomotion. In the prefrontal cortex and hippocampus, THC-induced alteration in GRKs and beta-arrestins primarily depends on other kinases, whereas ERK activation could be part of the molecular adaptations that underlie the complex behavioral phenotype that defines the addicted state.

Opioids and addiction: Emerging pharmaceutical strategies for reducing reward and opponent processes

Conventional strategies for treating opioid abuse include cognitive/behavioral therapy, maintenance therapy and managed withdrawal. These strategies deal with the addictive state, but much effort has shifted toward developing preventative measures. One approach is to reduce the rewarding properties of abused drugs, which in the case of prescription pharmaceuticals such as opioid analgesics is clearly a worthwhile endeavor. First, we will review recent studies demonstrating that mice lacking various G-protein coupled receptors and their ligands show diminished opioid reward. These studies point to considerable interdependence among different neuromodulatory systems for establishing drug reward. Thus, we will highlight the potential for combining opioids with other receptor targets to maximize analgesia and minimize reward in order to prevent the establishment of euphoric memories and opponent processes driving addiction. A more complex issue is treating opioid addicts where many physiological shifts have developed to oppose the acute drug effects. These opponent processes occur both at the cellular level (e.g. adenylate cyclase supersensitivity) and behavioral level (e.g. dysphoria and hyperalgesia). Evidence will be presented showing that even weak opioid agonists can effectively induce the intracellular process of adenylate cyclase supersensitivity. Furthermore, opioid-induced hyperalgesia, a behavioral opponent process, may manifest differently depending on the pain stimulus, and may require a priming drug dose in some cases. Environmental stress interacts with these opponent processes and drives relapse and thus, is another variable that needs to be considered in the development of innovative pharmacotherapy options for opioid addicts.

Extracellular signal‐regulated kinases (ERKs) modulate cocaine‐induced gene expression in the mouse amygdala

It is known that acute cocaine administration activates the extracellular signal-regulated kinase (ERK) pathway in the striatum, and results in transcription and translation of immediate early genes (IEGs). In the present study we investigated a possible involvement of ERK in the regulation of IEG expression in the amygdala, another brain structure known to be related to an addicted state. The patterns of cocaine-induced c-Fos, JunB and Zif268 protein expression were investigated, using an immunohistochemical approach, within distinct nuclei of the amygdala, either in the presence or absence of a selective inhibitor of the ERK pathway, SL327. Although these IEGs were similarly activated in the various nuclei of the amygdala after acute administration of cocaine, they showed different patterns after chronic injections. They also showed selective sensitivities to ERK inhibition. In particular, whereas c-Fos and JunB expressions were augmented following chronic cocaine treatment, as compared with acute treatment, Zif268 expression was decreased by this chronic treatment. Additionally, chronic blocking of ERK activation affected cocaine-induced c-Fos and JunB but not Zif268 expression. Thus, the differential involvement of ERK in chronic vs. acute regulation of IEGs may account for its specific role in addiction-related behavioral alterations, such as sensitization and tolerance.

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

Despite large numbers of studies describing neuroadaptations caused by chronic cocaine exposure, there remains considerable uncertainty as to whether alterations in dopamine (DA) neurotransmission are responsible for progression into an addicted state. High-intake, 24-h access cocaine self-administration (SA, 10 days) followed by an extended (7 days), but not 1 day deprivation period produces an increased motivation to SA cocaine as measured by a progressive ratio protocol. Following binge cocaine SA and deprivation, the status of DA terminals in the nucleus accumbens (NAc) was investigated using microdialysis in freely moving rats and voltammetry in brain slices. At 1 and 7 days following binge cocaine SA, baseline extracellular DA concentrations in the NAc core were decreased by 40 and 55% of control levels, in the 1 and 7 day deprivation groups, respectively. Acute cocaine (1.5 mg/kg, i.v.) administration increased extracellular DA (350%) in the NAc core of naïve animals but failed to significantly increase DA at 1 or 7 days following binge cocaine SA. The shell of the NAc showed a similar lack of effect of cocaine. Analysis of DA terminals in brain slices showed that cocaine was markedly less effective in inhibiting DA uptake at 1 and 7 days of cocaine deprivation (max effect 40% of control). Electrically stimulated DA release was decreased at 1 day and further decreased at 7 days of deprivation (67 and 49% of control, respectively). The rate of DA uptake was increased (150% of control) following binge SA, irrespective of deprivation period. Finally, presynaptic autoreceptors were subsensitive at both time points, as measured by the ability of quinpirole, a D2-like DA receptor agonist, to inhibit DA release. Thus, the NAc was hypodopaminergic and DA terminals were less sensitive to cocaine following binge cocaine SA and deprivation.