Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function

RATIONALE: The transition from initial drug use to drug addiction has been proposed to result from an allostatic decrease in reward function driven by an overactivation of brain antireward processes. OBJECTIVES: How decreased reward function explains compulsive drug use is not entirely clear at present, and is still a subject for debate. METHODS: We present a quantitative model of cocaine self-administration that integrates pharmacokinetic, pharmacodynamic, and motivational factors to address this question. The model assumes that reward system responsivity is a homeostatically regulated process where the desired level of responsivity (called the reward set point) is initially different from the baseline level. The reduction or correction of this difference or error in reward function would drive cocaine self-administration. RESULTS: Theoretical data obtained by computer simulation fit the experimental data obtained in animals self-administering cocaine (i.e., the within-session pattern of self-injections, the shape and curvature of the dose-injection function, the nonlinear relationship between drug intake and regulated drug effects). Importantly, simulation of an allostatic decrease in reward system responsivity exacerbates the initial error that drives self-administration, thereby increasing both the intake of, and the motivation for, the drug. This allostatic change manifests as a vertical shift in the dose-injection function similar to that seen in animals with escalating cocaine self-administration. CONCLUSIONS: The present model provides a satisfactory explanation of escalated drug intake and suggests a novel negative reinforcement view of addiction based on an allostatic decrease in reward function.     

Identification of new drug targets and biomarkers related to obesity and eating disorders: an approach based on reward deficit and addiction

Current pharmacological treatments for eating disorders and obesity are of limited value and thus the identification of novel targets is highly needed to enhance the development of more effective drugs. Among the bottlenecks limiting the introduction of new medicines is the reported heterogeneity of these diseases, which makes it difficult to find drugs with broad activity and the lack of animal models with translational validity, especially in the case of anorexia nervosa. Some kinds of obesity and eating disorders can be classified within the pathologies affecting the brain reward system together with drug addiction and others, and therefore specific treatments in these cases can be directed to restore normal function in brain reward pathways. Target identification in this field can greatly benefit from the combined application of genomic/proteomic techniques and robust animal models of reward deficits.     

Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies

The involvement of dopamine (DA) in drug reinforcement is well established, but much less in known about its contribution to addiction. We have used positron emission tomography to investigate in humans the role of DA in drug reinforcement, addiction and drug vulnerability. We have shown that during drug intoxication increases in striatal DA are associated with the drug's reinforcing effects only if the DA changes occur rapidly. These results corroborate the relevance of drug-induced DA increases and of pharmacokinetics in the rewarding effects of drugs in humans. During withdrawal, we have shown significant reductions in DA D(2) receptors and in DA release in drug abusers, which is likely to result in decreased sensitivity to non-drug-related reinforcing stimuli. The DA D(2) reductions were associated with decreased activity in the orbitofrontal cortex, which we postulate is one of the mechanisms underlying compulsive drug administration in the addict. In fact, during craving the orbitofrontal cortex becomes hyperactive in proportion to the desire for the drug. In non-drug-abusing subjects striatal DA D(2) receptors levels predicted the reinforcing responses to stimulant drugs, providing evidence that striatal DA D(2) receptors modulate reinforcing responses to stimulants in humans and may contribute to the predisposition for drug self-administration.     

The role of dopamine in human addiction: from reward to motivated attention

There is general consensus among preclinical researchers that dopamine plays an important role in the development and persistence of addiction. However, the precise role of dopamine in addictive behaviors is far from clear and only a few clinical studies on the role of dopamine in human addiction have been conducted so far. The present paper reviews studies addressing the role of dopamine in humans. There is substantial and consistent evidence that dopamine is involved in the experience of drug reward in humans. Dopamine may also be involved in motivational processes such as drug craving. However, given the inconsistent findings of studies using dopamine receptor (ant)agonists, the role of dopamine in the experience of craving is far from resolved. Recent theories claiming that dopamine signals salience and makes the brain paying attention to biological relevant stimuli may provide an interesting framework for explaining addictive behaviors. There is accumulating evidence that patients with drug and alcohol addiction have an aberrant focus on drug-related stimuli. Although there is some preliminary support for the role of dopamine in these attention processes, more studies have to be carried out in order to test the validity of these theories in human subjects.     

Recidivism in drug addiction: a behavioral analysis.

Current usage of the term addiction is criticized as vague, indiscriminate and ambiguous. “Addiction” is frequently applied to a variety of drugs without acknowledgement of their divergent psychopharmacological properties. Researchers disagree about whether the development of tolerance, psychological dependence, and stereotypical withdrawal patterns are necessary conditions of addiction. This issue is resolved by relying primarily on the behavioral rather than pharmacological concomitants of drug use. Consequently, addiction is defined as “reliable self-administration of drugs whenever they become available”. (Thompson &; Schuster, 1968). The high recidivism rates experienced in addiction is accounted for by environmental stimuli conditioned to the positive and negative effects of drug consumption. Relevant data from experimental animal studies are cited to support the role of learning mechanisms in relapse. In addition cognitive and affective factors are incorporated to explain recidivism in humans. The paper concludes that these multiple determinants of drug consumption must be considered and controlled before treatment is completed.     

Alcohol and drug expectancies as anticipated changes in affect: negative reinforcement is not sedation

Goldman and Darkes (2004) argued that all three basic alcohol-expectancy factors can be assessed with a brief questionnaire (AEMax), related to the circumplex model of emotion. I argue that negative reinforcement, one of the three basic expectancy factors, is not assessed with the AEMax. Importantly, negative reinforcement is positively related to problem drinking while sedation (the AEMax-factor that comes closest) is not. In a new dataset (from 119 students, collected in 2002), I demonstrate that sedation is related to negative expectancies and not to negative reinforcement. Different ways to assess all major expectancy factors are proposed.     

Caffeine as a model drug of dependence: recent developments in understanding caffeine withdrawal, the caffeine dependence syndrome, and caffeine negative reinforcement.

Caffeine is an excellent model compound for understanding drugs of abuse/dependence. The results of self-administration and choice studies in humans clearly demonstrate the reinforcing effects of low and moderate doses of caffeine. Caffeine reinforcement has been demonstrated in about 45% of normal subjects with histories of moderate and heavy caffeine use. Recent studies provide compelling evidence that caffeine physical dependence potentiates the reinforcing effects of caffeine through the mechanism of withdrawal symptom avoidance. Tolerance to the subjective and sleep-disrupting effects of caffeine in humans has been demonstrated. Physical dependence as reflected in a withdrawal syndrome in humans has been repeatedly demonstrated in adults and recently demonstrated in children. Withdrawal severity is an increasing function of caffeine maintenance dose, with withdrawal occurring at doses as low as 100 mg per day. Increased cerebral blood flow may be the physiological mechanism for caffeine withdrawal headache. Case studies in adults and adolescents clearly demonstrate that some individuals meet DSM-IV diagnostic criteria for a substance dependence syndrome on caffeine, including feeling compelled to continue caffeine use despite desires and recommendations to the contrary. Survey data suggest that 9% to 30% percent of caffeine consumers may be caffeine dependent according to DSM-IV criteria.     

NrCAM in addiction vulnerability: positional cloning, drug-regulation, haplotype-specific expression, and altered drug reward in knockout mice.

Several lines of evidence support roles for the cell adhesion molecule NrCAM in addictions. Fine mapping within a chromosome 7 region that contains previously linked and associated genomic markers identifies NrCAM haplotypes that are associated with substance abuse vulnerabilities in four samples of abusers and controls. Differential display identifies NrCAM as a drug regulated gene. NrCAM is expressed in neurons linked to reward and memory. NrCAM displays haplotype-specific gene expression in human post-mortem brain samples. Knockout mice display reduced opiate- and stimulant-conditioned place preferences. These observations support NrCAM as a positionally cloned and drug-regulated gene whose variants are likely to change expression and alter substance abuse vulnerabilities in human addictions and animal models of drug reward.     

The neuroscience of drug addiction: Rome built in a day

The Second Conference on the Neuroscience of Drug Addiction was a one-day meeting held in Rome, Italy at the Istituto Superiore di Sanità on 27 September 2002. Molecular, behavioral, pharmacological and clinical aspects of drug addiction were covered.     

d-Amphetamine stimulates unconditioned exploration/approach behaviors in crayfish: towards a conserved evolutionary function of ancestral drug reward

In mammals, rewarding properties of drugs depend on their capacity to activate a dopamine-mediated appetitive motivational seeking state—a system that allows animals to pursue and find all kinds of objects and events needed for survival. With such states strongly conserved in evolution, invertebrates have recently been developed into a powerful model in addiction research, where a shared ancestral brain system for the acquisition of reward can mediate drug addiction in many species. A conditioned place preference paradigm has illustrated that crayfish seek out environments that had previously been paired with psychostimulant and opioid administration. The present work demonstrates that the administration of d-amphetamine stimulates active explorative behaviors in crayfish through the action of the drug within their head ganglion. Crayfish, with a modularly organized and experimentally accessible, ganglionic nervous system offers a unique model to investigate (1) the fundamental, biological mechanisms of addictive drug reward; (2) how an appetitive/seeking disposition is implemented in a simple neural system, and (3) how it mediates the rewarding actions of major drugs of abuse.     

Multiple-choice procedure: an efficient approach for investigating drug reinforcement in humans

Two experiments demonstrated the efficiency of assessing drug reinforcement in humans by using a novel multiple-choice procedure. The distinguishing characteristic of the procedure is that it arranges intermittent reinforcement for choices between pairs of potential reinforcers. The procedure has three key operations: (1) a subject is exposed to the potential reinforcers; (2) a subject then makes two or more choices on a questionnaire; for each choice, the subject is required to choose one of two potential reinforcers (e.g. drug vs. drug choices and/or drug vs. money choices); and (3) subsequently only one of the choices, randomly selected, is reinforced. In the present experiments, two variations of the multiple-choice procedure were evaluated in twelve male drug abusers. Both experiments assessed the reinforcing effects of three drug conditions (200 and 400) mg/70kg pentobarbital and placebo) which were presented no more often than every to other day. The experiments demonstrated dose-related choice of pentobarbital over money as well as choice of a higher dose of pentobarbital over a lower dose or placebo. Orderly data were generated with a single-session exposure to each drug condition. Multiple-choice procedures should have applicability, not only to the investigation of drug reinforcement, but also to the study of non-drug reinforcement in humans.     

Feeding and reward: ontogenetic changes in an animal model of obesity

Given that food is a natural reinforcement, deficits in the reward system can lead to disordered eating behavior, inducing or worsening an already existing pre-obese phenotype. In order to evaluate developmental, food-reward-related measures we used the OLETF rat, an animal model of early-onset overeating-induced obesity, and a natural CCK-1 receptor knockout. Dopamine-like-receptor type 1 (D1R) and D2R levels were examined in a reward-related brain area (Nac shell) and sucrose preference was assessed at selected time points from weaning to adulthood (postnatal day [PND]90). In addition, a group of OLETF was pair fed (PF) to the amount of food consumed by same-age LETO controls (from weaning to PND 90) to examine the contribution of overweight to the alteration in DR expression. In addition, we examined food "craving"-like behavior by analyzing microstructural patterns of licking a palatable liquid diet. OLETF rats expressed significantly lower D2R levels than LETO controls only on PND 90. In PF OLETF, weight and D2R levels were normalized. In addition, OLETF presented exaggerated preference for the high sucrose concentration. After 30-day abstinence, OLETF rats presented significant increased initial rate of licking, suggesting food "craving". Thus, adult OLETF rats demonstrated altered D2R signaling similar to drug-induced sensitization, suggesting a link with their avidity for sucrose and their abnormal craving response. However, the current findings of a late deficit appearance and the novel PF results suggest that deficits in the motivation/regulatory systems of the OLETF rat are a developing process (at least from weaning and on) depending on the overeating and obese phenotype of the rats and not only on the CCK mutation.     

Cannabinoids reward sensitivity in a neurodevelopmental animal model of schizophrenia: A brain stimulation reward study

The comorbidity schizophrenia and cannabis has a high prevalence. The consumption of cannabis is ten times higher among schizophrenia patients, suggesting that these patients could be differentially sensitive to its motivational effects. To study this question, we investigated the motivational effects of cannabinoid agonists using the brain stimulation reward paradigm and a neurodevelopmental model of schizophrenia: neonatal ventral hippocampus lesions (NVHL). Using the curve-shift paradigm, we first compared the effect single dose (0.75 mg/kg) of amphetamine in sham and NVHL rats on reward and operant responding. Then, in different groups of NVHL and sham rats, we studied the effect of delta-9-tetrahydrocannabinnol (THC, 0.5 mg/kg, i.p.) and WIN55,212-2 (WIN, 1 and 3 mg/kg, i.p.) Rats were initially trained to self-administer an electrical stimulation to the posterio-medial mesencephalon. Once responding was stable, reward threshold defined as the frequency required to induce a half maximum response rate was measured before and after injection of the drug or the vehicle. Results show that amphetamine enhanced reward in sham and NVHL rats, an effect that was shorter in duration in NVHL rats. THC produced a weak attenuation of reward in sham rats while WIN produced a dose-dependent attenuation in NVHL; the attenuation effect of WIN was blocked by the cannabinoid antagonist, AM251. WIN also produced an attenuation of performance in sham and NVHL rats, and this effect was partially prevented by AM251. These results provide the additional evidence that the motivational effect of cannabinoids is altered in animals with a schizophrenia-like phenotype.     

The reward system and maternal behavior in an animal model of depression: a microdialysis study

Rationale and objectives Flinders sensitive line (FSL) rats, an animal model of depression, display a different pattern of maternal behavior compared to Sprague-Dawley (SD) controls. In this study, we examined the rewarding value of mother–infant interaction for FSL dams. Materials and methods In the main study, we measured monoamine levels in the nucleus accumbens (NAc) of early postpartum FSL and SD dams during an interaction with pups, using the microdialysis technique. In addition, we compared the preference patterns of FSL and SD rats using the conditioned place preference paradigm, with pups as the unconditioned stimuli. Results Dopamine (DA) levels in dialysates from the NAc of SD dams but not FSL dams were elevated while interacting with pups but the metabolism of DA to dihydroxyphenylacetic acid was greater in FSL than in SD dams. While SD dams showed a conditioned preference for a region that was associated with SD pups, FSL dams did not show a preference for regions associated either with SD or FSL pups, but water deprived FSL rats demonstrated a preference to a region associated with water, eliminating an alternative explanation of learning deficit in FSL rats. Conclusions Taken together, these results suggest that FSL dams are less rewarded by pups, compared to control dams.     

Injecting drug use in Romania: a field-report based on an initial assessment

There are indications of increased injecting drug use in Romania associated with the increased cross-border traffic of heroin. At the same time, there are indications of HIV transmission associated with drug injecting in countries close-by or neighbouring Romania. In the absence of data on patterns of injecting drug use, we undertook a preliminary assessment in four major Romanian cities (Bucharest, Iasi, Constanta and Timisoara) to describe the extent and nature of drug injecting and its associated adverse health consequences. The assessment is the first of its kind on injecting drug use in Romania. We found that little information exists on injecting drug use. In addition, we found recruiting IDUs into the assessment difficult. We note that future assessments need to find ways of recruiting IDUs directly in the community. We also note the need for future assessments to concentrate in greater detail on the potential for intervention developments in prevention, health promotion, treatment and policy.     

Haloperidol induces a partial reinforcement extinction effect in rats: implications for a dopamine involvement in food reward

The hypothesis that dopamine antagonist drugs attenuate the reinforcing properties of food was investigated in hungry rats trained to traverse a straight runway for food reward. Testing consisted of a single trial per day during which latencies to leave the start box and to traverse the alley were recorded. In each experiment, a reinforcement phase lasting 30 consecutive days was immediately followed by a 21 day extinction phase. The runway responses of animals that experienced intermittent food reward during the reinforcement phase of the experiments, was later found to be more resistant to extinction than those of continuously reinforced animals. This "partial reinforcement extinction effect" (PREE) was also observed in animals that experienced periodic reductions in the quantity, but not quality, of food reward. Intermittent pretreatment with 0.15 mg/kg of haloperidol during the reinforcement phase produced a PREE that was indistinguishable from that produced by reward omission on those same trials. Control groups for motor debilitation and for non-associative drug effects did not demonstrate a PREE. These results are consistent with the view that central dopamine substrates play a role in the neural basis of food reward.     

负二项回归模型用于肝炎患者复发次数的SAS程序实现

目的结合肝炎复发次数实例,选取负二项回归模型拟合数据,为计数资料的正确分析提供理论依据。方法对山西省太原市传染病医院2007年6月至12月乙型肝炎、丙型肝炎患者复发情况的随访调查资料,通过SAS软件GENMOD(广义线性模型)过程拟合负二项回归模型,对肝炎复发的影响因素进行分析。结果年龄越大、受感染时间越长、治疗信心越缺乏、认为收入对治疗的影响越明显的肝炎患者复发次数越多。结论SAS/GENMOD过程拟合负二项回归模型,程序简便,结果输出规范,可提供常用的连接函数和概率分布,结果可更准确地解释肝炎复发次数的情况。     

New perspectives in the studies on endocannabinoid and cannabis: a role for the endocannabinoid-arachidonic acid pathway in drug reward and long-lasting relapse to drug taking

Growing evidence on the involvement of cannabinoids in the rewarding effects of various kinds of drugs of abuse has suggested that not only the classical dopaminergic and opioidergic, but also the most recently established endocannabinoid system is implicated in the brain reward system. Furthermore, the interplay between the three systems has been shown to be an essential neural substrate underlying many aspects of drug addiction including craving and relapse. Relapse, the resumption of drug taking following a period of drug abstinence, is considered the main hurdle in treating drug addiction. Yet, little is known about its underlying mechanisms. The link between the endocannabinoid system and the arachidonic cascade is currently being clarified. While several findings have, indeed, shown the essential role of the endocannabinoid system in the reinstatement model, the endocannabinoid-arachidonic acid pathway may also be an important part in the neural machinery underlying relapse. This evidence may provide an alternative approach that will open a novel strategy in combating drug addiction.