Modeling the role of environment in addiction

The aim of this review is to provide an overview of the main types of animal models used to investigate the modulatory role of environment on drug addiction. The environment can alter the responsiveness to addictive drugs in at least three major ways. First, adverse life experiences can make an individual more vulnerable to develop drug addiction or to relapse into drug seeking. Second, neutral environmental cues can acquire, through Pavlovian conditioning, the ability to trigger drug seeking even after long periods of abstinence. Third, the environment immediately surrounding drug taking can alter the behavioral, subjective, and rewarding effects of a given drug, thus influencing the propensity to use the same drug again. We have focused in particular on the results obtained using an animal model we have developed to study the latter type of drug–environment interaction.     

Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats

Accumbal dopamine (DA) is generally accepted to participate in the neural mechanisms underlying drug dependence. Recently the involvement of accumbal DA in drug-seeking behaviour has gained more experimental attention. To study an involvement of accumbal DA in drug-seeking behaviour within and between daily self-administration behaviour, changes in extracellular DA concentration in the nucleus accumbens (NAc) shell were measured during the daily dynamics of intravenous heroin and cocaine self-administration. Groups of drug naive rats were allowed to intravenously self-administer heroin (30 microg/infusion) and cocaine (30 microg/infusion) during five consecutive daily 3 h sessions. Extracellular DA concentrations in the NAc were measured before and after a single 3 h session (acute) and before and after 5 consecutive 3 h sessions (repeated). Following acute and repeated heroin and cocaine self-administration the extracellular DA concentration in the NAc shell was increased by two-fold to three-fold over baseline. These changes in DA concentrations are thought to reflect a direct effect of heroin and cocaine on DA neurotransmission in the NAC shell. Measurement of basal DA concentrations before the self-administration sessions revealed that just before the scheduled 5th self-administration session the (absolute) basal DA levels in the NAc in heroin or cocaine self-administering animals were decreased by approximately halve, as compared to drug-naive animals. It is assumed that just before a scheduled next session the (daily) desire for the drug is high. This decrease in basal DA neurotransmission in the NAc shell may, therefore, reflect an involvement of accumbal DA in drug-seeking behaviour during daily self-administration behaviour. The results demonstrate that initiation of i.v. heroin and cocaine self-administration is linked with changes in extracellular levels of DA in the NAc shell. Moreover, the present data suggest that accumbal DA might be involved in processes underlying the motivational aspects involved in daily drug-seeking behaviour, and that neuroadaptive changes in the mesolimbic DA system due to repeated drug intake lead to an tonic decrease in overall DA activity in the NAc.     

Drug-sensitive reward in crayfish: an invertebrate model system for the study of SEEKING, reward, addiction, and withdrawal

In mammals, rewarding properties of drugs depend on their capacity to activate appetitive motivational states. With the underlying mechanisms strongly conserved in evolution, invertebrates have recently emerged as a powerful new model in addiction research. In crayfish natural reward has proven surprisingly sensitive to human drugs of abuse, opening an unlikely avenue of research into the basic biological mechanisms of drug addiction. In a series of studies we first examined the presence of natural reward systems in crayfish, then characterized its sensitivity to a wide range of human drugs of abuse. A conditioned place preference (CPP) paradigm was used to demonstrate that crayfish seek out those environments that had previously been paired with the psychostimulants cocaine and amphetamine, and the opioid morphine. The administration of amphetamine exerted its effects at a number of sites, including the stimulation of circuits for active exploratory behaviors (i.e., SEEKING). A further study examined morphine-induced reward, extinction and reinstatement in crayfish. Repeated intra-circulatory infusions of morphine served as a reward when paired with distinct visual or tactile cues. Morphine-induced CPP was extinguished after repeated saline injections. Following this extinction phase, morphine-experienced crayfish were once again challenged with the drug. The priming injections of morphine reinstated CPP at all tested doses, suggesting that morphine-induced CPP is unrelenting. In an exploration of drug-associated behavioral sensitization in crayfish we concurrently mapped measures of locomotion and rewarding properties of morphine. Single and repeated intra-circulatory infusions of morphine resulted in persistent locomotory sensitization, even 5 days following the infusion. Moreover, a single dose of morphine was sufficient to induce long-term behavioral sensitization. CPP for morphine and context-dependent cues could not be disrupted over a drug free period of 5 days.This work demonstrates that crayfish offer a comparative and complementary approach in addiction research. Serving as an invertebrate animal model for the exposure to mammalian drugs of abuse, modularly organized and experimentally accessible nervous systems render crayfish uniquely suited for studying (1) the basic biological mechanisms of drug effects, (2) to explore how the appetitive/seeking disposition is implemented in a simple neural system, and (3) how such a disposition is related to the rewarding action of drugs of abuse. This work aimed to contribute an evolutionary, comparative context to our understanding of a key component in learning, and of natural reward as an important life-sustaining process.     

Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration

Extracellular dopamine and DOPAC (3,4-dihydroxyphenylacetic acid) levels in nucleus accumbens were sampled by microdialysis and quantified with high- performance liquid chromatography during intravenous heroin self-administration sessions in rats. Dopamine levels in 10 and 20 min samples were elevated following the first injection of each session, reaching a plateau of elevation within the first two or three injections and falling back toward baseline only when drug access was terminated. Elevations were in the range of 150–300% when unit dosages of 0.05–0.2 mgkg were given. Increasing the work requirement from FR-1 to FR-10 did not appear to alter the degree of elevation of dopamine levels, and dopamine levels fell during extinction while lever-pressing rates increased 20-fold. While animals compensated for unit dose changes between 0.05 and 0.2 mg/kg/injection, adjusting their response rate such that the same hourly drug intake and the same asymptotic dopamine levels were maintained across these conditions, at 0.4 mg/kg/injection hourly drug intake and asymptotic dopamine levels were elevated beyond the levels sustained by the lower doses. These findings confirm that self-administered doses of intravenous heroin are sufficient to activate the mesolimbic dopamine system and suggest that significant heroin “craving” can emerge when dopamine levels are still moderately elevated, long before the development of dopamine depletion associated with opiate withdrawal. © 1995 Wiley-Liss, Inc.     

Left-handedness is statistically linked to lifetime experimentation with illicit drugs

Handedness has been linked to an enhanced risk of alcohol abuse, while less is known about other drugs. A convenience sample of 1004 male and female Italian participants (females=58%) from the general community (18 to 65 years old: average age = 30; standard deviation = 10, median = 25) was asked about: handedness (preference in writing); lifetime use of alcohol, tobacco, and illicit drugs; levels of psychological distress, as measured by the General Health Questionnaire (GHQ); and levels of delusion proneness, as measured by the Peters et al. Delusions Inventory (PDI). Overall, 92 individuals (9.2%) were classified as left-handed, with no significant difference reported among genders. Lifetime use of illicit drugs, primarily cannabis, was reported by 20% of the sample. In a multiple logistic regression analysis, after taking into account sex, age, and caseness on GHQ and PDI, left-handed people in the sample were statistically more likely to report lifetime experimentation with heroin, ecstasy/amphetamine, and, marginally, hallucinogens, but not alcohol or tobacco. Different mechanisms might contribute to an explanation of greater lifetime experimentation with some illicit drugs among left-handed people as compared to right-handed people. However, replications with clinical samples are necessary before any definitive statements can be made.     

Schedule-induced self injection of drugs

1. The schedule-induced polydipsia paradigm has been used to induce oral Ingestion of large volumes of alcohol, barbiturate and other drug solutions. We have developed a method of schedule-induced self Injection which allows the study of acquisition and maintenance of drug intake behaviour in changing environments free from the interference of taste factors or imbalances due to excessive water intake.2. In this paper we review our findings on the acquisition and maintenance patterns of amphetamine, methadone, heroin, alcohol, nicotine, cocaine, Δ⁹THC and haloperidol.3. For all drugs except amphetamine, the combination of schedule and nutritional deprivation leads to the highest rates of drug Intake although the schedule does not appear to be a potent factor at free feeding weight. Drug intake is the result of the interaction of environmental factors and pharmacological properties of the drugs, rather than the effects of drug or environmental factors separately.4. From a number of preliminary studies, data on corticosterone response in drug self-injection behaviour and the function of the nucleus accumbens septum are presented.     

海洛因依赖的亚冬眠疗法与美沙酮疗法对照观察

对自愿戒断海洛因依赖住院患者１１６例，分别用亚冬眠与美沙酮替代递减进行治疗。结果表明：亚冬眠和美沙酮替代递减之间效果存在着明显差异；后者能有效控制戒断症状，且容易递减和停药，病人依从性好，不影响病人意识，生活能自理，情绪平稳，副反应极少。     

Opioid maintenance therapy suppresses alcohol intake in heroin addicts with alcohol dependence: preliminary results of an open randomized study

An open randomized study lasting 12 months was performed to evaluate the efficacy of methadone or buprenorphine to suppress alcohol use in two hundred and eighteen heroin addicts with alcohol dependence. Daily maintenance doses of methadone were 80, 120, 160, and 200 mg/day, while doses of buprenorphine were 8, 16, 24, and 32 mg/day.As expected, both treatments were able to reduce both heroin use and addiction severity (measured with ASI interview). However, although both medications were able to suppress alcohol use, the highest dose of buprenorphine was better than the highest dose of methadone, in reducing alcohol craving, ethanol intake (measured as daily number of drinks), and the ASI subscale of alcohol use.The mechanism underlying the effects of the opioid maintenance therapy on the reduction of alcohol intake is still unclear.The results of the present study may represent the first clinical evidence of the potential effective use of the highest doses of buprenorphine for the suppression of ethanol intake in heroin addicts with alcohol dependence.     

A reconsideration of the concept of drug dependence

Recent experimental findings show that body weight reduced animals with a catheterized jugular vein self-inject large quantities of a range of psychoactive drugs when placed on a fixed time food delivery schedule. This method, known as schedule-induced self-injection (SiSi), has made it possible to study the interaction of pharmacological and environmental factors in the initiation and maintenance of dependency. In the present paper, it is proposed that the use of this paradigm provides a new model for investigating dependency. Its particular value is that it enables isolation of critical patterns of interaction between pharmacological and environmental factors involved in drug seeking behavior, and thus enables drug seeking behavior and dependency to be reconceptualized in terms of an interaction phenomenon. This reconceptualization may provide a basis for an alternative approach to understanding human drug problems, as identification of an interaction pattern provides an opportunity for intervention.     

美沙酮维持治疗海洛因依赖患者的吸烟行为与疼痛强度

目的探讨接受美沙酮维持治疗(methadone maintenance treatment,MMT)的海洛因依赖患者(heroindependent patients,HDPs)吸烟行为与疼痛强度关系。方法 603例MMT门诊HDPs完成社会人口学和临床特征问卷、吸烟问卷、吸烟严重程度指数评估和Zung氏抑郁自评量表,用五点口述分级评分法评估疼痛强度。结果协方差分析控制社会人口学变量、临床特征变量和抑郁症状的混杂作用后,吸烟HDPs的疼痛强度高于非吸烟HDPs(F=11.836,P=0.002),两两比较,中重度尼古丁依赖患者疼痛强度最高,轻度尼古丁依赖患者次之,无尼古丁依赖患者疼痛强度最低[(3.11±1.04)vs.(2.67±1.13)vs.(2.47±1.15),均P0.01]。结论 MMT门诊HDPs的吸烟行为与疼痛存在显著关联,尼古丁依赖程度越重,疼痛强度越高。     

One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter

We have previously shown that brief (1 h) and extended (6 h) daily access to IV cocaine self-administration produce different behavioral and neural consequences following 2 weeks of drug withdrawal. Brief daily access produced stable consumption of the drug and, after withdrawal, a sensitized locomotor response and an enhanced c-Fos labeling to a single cocaine challenge. In contrast, extended daily cocaine self-administration produced escalation of drug consumption over trials but no enhanced behavioral or neurochemical response after withdrawal. Cocaine affects dopaminergic (DA) function by binding to the presynaptic transporter and thereby preventing reuptake of the neurotransmitter-an action thought to be responsible for the drug's reinforcing properties. In an extension of our previous work, the current study, using receptor autoradiography, compared binding (by [3H]WIN35428) of the dopamine transporter (DAT) in animals having experienced either brief or extended daily access to cocaine over 8 days, followed by 14 days of withdrawal. DAT densities were found to increase in the nucleus accumbens core (N.Acc Core) and the dorsal striatum (but not in the N.Acc shell, medial prefrontal cortex (mPFC), or ventral tegmental area (VTA)) of the 1-h, but not 6-h, subjects. In other words, elevations in DAT density were not associated with the 6-h access group, the group that models patterns of drug-use in human addicts, and therefore are likely to be independent of the neuroadaptations that occur in the "addictive" process. Such conclusions are also consistent with brain-imaging studies of human cocaine addicts. Additional research will be needed to identify the specific neural changes relevant to addiction.     

Mirtazapine attenuates cocaine seeking in rats

BackgroundRelapse to cocaine use is a major problem in the clinical treatment of cocaine addiction. Antidepressants have been studied for their therapeutic potential to treat cocaine use disorder. Research has suggested that antidepressants attenuate both drug craving and the re-acquisition of drug-seeking and drug-taking behaviors. This study examined the efficacy of mirtazapine, an antidepressant/anxiolytic, in decreasing cocaine seeking in rats.MethodsWe used the cocaine self-administration paradigm to assess the effects of mirtazapine on rats trained to self-administer cocaine or food under a fixed-ratio schedule. Mirtazapine (30 mg/kg, i.p.) was administered during extinction.ResultsMirtazapine significantly attenuated non-reinforced lever-press responses during extinction. Moreover, the mirtazapine dosed for 30 days during extinction produced sustained attenuation of lever-press responses during re-acquisition of cocaine self-administration, without changing food-seeking behavior. Our results showed that mirtazapine attenuated the re-acquisition of cocaine-seeking responses.ConclusionOur study pointed to the efficacy of mirtazapine in reducing the risk of drug relapse during abstinence, suggesting for its potential use as a novel pharmacological agent to treat drug abuse.     

Protective effects of timolol against the neuronal damage induced by glutamate and ischemia in the rat retina

Smoking is considered the leading cause of preventable death in the United States, but studies in animals suggest that nicotine is only weakly reinforcing. The maintenance of a dangerous habit by a weakly reinforcing agent has been the topic of some dispute. Using a two-lever "choice" self-administration procedure developed in our laboratory, we evaluated drug preferences as an index of relative reward strength for nicotine versus cocaine in nicotine-trained rats. Rats were initially exposed to each drug separately in single-lever self-administration sessions and then allowed to choose between them in a two-lever choice test session offering both drugs. When offered choices between different nicotine doses [8, 25, and 75 microg/kg/injection (inj), free base], rats responded approximately equally for any dose, regardless of which doses were compared. Rats clearly preferred 267 or 800 microg/kg/inj cocaine hydrochloride to any of the nicotine doses. These results indicate that cocaine has greater reward strength than nicotine and supports previous findings that self-administering rats seek to maximize reward magnitude regardless of the self-administered drug or training history. It is possible that dependence elevates nicotine's reward magnitude or nicotine addiction may rely more importantly upon negative rather than pure positive reinforcement.     

Cocaine-induced activation of striatal neurons during focused stereotypy in rats

As psychomotor stimulants, both amphetamine and cocaine elicit episodes of repetitive motor activation (focused stereotypy) known to involve the mesostriatal dopamine system. During amphetamine-induced focused stereotypy, motor-related neurons in the striatum respond with either an excitation or inhibition, depending on dose and behavioral pattern, whereas nonmotor-related units are inhibited. To assess striatal activity during the focused stereotypy induced by cocaine, both types of striatal units were recorded in ambulant rats. Either 20 or 40 mg/kg cocaine caused highly focused sniffing and head bobbing, which occurred in conjunction with activation of both motor- and nonmotor-related neurons. The activation of motor-related units was evident even when firing rate was compared during periods of matched pre- and post-drug behavior, arguing against movement as the sole basis for the drug-induced neuronal excitation. Subsequent administration of haloperidol (1.0 mg/kg) reversed but did not completely block the neuronal activation, while the behavioral response shifted away from focused stereotypy toward an increase in ambulation. Thus, the level of activation of both motor- and nonmotor-related striatal neurons may play a critical role in the behavioral response pattern induced by cocaine.     

The transition from controlled to compulsive drug use is associated with a loss of sensitization

Rats provided limited daily access to cocaine (1 h) maintain stable levels of drug self-administration over time while those switched to longer access (6 h or more) exhibit escalating patterns of drug intake. These results are reminiscent of human recreational and compulsive drug-taking behavior, respectively. We found that the brains of cocaine-self-administering rats were also qualitatively different in subjects having experienced 6-h (Coc6h) daily access compared to 1-h (Coc1h) access. Fourteen days after an eight-day protocol of cocaine self-administration, all subjects received one infusion of cocaine. Coc1h animals showed enhanced c-Fos reactivity in dopaminergic mesocorticolimbic brain regions and a sensitized locomotor response to IV cocaine. In contrast, both the neural and behavioral sensitization to cocaine was diminished in Coc6h animals. These data suggest that the transition to escalating patterns of drug use is associated with neuroadaptive changes that counteract those initially associated with controlled stable patterns of drug use.     

东莨菪碱和氯丙嗪联合戒毒的疗效分析

目的：探索对海洛因依赖者较理想的戒毒方法。方法：采用东莨菪碱和小剂量氯丙嗪联合静脉滴注对海洛因依赖者40例进行戒毒治疗,与单用美沙酮脱瘾60例比较。结果：东莨菪三和氯丙嗪联合对海洛因依赖者戒毒控制症状好,安全、副作用小。结论：东莨菪碱和氯丙嗪联合对海洛因依赖者戒毒有一种值得推广戒毒治疗方法。     

Effects of surgical and pharmacological adrenalectomy on the initiation and maintenance of intravenous cocaine self-administration in rats

Previous research has suggested the potential involvement of the hypothalamic-pituitary-adrenal (HPA) axis in psychostimulant reinforcement. In particular, we have found significant correlations between electric footshock-induced increases in plasma corticosterone and the acquisition, or lack thereof, of intravenous cocaine self-administration in rats. The experiments presented here were designed to further determine the role for corticosterone in cocaine reinforcement in rats by decreasing plasma levels of the hormone with surgical and pharmacological adrenalectomies. Bilateral adrenalectomy completely abolished the acquisition of intravenous cocaine self-administration over a wide range of doses (0.03125 to 1.0 mg/kg/infusion) without affecting food maintained responding. This suppression of self-administration was partially reversed by adding corticosterone (100 μg/ml) to the rats' drinking water. In another group of rats, pretreatment with metyrapone, which blocks the synthesis of corticosterone, resulted in dose-related decreases in ongoing cocaine self-administration. These data suggest that corticosterone is not only important, but may also be necessary for both the acquisition and maintenance of cocaine reinforcement in rats.     

The effects of four days of continuous striatal microdialysis on indices of dopamine and serotonin neurotransmission in rats

The effects of 4 days of continuous microdialysis with a small-diameter concentric-style probe on indices of striatal dopamine (DA) and serotonin neurotransmission were assessed. It was found that over 4 days of dialysis, there was a marked time-dependent decrease in the basal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in dialysate and in amphetamine-stimulated DA release. In contrast, there was no decrease in basal DA or in the ability of cocaine to elevate the concentration of DA in dialysate over the same period of time. There were only very modest changes in dialysate levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), relative to the marked changes in DA metabolites. It is suggested that 4 days of continuous dialysis does not result in a non-specific decrease in diffusibility of these compounds into the dialysis probe, but that the changes are more likely due to probe-induced damage to the nigrostriatal DA system. It is also suggested that a “stable” basal concentration of DA in dialysate is an especially poor indicator of the integrity of the dopaminergic input to the striatum. The implications of these findings for within-subjects design microdialysis experiments are discussed.     

Selective activation of accumbens neurons by cocaine-associated stimuli during a water/cocaine multiple schedule

Electrophysiological recording procedures were used to examine the responsiveness of nucleus accumbens (Acb) neurons to stimuli associated with cocaine delivery during a multiple schedule for water reinforcement and cocaine self-administration. Rats (n=9) were trained to press one lever for water reinforcement (0.05 ml/resp.; fixed ratio 1; FR1; 15 min) and a second spatially distinct lever for intravenous cocaine (0.33 mg/infusion; FR1; 2 h). The delivery of each reinforcer was signaled by different auditory stimuli. Of 101 neurons, 52 cells were classified as phasically active, exhibiting one of four well-defined types of patterned discharges relative to the water- or cocaine-reinforced response [J. Neurosci., 14(12) (1994) 7735; J. Neurosci., 20(11) (2000) 4255]. Acb cells were examined in test sessions consisting of 'probe' trials during which the stimulus previously paired with cocaine infusion was randomly presented in a response-independent manner during the self-administration portion of the session. Results showed that only neurons that exhibited changes in firing rate within seconds following the reinforced response for cocaine (but not water) were activated by the stimulus. This finding indicates that the responsiveness of cocaine selective neurons to cocaine-associated stimuli likely represents a conditioned response as opposed to a generalized stimulus-evoked discharge.     

Ceftriaxone prevents the induction of cocaine sensitization and produces enduring attenuation of cue- and cocaine-primed reinstatement of cocaine-seeking

Ceftriaxone is a beta-lactam antibiotic which has been found to increase the expression and function of the major glutamate transporter, GLT-1. It has previously been shown that GLT-1 expression is decreased in the nucleus accumbens following cocaine self-administration and extinction training; ceftriaxone given in the days immediately prior to reinstatement testing attenuates both cue- and cocaine-primed reinstatement. Here we tested the ability of ceftriaxone pre-treatment (for 5 days prior to the first cocaine exposure) to prevent the induction of cocaine sensitization and the acquisition of cocaine self-administration. We also tested whether ceftriaxone administered only during self-administration attenuates the reinstatement of extinguished cocaine-seeking. We found that ceftriaxone did not affect the acquisition of cocaine self-administration but was able to attenuate reinstatement weeks after ceftriaxone administration ceased. This attenuation in reinstatement was accompanied by a restoration of GLT-1 expression in the nucleus accumbens. Ceftriaxone also attenuated locomotor behavior following the first cocaine injection and prevented the induction of cocaine but not caffeine sensitization. While ceftriaxone-treated animals did not sensitize to caffeine, they displayed reduced caffeine-induced locomotion following repeated caffeine treatment, indicating a possible dopaminergic effect of ceftriaxone. Taken together, these results indicate that ceftriaxone produces enduring changes in glutamate homeostasis in the nucleus accumbens which counteract addiction-related behaviors.