Cocaine receptors on dopamine transporters are related to self-administration of cocaine

Although cocaine binds to several sites in the brain, the biochemical receptor mechanism or mechanisms associated with its dependence producing properties are unknown. It is shown here that the potencies of cocaine-like drugs in self-administration studies correlate with their potencies in inhibiting [3H]mazindol binding to the dopamine transporters in the rat striatum, but not with their potencies in binding to a large number of other presynaptic and postsynaptic binding sites. Thus, the cocaine receptor related to substance abuse is proposed to be the one associated with dopamine uptake inhibition.     

Evidence for addiction-like behavior in the rat

Although the voluntary intake of drugs of abuse is a behavior largely preserved throughout phylogeny, it is currently unclear whether pathological drug use ("addiction") can be observed in species other than humans. Here, we report that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine. As in humans, this addiction-like behavior is present only in a small proportion of subjects using cocaine and is highly predictive of relapse after withdrawal. These findings provide a new basis for developing a true understanding and treatment of addiction.     

Relapse to cocaine-seeking after hippocampal theta burst stimulation

Treatment efforts for cocaine addiction are hampered by high relapse rates. To map brain areas underlying relapse, we used electrical brain stimulation and intracranial injection of pharmacological compounds after extinction of cocaine self-administration behavior in rats. Electrical stimulation of the hippocampus containing glutamatergic fibers, but not the medial forebrain bundle containing dopaminergic fibers, elicited cocaine-seeking behavior dependent on glutamate in the ventral tegmental area. This suggests a role for glutamatergic neurotransmission in relapse to cocaine abuse. The medial forebrain bundle electrodes supported intense electrical self-stimulation. These findings suggest a dissociation of neural systems subserving positive reinforcement (self-stimulation) and incentive motivation (relapse).     

Epidemiology of drug abuse: an overview

Issues regarding the use of epidemiology in drug abuse research are discussed and systems for monitoring national trends and identifying risk factors are described. Data indicate a general decline in marijuana use among youth, a cohort aging effect among heroin and marijuana users, and increased prevalence and health consequences associated with cocaine use.     

Cocaine addiction: psychology and neurophysiology

Cocaine was considered incapable of producing dependence in 1980 but was recently proclaimed the drug of greatest national health concern. Recent clinical and preclinical investigations demonstrate that cocaine produces unique abuse and withdrawal patterns that differ from those of other major abused drugs and suggest that long-term cocaine abuse produces neurophysiological alterations in specific systems in the central nervous system that regulate the capacity to experience pleasure. It will be necessary to develop clinically pertinent research models before these findings can be considered definitive, but these evolving ideas have already led to applications of promising experimental treatments for cocaine abuse.     

High impulsivity predicts the switch to compulsive cocaine-taking

Both impulsivity and novelty-seeking have been suggested to be behavioral markers of the propensity to take addictive drugs. However, their relevance for the vulnerability to compulsively seek and take drugs, which is a hallmark feature of addiction, is unknown. We report here that, whereas high reactivity to novelty predicts the propensity to initiate cocaine self-administration, high impulsivity predicts the development of addiction-like behavior in rats, including persistent or compulsive drug-taking in the face of aversive outcomes. This study shows experimental evidence that a shift from impulsivity to compulsivity occurs during the development of addictive behavior, which provides insights into the genesis and neural mechanisms of drug addiction.     

Drug seeking becomes compulsive after prolonged cocaine self-administration

Compulsive drug use in the face of adverse consequences is a hallmark feature of addiction, yet there is little preclinical evidence demonstrating the actual progression from casual to compulsive drug use. Presentation of an aversive conditioned stimulus suppressed drug seeking in rats with limited cocaine self-administration experience, but no longer did so after an extended cocaine-taking history. In contrast, after equivalent extended sucrose experience, sucrose seeking was still suppressed by an aversive conditioned stimulus. Persistent cocaine seeking in the presence of signals of environmental adversity after a prolonged cocaine-taking history was not due to impaired fear conditioning, nor to an increase in the incentive value of cocaine, and may reflect the establishment of compulsive behavior.     

Nucleus accumbens long-term depression and the expression of behavioral sensitization

Drug-dependent neural plasticity related to drug addiction and schizophrenia can be modeled in animals as behavioral sensitization, which is induced by repeated noncontingent or self-administration of many drugs of abuse. Molecular mechanisms that are critical for behavioral sensitization have yet to be specified. Long-term depression (LTD) of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR)-mediated synaptic transmission in the brain has been proposed as a cellular substrate for learning and memory. The expression of LTD in the nucleus accumbens (NAc) required clathrin-dependent endocytosis of postsynaptic AMPARs. NAc LTD was blocked by a dynamin-derived peptide that inhibited clathrin-mediated endocytosis or by a GluR2-derived peptide that blocked regulated AMPAR endocytosis. Systemic or intra-NAc infusion of the membrane-permeable GluR2 peptide prevented the expression of amphetamine-induced behavioral sensitization in the rat.     

Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement

Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.     

Ice: a new dosage form of an old drug

Ice, which has been described as the drug of the 1990s, is a pure form of (+)methamphetamine hydrochloride; it is more dangerous because of its purity and because it can be inhaled. Taken by this route, the drug causes an effect similar to that from an intravenous dose, and much more intense than that from ingestion. The detailed mechanism of action differs from that of cocaine, but the overall stimulant effect of methamphetamine is similar. Methamphetamine effects, however, persist for hours, whereas cocaine effects are over in minutes. Ice is, therefore, just another agent for abuse by those seeking psychostimulation and, as with cocaine, compulsive abusers of amphetamines consume the drug repeatedly and continuously. Unlike cocaine, methamphetamine is a synthetic compound and is manufactured in illicit laboratories within the United States.     

浅谈如何科学认识和合理使用兽药

兽药在畜禽养殖过程为疾病的预防和治疗发挥了重要的作用,在当前养殖条件下,畜禽养殖还离不开兽药。尽管国家和大众对兽药残留、耐药性问题的越来越重视,近年来出台多项“减抗禁抗”措施,但并不意味着兽药就是有害的。这些政策的施行更多的是为兽药如何科学使用提供指导,既避免兽药的滥用造成残留和耐药性问题,也可以降低畜禽养殖中饲料成本,提高兽药的治疗效果。拥有良好的政策和监管体系,也为市场提供了更安全、可靠的绿色健康食品。     

The drug dilemma: manipulating the demand

Drug abuse in the United States has posed a dilemma during most of this century. Intemperate use of reinforcing drugs is hazardous to health and safety, but strict prohibition fosters an illicit market with criminal effects that may be equally harmful. The crux of the problem is the willingness of millions of people to risk toxicity and arrest to gain psychopharmacological rewards. Cocaine is the present source of most concern. Recommendations for reducing demand and abuse are given, including the implementation of preventive techniques, the investigation of various treatments, the use of modern chemical and electronic technology, and the development of new pharmacological alternatives.     

Insights into African swine fever virus immunoevasion strategies

African swine fever(ASF) is an acute and highly contagious disease that causes severe economic losses to the swine industry. ASF is caused by infection of African swine fever virus(ASFV) in domestic pigs, leading to almost 100% mortality. However, no effective vaccines and pharmacologic treatment against ASF are available. ASF poses a severe threat to the swine industry and the economy. Here we summarize potential virus-host cell interaction mechanisms involving the suppression of innate and adaptive immune responses to ASFV entry and infection. These mechanisms include modulation of apoptosis, inhibition of inflammatory responses, reduction of IFN production, inhibition of autophagy, and suppression of MHC-I expression. Insights into immunoevasion strategies by ASFV may shed light on the development of vaccines, as well as preventive and therapeutic drugs.     

Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey

Fenfluramine, over a dose range from 0.003 to 3 milligrams per kilogram of body weight, failed to maintain self-injection behavior in rhesus monkeys that had initiated and maintained responding for cocaine or methohexital. This absence of a positive reinforcing effect could not be attributed to a slow onset of drug effect or to the use of behaviorally inactive doses. Fenfluramine, because of its distinctive properties, may produce fewer problems of human abuse than do amphetamine-type agents.     

Blood-brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection

Labeled morphine, codeine, heroin, or methadone was injected as a bolus into the common carotid artery of the rat, and the rat was decapitated 15 seconds later. The brain uptake of the drug was calculated by measurement of the brain content of the drug as a percentage of a labeled, highly diffusible reference substance simultaneously injected. The uptake of morphine was below measurability; the uptake of codeine was 24 percent; heroin, 68 percent; and methadone, 42 percent. Brain uptakes of morphine and codeine were also studied after intravenous injection and correlated well with uptakes after carotid injection; the uptake of codeine being nearly complete by 30 seconds. These studies indicate that brain uptake of certain of these drugs is very rapid and that uptake of heroin injected intravenously is probably limited by the regional flow of blood in the brain. The possible relation of this rapid penetration of the blood-brain barrier by heroin to its strongly addictive properties is discussed.     

余午亭《诸证析疑》学术思想浅析

本文对明代新安医家余午亭所著《诸证析疑》的学术思想及临证经验进行初步探讨,余午亭临证强调要详辨寒热虚实,不可执一;辨证施治,独重脉法,但要因人而异;组方用药,当药随症施,不可妄用参芪。其论治思想及诊疗经验至今对临床疾病治疗仍有重要指导意义。     

Effects of veratrine and cocaine on cerebral carbohydrate-amino acid interrelations

The rate of aerobic transformation of glucose-U-C(14) into radioactive amino acids by slices of rat-brain cortex is greatly influenced by the K(+)/Ca(++) ratio in the incubating medium. Protoveratrine has effects on the amino acid pattern resembling that due to an increase in the K(+)/Ca(++) ratio. These effects are antagonized by cocaine and may be correlated with the neurophysiological activities of these drugs.     

Emergence of drug-resistant influenza virus: population dynamical considerations

Given the considerable challenges to the rapid development of an effective vaccine against influenza, antiviral agents will play an important role as a first-line defense if a new pandemic occurs. The large-scale use of drugs for chemoprophylaxis and treatment will impose strong selection for the evolution of drug-resistant strains. The ensuing transmission of those strains could substantially limit the effectiveness of the drugs as a first-line defense. Summarizing recent data on the rate at which the treatment of influenza infection generates resistance de novo and on the transmission fitness of resistant virus, we discuss possible implications for the epidemiological spread of drug resistance in the context of an established population dynamic model.     

Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward

The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit-level contribution of these cell types to cocaine reward.     

Drug abuse control: policy turns toward rehabilitation

Heroin addiction is the most difficult to control and the most socially destructive form of addiction in America today. Heroin is a fact of life and a cause of death among an increasing number of citizens in America, and it is heroin addiction that must command priority in the struggle against drugs.-President Nixon in his drug message to Congress on 17 June.