Gene/Protein Disease Symptom Drug Enzyme Compound
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 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemical dependence is a leading cause of morbidity and death in the United States. At least 20% of patients seen by primary care physicians in both the outpatient and inpatient setting are chemically dependent. Up to 90% of these patients go undiagnosed by their primary physicians. Chemical dependence is defined as a chronic, progressive illness characterized by the repeated and persistent use of alcohol or drugs despite negative health, family, work, financial, or legal consequences. Primary care physicians are in an ideal position to detect chemical dependence at its earliest stages, when irreversible medical consequences and death are most likely preventable. Alcohol is the most common drug of abuse. Improving the rate of recognition of chemical dependence depends on being familiar with the constellation of physical, mental, and social indicators. Early medical manifestations of alcoholism common in the primary care setting include: gastric complaints, elevated blood pressure, palpitations, traumatic injuries, headaches, impotence, and gout. Early psychosocial manifestations common in both alcohol and drug dependence include anxiety, depression, insomnia, persistent relationship conflicts, work or school problems, and financial or legal problems. Particularly useful laboratory indicators of alcoholism include elevated levels of GGT and MCV, both displaying high specificity, with the GGT level being the most sensitive. Similarly specific laboratory tests for drug dependence are not available. Any patient presenting with any of the above medical, psychosocial, or laboratory manifestations should be screened for chemical dependence. The CAGE questionnaire for alcoholism, a four-question test, is particularly well suited to the primary care setting, where it can be administered in fewer than 60 seconds. The CAGE has demonstrated high sensitivity (in the 80% range) and specificity (approximately 85%) for alcoholism. Comparably convenient instruments do not yet exist for drug dependence, although a 28-item instrument, the DAST (Drug Abuse Screening Test), has demonstrated high sensitivity and specificity for drug abuse.
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PMID:Early recognition of chemical dependence. 846 47

The effects of prenatal cocaine exposure and protein malnutrition on orientation to home nest material was assessed in rat pups. Sprague-Dawley dams were fed a diet of low protein content (6% casein), and isocaloric diet of adequate protein content (25% casein, control), or a laboratory chow diet prior to mating and throughout pregnancy. Within each diet group, rats received either cocaine injections (30 mg/kg IP 2 times per week prior to mating and the 30 mg/kg SC daily from day 3 to 18 of pregnancy) or saline injections. All litters were fostered on the day of birth to control mothers fed an adequate diet. On postnatal days 7, 9, and 11, a single pup from each litter (n = 11-15 per treatment) was tested repeatedly in a clean test cage for the rapidity of approach, and level of attraction to their own home (nest) bedding compared with fresh bedding. Prenatal malnutrition and prenatal cocaine exposure each gave rise to independent effects on performance, based upon factor analysis. Prenatal malnutrition, but not prenatal cocaine increased the time taken for rat pups to approach their nest bedding, reduced the time spent on this bedding, decreased the number of entries into the sector containing the home bedding and reduced pup weight. Prenatal cocaine, but not prenatal malnutrition, produced a reduction in activity, but had no effect on pup weight. The lower activity level was most pronounced on postnatal day 7. Surprisingly, interactive effects of prenatal cocaine and prenatal malnutrition were not observed on any behavior examined. Nevertheless, the co-existence of drug addiction and malnutrition in human populations raises the possibility that some of the effects generally attributed to drug exposure may, in fact, be due to malnutrition.
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PMID:Differential effects of prenatal protein malnutrition and prenatal cocaine on a test of homing behavior in rat pups. 887 84

Strategies used to explore the role of stressors in drug addiction include measuring stressor's effects on drug's rewarding properties. The current investigation explored the effect of an acute stressor on morphine conditioned place preference. Twenty-four hours following either inescapable tail shock or home-cage control treatment, all subjects were conditioned with morphine (0, 1, 2, and 3 mg/kg s.c.) over 2 days, and later tested for conditioned place preference. Inescapably shocked subjects demonstrated a potentiated place preference compared to controls. The inescapable shock-induced potentiated place preference developed even when conditioning was delayed until 6 and 7 days following the stressor, while no longer occurring after a 14- and 15-day interval. The potentiation was not a result of reduced locomotion in the inescapably shocked subjects, as activity in inescapably shocked and home-cage control subjects was the same following "mock" saline conditioning. Furthermore, the anxiogenic methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0.3 mg/kg i.p.), which produces effects similar to those produced by inescapable shock, also potentiated morphine place preference. In addition, the potentiation in inescapably shocked subjects was dependent upon the stressor's uncontrollability, as identical escapable shock did not potentiate place preference above control subjects. Finally, the inescapable shock-induced potentiated place preference was drug specific, as amphetamine place preference was not affected.
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PMID:Uncontrollable stress potentiates morphine's rewarding properties. 967 49

Rigorous experimental design can minimize the high risk of false positives and false negatives in the behavioral phenotyping of a new transgenic or knockout mouse. Use of well established, quantitative, reproducible behavioral tasks, appropriate Ns, correct statistical methods, consideration of background genes contributed by the parental strains, and attention to litter and gender issues, will maximize meaningful comparisons of -/-, +/-, and +/+ genotypes. Strategies developed and used by our laboratory are described in this review. Preliminary observations evaluate general health and neurological reflexes. Sensory abilities and motor functions are extensively quantitated. Specific tests include observations of home cage behaviors, body weight, body temperature, appearance of the fur and whiskers, righting reflex, acoustic startle, eye blink, pupil constriction, vibrissae reflex, pinna reflex, Digiscan open field locomotion, rotarod motor coordination, hanging wire, footprint pathway, visual cliff, auditory threshold, pain threshold, and olfactory acuity. Hypothesis testing then focuses on at least three well-validated tasks within each relevant behavioral domain. Specific tests for mice are described herein for the domains of learning and memory, feeding, nociception, and behaviors relevant to discrete symptoms of human anxiety, depression, schizophrenia, and drug addiction. An example of our approach is illustrated in the behavioral phenotyping of C/EBPdelta knockout mice, which appear to be normal on general health, neurological reflexes, sensory and motor tasks, and the Morris water task, but show remarkably enhanced performance on contextual fear conditioning.
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PMID:Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. 1044 92

Drug-associated contextual cues can exert a powerful influence on behavior through associative pairing between the drug and the environment. However, the anatomical and molecular substrates for these effects are not well characterized. Using a drug-conditioning paradigm, we examined the expression of the immediate early gene product, Fos, within specific brain circuits using immunocytochemical detection. Rats were given either morphine (5 mg/ml/kg) or saline once a day for 10 days. The drug administration was always paired with a specific environment (activity monitors) different from the home cage. Following this treatment, the rats were returned to the cages at various times thereafter, with only a mock injection. Conditioned behavioral activation was observed in rats at 3, 5, and 7 days following treatment with morphine. In rats showing the conditioned motor response, several cortical and limbic areas showed substantial increases in the number of Fos positive cells, indicating that these regions were more active during exposure to the drug-paired environment. Areas that were most activated included prefrontal cortex, cingulate cortex, nucleus accumbens, and preoptic area. Further analysis showed that this increase in Fos expression was not directly related to the increase in motor activity, and that the drug-associated conditioning and Fos expression was lessened at 7 days and absent by 14 days post-treatment. These results are discussed in terms of their relevance to the problem of relapse in drug addiction.
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PMID:Morphine-associated environmental cues elicit conditioned gene expression. 1088 Oct 35

Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression of the dopamine transporter (DAT) to 10% of wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo microdialysis revealed that released dopamine was cleared at a slow rate in knockdown mice, which resulted in a higher extracellular dopamine concentration. Unlike the DAT knockout mice, the DAT knockdown mice do not display a growth retardation phenotype. They have normal home cage activity but display hyperactivity and impaired response habituation in novel environments. In addition, we show that both the indirect dopamine receptor agonist amphetamine and the direct agonists apomorphine and quinpirole inhibit locomotor activity in the DAT knockdown mice, leading to the hypothesis that a shift in the balance between dopamine auto and heteroreceptor function may contribute to the therapeutic effect of psychostimulants in attention deficit hyperactivity disorder.
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PMID:Hyperactivity and impaired response habituation in hyperdopaminergic mice. 1117 62

Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225-250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine. (+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.
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PMID:Effects of dizocilpine [(+)-MK-801] on the expression of associative and non-associative sensitization to D-amphetamine. 1467 14

Despite the high prevalence of tobacco abuse among adolescents, the neurobiology of nicotine addiction has been studied mainly in adult animals. Repeated administration of this drug to adult rats induces behavioral sensitization. Nicotine activates the HPA axis in adult rats as measured by drug-induced increases in ACTH and corticosterone. Both behavioral sensitization and corticosterone are implicated in drug addiction. We examined the expression of behavioral sensitization induced by nicotine as well as the changes in corticosterone levels after repeated injections of nicotine in adolescent and adult animals. Adolescent and adult rats received subcutaneous (s.c.) injections of saline or 0.4 mg/kg of nicotine once daily for 7 days. Three days after the last injection animals were challenged with saline or nicotine (0.4 mg/kg; s.c.). Nicotine-induced locomotion was recorded in an activity cage. Trunk blood samples were collected in a subset of adolescent and adult rats and plasma corticosterone levels were determined by radioimmunoassay. Adult, but not adolescent, rats expressed behavioral sensitization. Pretreatment with nicotine abolished corticosterone-activating effect of this drug only in adult animals, indicating the development of tolerance at this age. Our results provide evidence that adolescent rats exposed to repeated nicotine display behavioral and neuroendocrine adaptations distinct from that observed in adult animals.
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PMID:Differential behavioral and neuroendocrine effects of repeated nicotine in adolescent and adult rats. 1574 Jul 83

Craving and relapse are core symptoms of drug addiction and alcoholism. It is suggested that, after chronic drug consumption, long-lasting neuroplastic changes within the glutamatergic system are important determinants of addictive behavior. Here, we show that the AMPA type glutamate receptor plays a crucial role in alcohol craving and relapse. We observed, in two animal models of alcohol craving and relapse, that the AMPA antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2, 3-benzodiazepine] dose-dependently reduced cue-induced reinstatement of alcohol-seeking behavior and the alcohol deprivation effect. The involvement of the AMPA receptor in these phenomena was further studied using mice deficient for the GluR-C AMPA subunit [GluR-C knock-out (KO)]. GluR-C KOs displayed a blunted, cue-induced reinstatement response and alcohol deprivation effect, when compared with wild-type controls; however, no differences between genotypes could be observed regarding ethanol self-administration under operant or home cage drinking conditions. These results imply a role for GluR-C in alcohol relapse, although this phenotype could also be attributable to a reduction in the total number of AMPA receptors in specific brain areas. In conclusion, AMPA receptors seem to be involved in the neuroplastic changes underlying alcohol seeking behavior and relapse. Thus, AMPA receptors represent a novel therapeutic target in preventing relapse.
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PMID:Involvement of the AMPA receptor GluR-C subunit in alcohol-seeking behavior and relapse. 1643 10

Many similarities exist between the overconsumption of food, which results in obesity, and drug addiction. The present study investigated the effects of anorectic drugs on responding maintained by high incentive, but nutritionally unnecessary, food reinforcers using an FI15(fixed-ratio 10:S) schedule of reinforcement, similar to that used in studies on the incentive properties of drugs of abuse. Rats were trained to respond on a lever to gain access to two high incentive foods--chocolate chip cookies and cheese. Under the FI15(FR10:S) schedule, every 10th response (fixed-ratio 10) delivered a tone and light conditioned stimulus. The first ratio completed 15 min after the start of the session produced the conditioned stimulus and opened a door to give access to a piece of cookie. After 5 min to consume the high incentive food, a second 15-min interval was started, terminating in access to a second reinforcer, cheese. Once trained, the rats were given free access to laboratory chow in the home cage. They continued to work for the high incentive foods for a period of over 1 year, showing a pattern of responding appropriate to an FI(fixed-ratio) schedule. Naloxone (1.0 mg/kg), fenfluramine (1 and 2 mg/kg), D-amphetamine (0.25 and 0.5 mg/kg), and rimonabant (3 mg/kg) significantly reduced responding, especially in the second interval. In contrast, complete removal of the high incentive food from the test procedure did not immediately reduce the rate of responding, tending to increase it in the second of the intervals. Apparently, the drugs did not reduce responding by reducing the experienced magnitude of the high incentive food, but more probably by reducing the animals' motivation.
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PMID:The effects of anorexic drugs on free-fed rats responding under a second-order FI15-min (FR10:S) schedule for high incentive foods. 1721 98


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