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To the authors' knowledge this is the first report of a patient with Münchausen's syndrome occurring as comorbidity with anorexia nervosa. The Münchausen's symptoms, together with other self-damaging and addictive behaviors, were used interchangeably to avoid anorexic feelings. The Münchausen's syndrome and self-damaging behavior in anorexia nervosa are discussed.
Numerous studies on the involvement of dopamine receptors in the genetics of alcoholism focused on associations between a polymorphism of the D2 dopamine receptor (DRD2) gene and alcohol dependence. However, the results of these studies are conflicting. Another receptor, the D3 dopamine receptor (DRD3), may be of additional interest since it is specifically located in the limbic area, and in particular in the nucleus accumbens which plays a significant role in the reward process of addiction behavior. We thus tested the association in three independent samples of alcoholic patients, with different origins and various inclusion criteria. No difference in the DRD3 gene polymorphism emerged between controls and alcoholic patients, regardless of their origin, inclusion criteria, or presence or absence of the DRD2 TaqI A1-allele. Despite the fact that more information could have been considered and that association studies provide limited information, there is good evidence that this DRD3 polymorphism does not play a major role in the genetic component of alcoholism.
The dopamine D4 receptor gene contains a polymorphic sequence consisting of a variable number of 48-base-pair (bp) repeats, and there have been a number of reports that this polymorphism is associated with variation in novelty seeking or in substance abuse and addictive behaviors. In this study we have assessed the linkage and association of DRD4 genotype with novelty seeking, alcohol use, and smoking in a sample of 377 dizygotic twin pairs and 15 single twins recruited from the Australian Twin Registry (ATR). We found no evidence of linkage or association of the DRD4 locus with any of the phenotypes. We made use of repeated measures for some phenotypes to increase power by multivariate genetic analysis, but allelic effects were still non-significant. Specifically, it has been suggested that the DRD4 7-repeat allele is associated with increased novelty seeking in males but we found no evidence for this, despite considerable power to do so. We conclude that DRD4 variation does not have an effect on use of alcohol and the problems that arise from it, on smoking, or on novelty seeking behavior.
Physicians may be far more likely than other professionals and the general public to experience problems with drug and alcohol dependence. The availability of drugs, difficulty of detection, reluctance to confront addictive behaviors, unwillingness to admit weakness, and the lack of ways to detect and manage impaired physicians exacerbate the complexities of preventing and treating the problem. This literature review explores the complicating factors and suggests that prevention can be enhanced through medical education, candid disclosure of facts, acceptance, and understanding of substance abuse as a medical disorder.
Recent studies have implicated the bed nucleus of the stria terminalis (BST) as a potential brain substrate for mediating drug-related behaviors. Neuroanatomical studies have demonstrated that reciprocal projections exist from the BST to the ventral tegmental area (VTA), a dopamine reward substrate proposed to play a role in alcohol abuse. In the present study, we evaluated the role of the D(1) and D(2) dopamine receptors of the BST in regulating alcohol and sucrose-motivated behaviors. Alcohol-preferring (P) rats were trained under an FR4 operant schedule to self-administer either EtOH (10% v/v) or sucrose (2% w/v). Following training, we evaluated the capacity of a competitive D(1) (SCH 23390; 0.5-20.0 microg) and a D(2) (eticlopride; 0.5-20.0 microg) dopamine antagonist to selectively reduce EtOH-maintained responding. Naltrexone, (5-30.0 microg), the nonselective opioid antagonist, was used as a reference agent. The results showed that SCH 23390 dose-dependently reduced alcohol-motivated responding. Responding was reduced with the 20.0 microg dose to about 97% of control levels. SCH 23390 also reduced sucrose responding; however, the magnitude of effects was substantially lower with the highest doses (2.5, 20.0 microg) (68-79% of control levels). In contrast, eticlopride failed to significantly alter alcohol responding and reduced sucrose responding only with the 10.0 microg dose. Unlike the dopamine antagonists, all naltrexone doses failed to alter EtOH or sucrose-maintained responding. The results suggest a salient role for the D(1), but not the D(2) and opioid receptors in selectively modulating EtOH-motivated behaviors in the BST.
The present work was conducted to obtain clues for the possible roles of a novel stimulant-inducible gene mrt1 (methamphetamine-responsive transcript 1) encoding a PDZ-PX protein in stimulant-induced behavioral sensitization. In the young adult rats, repeated daily treatment with methamphetamine (4 mg/kg, intraperitoneally, once a day) for 5 days caused an enhanced behavioral response to methamphetamine: behavioral sensitization. The 5-day intermittent administration of MAP upregulated the basal expression of mrt1 transcripts and eliminated the increasing effects of a challenge dose of MAP (1.6 mg/kg, i.p.) or cocaine (30 mg/kg, i.p.) on mrt1 expression on day 14 of withdrawal in the neocortex that has been considered to be composed of a neuron circuit implicated in the sensitization phenomenon. In contrast, the basal expression of other stimulant-inducible and plasticity-related genes arc and homer1a and the ability of MAP or cocaine challenge to augment the amounts of their transcripts were not affected by the repeated MAP regimen in the cortical area. These findings suggest the differential regulation by stimulant of neocortical mrt1, arc, and homer1a expression in the behaviorally sensitized animals and supports the view that stimulant induction of mrt1 may be involved in the early molecular signalings for stimulant sensitization.
Elevated glucocorticoids, during pregnancy, alter emotionality and increase propensity to drug abuse later in life, albeit through substrates and mechanisms are largely unknown. In this study, we examined whether antenatal glucocorticoid exposure induces enduring structural changes in the nucleus accumbens (NAcc), an important relay point in the reward limbic circuitry. To this end, rat dams were exposed to the synthetic glucocorticoid dexamethasone (DEX) on days 18 and 19 of gestation, and stereological tools were used to assess the total volume of, and neuronal numbers in, the NAcc, as well as the density of mesencephalic dopaminergic inputs from the ventral tegmental area (VTA) to the NAcc in their adult offspring. Further, we used measures of bromodeoxyuridine incorporation into NAcc cells to examine whether DEX-induced effects on cell proliferation represent another mechanism through which glucocorticoids alter the structure of mesolimbic pathways and might influence addictive behavior. Our studies show that exposure to DEX during late gestation results in significantly reduced volumes and cell numbers in the NAcc. The latter measure correlated strongly with a reduced rate of cell proliferation in DEX-exposed animals. Moreover, the treatment resulted in a decreased number of cells expressing tyrosine hydroxylase in the VTA and an impoverished dopaminergic innervation of the NAcc. These observations, which identify glucocorticoid-sensitive structures and neurochemical targets within the developing "reward pathway," pave way for future studies designed to understand how early life events can predispose individuals for developing drug dependence in adolescent and adult life.
We describe a memory-based system for psychotherapy, Dr. Bob, built to run on the data parallel processor Thinking Machines, Inc., CM-2a Connection Machine. The system retrieves, in parallel, stories of alcohol addiction and sexual abuse which can be used by psychiatrists in working with their patients as part of their work in recovering from addictive behavior and psychological trauma. The program is written in *LISP (pronounced Star LISP), a version of LISP used in programming Connection Machines.
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The long-term dropout rate was examined in a physical exercise rehabilitation program in which 203 cardiac patients were followed for 40 months. The dropout curve was found to be downward-sloping and negatively accelerated with most of the dropouts occurring during the first 3 months. This dropout rate appeared to resemble the group release curve previously found in the treatment of addictive behaviors. Implications of the present findings are discussed in terms of the development of strategies to facilitate long-term compliance.
Native Americans have experienced substantial problems with alcohol since its introduction to their culture by early European settlers. Epidemiological data indicate that elevated morbidity and mortality attributable to alcohol abuse among this population remain at epidemic levels. Adolescent drinking patterns and family and peer influences on alcohol use are examined. A multifactorial etiology is indicated in the origin of Native American alcohol abuse. Some scholars have ascribed this problem to historical factors such as the introduction of alcohol to Native Americans by aberrant role models, while other researchers subscribe to various physiological theories which support the "firewater myth" suggesting that Native Americans may be genetically predisposed to crave ever increasing doses of alcohol during a rapid loss of control of their senses. The physiological theories generally suggest significant differences in alcohol absorption and metabolism rates between Native Americans and caucasians. A wide variety of social factors appear to be implicated in Native American drinking problems. Cultural and social orientations, socioeconomic conditions, "stake theory," failure to develop social sanctions regulating drunken deportment, passive-aggressive syndromes, and emotional repression contribute to Native American alcohol abuse. Treatment regimes for Native American alcoholics are examined briefly. Nativistic movements, conversion to evangelistic regions, therapies grounded in the medical model, and Native American group-oriented efforts have demonstrated varying degrees of success. Clearly, prevention would be preferable to the frustration of attempting to change the highly addictive behavior patterns characteristic of alcoholism. Suggestions for health education interventions are presented including an example of one effort currently being implemented.
RATIONALE: Occupancy of dopamine D2 receptors by antipsychotic drugs depends on the individual availability of D2 receptors and on the dose and type of antipsychotic medication. It has been suggested that a low availability of these receptors may increase the risk for addictive behavior. OBJECTIVE: This study aims to show that patients with relatively high occupancy of D2 receptors by antipsychotic drugs are more prone to nicotine consumption. METHODS: Striatal D2 receptor occupancy by equivalent doses of olanzapine or risperidone was assessed with [123I]iodobenzamide single-photon emission computed tomography (SPECT) in 36 patients with schizophrenia. Smoking status at the time of SPECT imaging was assessed. The number of cigarettes used in the following three consecutive years was estimated with the Life Chart Schedule (LCS). RESULTS: There was a positive and significant relation between D2 receptor occupancy following treatment with olanzapine (n=19) or risperidone (n=12) and the number of cigarettes smoked in three consecutive years (r=0.60, p<0.001) in patients who smoked. There was a significant difference in the percentage of D2 occupancy for smokers (mean 74.3%, SD 12.8, n=31) and nonsmokers (mean 49.8%, SD 9.1, n=5). CONCLUSION: Frequency of cigarette smoking in schizophrenic patients treated with antipsychotic medication is significantly and negatively related to the availability of striatal D2 receptors.
RATIONALE: Despite decades of research specifying harmful effects produced by 3,4-methylenedioxymethamphetamine (MDMA; a principal component of 'ecstasy' pills), young people (and adults) continue to use it. In an attempt to model human MDMA consumption patterns, preclinical investigators have sought to establish reliable patterns of intravenous MDMA self-administration in rodents. OBJECTIVE: The objective of this report is to offer a critical review of published data (including our own novel findings) that reveal MDMA self-administration in rodents. RESULTS: The data indicate that MDMA serves as a reinforcer in rodents, though the responses are not similar to those previously reported for psychostimulants (i.e., cocaine). Important differences between rodent models and human use patterns include frequency of dosing and dosage exposure, routes of administration, tolerance that develops to MDMA after repeated exposure, polydrug use in humans but not by rodents, limits on the repertoire of behaviors that can be exhibited by rodents undergoing IV self-administration procedures, and the question of neurotoxicity as it relates to models of self-administration. CONCLUSIONS: While MDMA is not as potent a reinforcer as other drugs of abuse, the fact remains that young people and adults continue to use the drug, and therefore, additional research is needed to determine why drugs with low reinforcing effects continue to be abused.
RATIONALE: Repeated intermittent administration of psychostimulant drugs such as amphetamine and cocaine can cause sensitization (reverse tolerance) to the locomotor-stimulating actions in rats. Sensitization to the stimulant effects of these drugs might contribute to the development and maintenance of addictive behaviors (e.g. compulsive drug use). OBJECTIVES: Studies were designed to systematically examine how testing conditions affect the development and expression of locomotor sensitization to cocaine and amphetamine. METHODS: Rats were treated once daily with intraperitoneal (i.p.) administration of amphetamine (0.5-2.0 mg/kg) or cocaine (5.0-20 mg/kg) and placed in activity chambers for 30, 60, or 120 min. All amphetamine-preexposed rats were challenged with 0.5 mg/kg amphetamine, and all cocaine-preexposed rats were challenged with 5.0 mg/kg cocaine for 120-minute activity tests 2 weeks after the final injection. RESULTS: Rats treated repeatedly with 2.0 mg/kg amphetamine and tested for 60 min in activity chambers or 20 mg/kg cocaine and tested for 30 min in activity chambers were most active in response to the drug challenge. These time points coincide with the maximal behavioral effects of each drug, as measured after the first injection. In contrast, rats treated with 2.0 mg/kg amphetamine and tested for 30 min or 20 mg/kg cocaine and tested for 120 min were least active in response to the drug challenge. CONCLUSIONS: Repeated association of the peak behavioral effects of high doses of amphetamine or cocaine with the drug-paired environment produces maximal expression of sensitized locomotor responses. Certain testing conditions appear to disrupt sensitization to these same doses of the drugs.
RATIONALE: D1-Like agonists are self-administered by drug-naive animals, whereas D2-like agonists reinstate cocaine-seeking behavior, but the rewarding and reinstating effects of D1- and D2-like agonists in pavlovian-based conditioned place preference are equivocal. OBJECTIVE: To compare the ability of D1 and D2 agonists to produce conditioned place preference with their modulation of expression and reinstatement of an established cocaine place preference. METHODS: Using an unbiased procedure, we measured the place preference induced by the D1 receptor agonist SKF 81297 and the D2/D3 receptor agonist quinpirole in drug-naive or cocaine-exposed rats. The rewarding effects of the D1 agonists SKF 82958, ABT-431, A-77636, and the D2/D3 receptor agonist 7-OH-DPAT were also tested. Additionally, we tested the ability of SKF 81297 and quinpirole to modulate expression and reinstatement of an established cocaine place preference. RESULTS: The D1 receptor agonists SKF 81297, SKF 82958, and ABT-431 produced dose-dependent conditioned place preferences, whereas A-77636 produced only place aversion, and the D2/D3 agonists quinpirole and 7-OH-DPAT were without effect in drug naive rats. In cocaine-treated rats, SKF-81297-induced place preference was reduced, whereas quinpirole-induced place preference was revealed. Pretreatment using either D1 or D2/D3 agonists blocked expression of an established cocaine place preference, but only the D1 agonist SKF 81297 and cocaine dose-dependently reinstated an extinguished cocaine place preference, whereas the D2/D3 agonist quinpirole induced place aversion but failed to alter cocaine-induced reinstatement. CONCLUSIONS: D1, but not D2/D3, agonists mediate rewarding effects and reinstatement of cocaine place preference, but the reinstating effects differ markedly from self-administration paradigms.
Chromosomal regions near the mu opioid receptor gene are implicated in morphine preference by quantitative trait loci studies. Differences in expression of the mu opioid receptor are expected to contribute to differences in inter-individual (humans) or strain-specific (mice) responses to painful stimuli, opiate drugs, and addictive behaviors. The search for relevant genetic elements is hindered by a lack of inter-strain (or inter-individual) genomic sequence information. This work describes 9.3 kb of DNA sequence surrounding exons 2 and 3 of the murine mu opioid receptor gene from both 129/Sv and C57BL/6 strains. While the exons are perfectly conserved, intronic sequences demonstrate approximately a 2.5% divergence between the strains. Polymorphism within these intronic regions may effect either primary transcript stability or C-terminal splicing. Homologous recombination frequencies of targeting vectors harboring mu opioid receptor gene sequences have also been compared in embryonic stem cells derived from these strains. Non-isogenic targeting reduces homologous recombination in both 129/Sv and C57BL/6 embryonic stem cells by greater than 15-fold. These findings are the first to examine C57BL/6 embryonic stem cells for non-isogenic targeting frequencies and to define polymorphisms that exist between these mouse strains which might contribute to opioid behaviors.
The evidence for an increased incidence of rates of psychosocial disorders including depression, suicide, delinquency, eating disorders, and drug and alcohol abuse is summarized. Findings from prospective studies, family genetic studies, community surveys, repeated cross-sectional surveys, and data from mortality and police statistics suggest that the increase over time of several of these disorders is supported by epidemiological evidence, particularly for suicide, delinquency, addictive behaviors, and depression. Several studies also indicate that an earlier age of onset for these disorders is seen in the most recent birth cohorts, with most of these disorders having their onset in adolescent years. The implications of these findings for child psychiatric treatment and services are discussed.
The lower incidence of Parkinson's disease (PD) among smokers may be explained by a protective effect of cigarette smoke, or by a tendency to avoid addictive behaviors among future PD cases. We conducted an indirect test of the latter hypothesis by comparing the incidence of PD between alcoholics and nonalcoholics in the General Practice Research Database of the United Kingdom. Our case-control study included 1,019 cases and 10,123 matched controls. Overall, we did not find a lower incidence of PD among alcoholics compared with nonalcoholics (odds ratio: 1.09; 95 % CI: 0.67, 1.78).