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PubMed2000

Craving: what can be done to bring the insights of neuroscience, behavioral science and clinical science into synchrony.

Alcohol self-administration behavior is the common thread that is necessary to bring the insights of neuroscience, behavioral science and clinical science into synchrony around the concept of craving. Animal models should address the molecular and cellular changes that take place in behaviorally relevant brain regions of rats consequent to chronic self-administration of ethanol. Animal models can focus on the biology of the anticipatory state in alcohol preferring/consuming rats, as well as studies of the effects of possible medications on this state in the animal model, on actual alcohol consuming behavior, and on the residual effects of chronic alcohol on the non-human mammalian brain. In human studies of craving, cue-reactivity in the absence of the opportunity to drink alcohol does not have the same salience as cue-reactivity in which drinking is possible. Moreover, actual drinking behavior serves to validate self-reports of craving. Studies of limited alcohol self-administration in the laboratory are an essential element in screening new medications for the treatment of alcoholism. Studies to date suggest no adverse reaction to the participation of alcoholic subjects in limited alcohol self-administration studies, but the research community should continue to monitor carefully the outcomes of alcohol-dependent subjects who participate in this type of research, and efforts should always be made to encourage these subjects to enter active treatment. In outpatient clinical trials of new treatments for alcoholism, the assessment of craving should include queries regarding symptoms and signs of protracted abstinence such as sleep disturbances, as well as questions regarding situational craving. Field observations of alcoholics in their favorite drinking environments would contribute greatly to our understanding of the real-world phenomenology of craving.

Alcohol Drinking↗

PubMed2000

Transdisciplinary concepts and measures of craving: commentary and future directions.

A new theoretical model of craving is needed that uses a common language and standardized measures. The new conceptual model must fully integrate discoveries from cellular biology, neuroscience, animal and human laboratory, cognitive-behavioral social learning and socio-cultural disciplines. A transdisciplinary synthesis can then guide methods and measurement development. Mapping the structural pathways and interactions among mediators and moderators of craving will improve the diagnostic and prognostic tools in order to inform new treatments and prevention strategies.

Animals↗

PubMed2002

The apomorphine test: a biological marker for heroin dependence disorder?

This experimental study was conducted in the inpatient detoxification addictive behavior unit of the Sant Pau Hospital in Barcelona and included 22 healthy subjects (HS) and 42 intravenous heroin-dependent subjects (HDS). Apomorphine-induced yawning rates were investigated in three different groups; heroin-dependent patients stabilized on d-propoxiphene, heroin-dependent patients recently withdrawn from d-propoxiphene and normal controls. Yawning responses were recorded continuously by independent observers for periods of 45 minutes following administration of low doses of subcutaneous apomorphine and NaCl. The lowest subcutaneous apomorphine dose able to induce a significantly higher number of yawning responses in HS was 0.005 mg/kg. The yawning responses induced by this dose in HDS were also significantly higher than those induced by placebo. When comparing the number of yawning responses between the study groups, differences were observed only between HDS and HS and no effect of gender was obtained. The apomorphine test may be useful in assessing central dopamine system alterations associated with chronic heroin consumption and could be a stable and reliable biological marker of heroin-dependence disorders.

Adult↗

PubMed2004

Nicotine craving and cue exposure therapy by using virtual environments.

Smokers who are exposed to cues associated with smoking show cardiovascular reactivity and an increase in smoking urges as compared to when they are presented with neutral cues. Cue exposure therapy (CET), which refers to the repeated exposure to drug-related cues in order to extinguish this learned association, has increasingly been proposed as a potential treatment of addictive behaviors, including tobacco smoking. The result of our pilot study suggests that a cue elicited using a virtual environment (VE) is more effective than other cue exposure devices. The VE was composed of craving environments (virtual bar) and objects (an alcoholic drink, a packet of cigarettes, a lighter, an ashtray, a glass of beer, and advertising posters) that are likely to trigger craving, a smoking avatar, and an audio environment that included the noisy sound and music of a restaurant. Sixteen late-adolescent males who smoked at least 10 cigarettes a day were recruited to participate in the VE-CET study. The CET virtual bar program consisted of six sessions, and the participants were exposed repeatedly to each session using different questions and procedures. Although the effects of CET did not yield significant reductions in all of the dependent variables, the craving for cigarettes was gradually decreased during the course of the sessions. This tendency was closely related to the reduction in the smoking count between the morning before the experiment and the start of the experiment. Based on these preliminary results, it appears that VE-CET maybe a useful tool to use in treatment programs to help reduce craving in those who are nicotine dependent.

Adolescent↗

PubMed2006

Repeated cocaine administration promotes long-term potentiation induction in rat medial prefrontal cortex.

Although drug-induced adaptations in the prefrontal cortex (PFC) may contribute to several core aspects of addictive behaviors, it is not clear yet whether drugs of abuse elicit changes in synaptic plasticity at the PFC excitatory synapses. Here we report that, following repeated cocaine administration (15 mg/kg/day intraperitoneal injection for 5 consecutive days) with a 3-day withdrawal, excitatory synapses to layer V pyramidal neurons in rat medial prefrontal cortex (mPFC) become highly sensitive to the induction of long-term potentiation (LTP) by repeated correlated presynaptic and postsynaptic activity. This promoted LTP induction is caused by cocaine-induced reduction of gamma-aminobutyric acid (GABA)(A) receptor-mediated inhibition of mPFC pyramidal neurons. In contrast, in slices from rats treated with saline or a single dose of cocaine, the same LTP induction protocol did not induce significant LTP unless the blockade of GABA(A) receptors. Blockade of the D1-like receptors specifically prevented the cocaine-induced enhancement of LTP. Repeated cocaine exposure reduced the GABA(A) receptor-mediated synaptic currents in mPFC pyramidal neurons. Biotinylation experiments revealed a significant reduction of surface GABA(A) receptor alpha1 subunit expression in mPFC slices from repeated cocaine-treated rats. These findings support an important role for cocaine-induced enhancement of synaptic plasticity in the PFC in the development of drug-associated behavioral plasticity.

Animals↗

PubMed2002

Healthy Body/Healthy Spirit: a church-based nutrition and physical activity intervention.

African-Americans (AAs) are significantly less likely to be physically active than other Americans, and, like all Americans, they consume fewer than the recommended five fruit and vegetable (F & V) servings per day. This study, titled Healthy Body/Healthy Spirit, has two primary aims: (1) to test the effectiveness of a culturally tailored self-help dietary (focusing on F & V intake) and physical activity (PA) intervention compared to standard health education materials, and (2) to test the effectiveness of using Motivational Interviewing (MI), delivered by telephone, to modify PA and dietary habits. The study is a randomized effectiveness trial with three experimental conditions. Group 1 (comparison) will receive standard (existing commercial) nutrition and PA intervention materials, Group 2 (TX1) will receive a culturally tailored self-help nutrition and PA intervention of similar intensity as Group 1, and Group 3 (TX2) will receive the same intervention as Group 2, plus four telephone counseling calls based on MI. Participants will be AA adults recruited through local black churches. Despite the extensive use of MI to modify addictive behaviors, this represents one of the first controlled field trials to employ MI to address diet and PA. Secondly, this is one of the first studies to test the effectiveness of a self-help diet and PA intervention tailored for an African-American church population.

Adult↗

PubMed2004

Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use.

Fatty acid amide hydrolase (FAAH) inactivates the endogenous cannabinoid (endocannabinoid) anandamide and related lipid transmitters in vivo. A single nucleotide polymorphism (SNP) in the human FAAH gene (385C to A) has recently been described that, in homozygous form, is over-represented in subjects with problem drug use. This SNP, which converts a conserved proline residue in FAAH to threonine (P129T), suggests a potential role for the FAAH-endocannabinoid system in regulating addictive behavior. Nonetheless, the impact of the 385A mutation on the biochemical and cellular function of FAAH remains unknown. Here, we report that T-lymphocytes isolated from patients homozygous for the P129T-FAAH variant express less than half of the FAAH protein and activity observed in wild-type (WT) lymphocytes. Transfected COS-7 cells also expressed significantly lower levels of P129T-FAAH compared with WT-FAAH, indicating that the aberrant expression of the former protein is not a cell type-specific phenomenon. A comparison of the transcription/translation efficiencies and cellular stabilities of WT- and P129T-FAAH proteins revealed that the reduced expression of the mutant enzyme is due to a post-translational mechanism that precedes productive folding. These findings indicate that the natural 385A SNP in the human FAAH gene produces a mutant enzyme with reduced cellular stability, thus fortifying a potential link between functional abnormalities in the endocannabinoid system and drug abuse and dependence.

Amidohydrolases↗

PubMed2000

Reproducibility of the University of Toronto self-administered questionnaire used to assess environmental sensitivity.

Environmental sensitivity patients report symptoms provoked by low-level exposure to a wide range of substances. Features of published case definitions include nature of onset, chronicity, symptom provocation by multiple substances, symptom provocation by an escalating number of exposures, involvement of multiple body systems including the nervous system, provocation by unrelated substances, and addictive behaviors. This study assessed the reproducibility of a Canadian self-administered questionnaire, the University of Toronto Health Survey, designed to determine the prevalence of the features described in these case definitions. A total of 191 eligible respondents aged 16-70 years who attended several types of medical practices in 1994 were invited to complete a second questionnaire 5-7 months after the first; 134 (70.2%) complied. Total agreement on whether patients satisfied each of seven case definitions ranged from 80% to 90%. After adjustment for chance, major agreement was observed for three of the seven case definitions (kappa = 0.69, 0.68, and 0.78). The survey achieved good reproducibility regarding self-report of symptoms described in published case definitions of environmental sensitivity.

Adolescent↗

PubMed2004

Motivational strategies with alcohol-involved older adults: implications for social work practice.

Social workers and other health care professionals address problem drinking by older adults inconsistently. Reasons include client-related variables (for example, denial and poor information), practitioner-related factors (for example, inadequate knowledge about addictive behaviors, underdeveloped assessment tools, and limited empirically validated treatment options), and societal factors associated with "ageism." This article explores the nature and extent of problem drinking among older adults and barriers to assistance. The article outlines practice strategies that draw on motivational interviewing principles and a client's motivational readiness to change for reaching out to older adults, assessing their needs, and encouraging them to seek assistance.

Adult↗

PubMed1999

Long-term opioid analgesic therapy for severe refractory lumbar spine pain.

OBJECTIVES: To determine the effect of opioid analgesics on pain and function in patients with severe, refractory low back pain and to see if any benefits were sustained long term. DESIGN: Longitudinal evaluation was conducted in two stages. Stage I was an opioid trial, and stage II was long-term treatment. Treated patients were compared with dropouts and trial failures. OUTCOME MEASURES: Pain was measured by the Numerical Rating Scale (NRS) and function was measured by the Oswestry Low Back Disability Score (OSW). Outcomes were evaluated by patient questionnaire and therefore not subject to investigator bias. SETTING: Private office practice. METHODS: Patients were treated for 6-12 weeks with a long-acting or sustained-release opioid. Those who improved significantly were treated long term. The treatment group was compared with dropouts and failures. RESULTS: Thirty-three patients underwent opioid trial. Treatment was discontinued because of intolerable side effects in 5 patients. In the remaining 28, mean NRS improved from 8.6 to 5.9 (p < 0.001), and mean OSW improved from 64 to 54 (p < 0.001). There were 21 patients treated long term (mean, 32 months). NRS improved from 8.45 to 4.90 (p < 0.001), and OSW improved from 64 to 50 (p < 0.001). Two patients returned to work. The changes in pain and function in the treatment group were significantly better than the comparison group. There was no drug diversion, addictive behavior, or organ toxicity. Doses remained stable. CONCLUSION: Long-term opioid analgesic therapy is reasonable treatment for some well-selected patients with refractory low back pain who have failed all other forms of care.

Humans↗

PubMed1997

Child sexual abuse and emotional and behavioral problems in adolescence: gender differences.

OBJECTIVE: To compare sexually abused boys with sexually abused girls and with their non-sexually abused counterparts with regard to (1) the type of mental health problems they experience; and (2) the number and patterns of such problems. METHOD: The sample comprised 745 secondary school students, aged 12 to 19 years, with a self-reported history of sexual abuse (151 boys and 594 girls) and 745 matched students without such a history. Sexually abused and non-sexually abused boys and girls were compared with regard to four problem categories: emotional problems, aggressive/criminal behaviors, addiction-risk behaviors, and suicidality. RESULTS: A larger proportion of sexually abused adolescents than nonabused adolescents reported problems in the separate categories and in a combination of problem categories. Sexually abused boys had considerably more emotional and behavioral problems, including suicidality, than their female counterparts. There were differences between the specific combinations of problem categories reported by sexually abused girls and boys. These differences could not be attributed to the finding that sexually abused boys were more often the victim of concurrent physical abuse than sexually abused girls. CONCLUSIONS: The results suggest that although there was a strong association between being sexually abused and the existence of a multiple problem pattern in both sexes, the aftermath for boys might be even worse or more complex than for girls.

Adolescent↗

PubMed2000

Comparison of self-ratings and therapist ratings of outpatients' psychosocial status.

In psychiatric treatment, differences between therapists' observer ratings and patients' self-ratings are well known. We studied these differences in a sample of chronically mentally ill outpatients. The results show that the patients rated their psychosocial status significantly better than their therapists. By means of multiple regression analysis, we designed a model to explain the specific differences. By placing more emphasis on leisure activities and less emphasis on addictive behavior, compliance, and psychopathology, therapists might predict global ratings given by patients more accurately. This model helps therapists obtain a better understanding of their patients.

Adult↗

PubMed2002

Neurologic complications of substance abuse.

In addition to overdose, withdrawal, and addictive behavior, licit and illicit drugs produce a wide range of neurologic complications. Trauma results from intoxication and from violence related to a drug's illegality. Infection, including AIDS, is most often a consequence of parenteral use. Seizures can be secondary to either toxicity or withdrawal. Stroke can be ischemic or hemorrhagic. Persistent cognitive dysfunction affects alcoholics and probably users of other drugs as well. Teratogenicity is better documented for ethanol and tobacco than for illicit drugs. Other complications of recreational drug use include peripheral neuropathy, myelopathy, parkinsonism, leukoencephalopathy, optic atrophy, and cerebellar ataxia.

Humans↗

PubMed2003

Persistent alterations of vasopressin and N-terminal proatrial natriuretic peptide plasma levels in long-term abstinent alcoholics.

BACKGROUND: During alcohol withdrawal and early abstinence, severe alterations of electrolyte and water homeostasis and their regulating hormones are well recognized. Almost nothing is known about regeneration of these functions with long-term abstinence. This cohort study was designed to monitor determinants of electrolyte and water balance over 280 days of abstinence in alcohol-dependent men compared with healthy controls. METHODS: Vasopressin (AVP), N-terminal proatrial natriuretic peptide, aldosterone, angiotensin II, and electrolytes, together with major parameters of kidney and liver function, were monitored in 35 male alcoholics aged 44 +/- 8 years. Of these, 21 could be followed up to 280 days of strictly controlled abstinence due to their participation in the Outpatient Long-Term Intensive Therapy for Alcoholics. The control group comprised 20 healthy male volunteers aged 39 +/- 7 years. RESULTS: Basal AVP levels were found to be suppressed over the whole study period. In contrast, N-terminal proatrial natriuretic peptide remained increased over all 280 days. No persistent alterations were found for aldosterone or angiotensin II. Sodium and potassium in plasma and urine returned to normal within a few weeks. Creatinine clearance, urea nitrogen in plasma and urine, urinary osmolality, hematocrit, and hemoglobin remained low as compared with controls over the entire study. CONCLUSIONS: Chronic alcohol abuse causes severe and persistent alterations in the hormonal regulatory systems of electrolyte and water balance. The suppressed basal secretion of AVP may reflect a dysregulation in the brain that influences the hypothalamic-pituitary-adrenal axis function, mood, memory, addiction behavior, and craving during alcohol abstinence. These findings may provide a ground for future therapeutic approaches to stable abstinence.

Adult↗

PubMed2006

Human clock, PER1 and PER2 polymorphisms: lack of association with cocaine dependence susceptibility and cocaine-induced paranoia.

Considerable research points to the importance of genetic mechanisms in psychostimulant addiction. Behavioral sensitization, a well-documented response to repeated stimulant exposure, may be mechanistically important in clinical features of the disorder, including escalating patterns of drug use, craving and drug-induced paranoia. Basic studies in both Drosophila melanogaster and mice have suggested the importance of circadian rhythm genes in locomotor sensitization and reward. The primary objective of the current study was to assess the potential involvement of three human orthologs (CLOCK, PER1 and PER2) in clinical phenotypes of the disorder. Allelic associations of three single nucleotide polymorphisms (SNPs) were assessed for both cocaine dependence and cocaine-induced paranoia in 186 cases and 273 controls. Potential population stratification biases were controlled for by means of within-population comparisons, and by structured association methods (using all populations). No differences in allele frequencies were found for any of the three single nucleotide polymorphisms studied between cocaine dependent and control subjects or between paranoid and nonparanoid cocaine users. These results do not support the involvement of genetic variation in these three circadian gene SNPs for influencing risks for either of these cocaine phenotypes.

Animals↗

PubMed2003

Preattentive processing of alcohol stimuli.

An experiment was conducted to test the automatic analysis of briefly presented alcohol stimuli in alcohol-dependent individuals. Alcoholics and controls were exposed to four different conditions: two brief (30 ms) and two long (130 ms) exposure conditions, each containing alcoholic and non-alcoholic pictures. Heart rate (HR) interbeat intervals were recorded and phasic cardiac responses assessed. Alcoholics had a stronger initial HR deceleration after exposure to masked alcohol slides compared with masked control slides, indicating a preattentive analysis of alcohol stimuli. This initial HR deceleration in the masked condition suggests an automatic attentional focusing to degraded alcohol cues. No such attentional effect was found when the pictures were presented unmasked and were clearly perceived. The implication of these results for the understanding of relapse in addictive behavior is discussed.

Alcohol Drinking↗

PubMed1994

Hypothalamic-pituitary-thyroid axis in chronic alcoholism. II. Deiodinase activities and thyroid hormone concentrations in brain and peripheral tissues of rats chronically exposed to ethanol.

Thyroxine (T4), triiodothyronine (T3) concentrations, and the activities of the three deiodinase isoenzymes were measured in different brain regions and peripheral tissues of rats. According to an animal model of alcohol addiction, "behaviorally" dependent rats having lost control over their intake of ethanol were compared with alcohol-naive controls and ethanol-experienced, but "controlled" consumers. The two kinds of alcohol-experienced rats were investigated either 24 hr or 3 months after ethanol withdrawal. The results of these four groups were compared with those of an ethanol-naive control group. During withdrawal, the activities of type II 5'-deiodinase (which catalyzes deiodination of T4 and T3 in the CNS) in both the "behaviorally dependent" rats and the "controlled drinkers" were significantly lower than in the alcohol-naive controls in the frontal cortex, parieto-occipital cortex, hippocampus, and striatum, but not in the cerebellum or pituitary. Probably as a result, the tissue concentrations of T4 were higher in areas of the CNS in the groups exposed to alcohol. However, the T3 concentrations were normal. No relevant differences were seen between the activities of type III 5-deiodinase (which catalyzes the further deiodination of T3) observed in these groups. After 3 months of abstinence, the type II 5'-deiodinase activities had almost returned to normal in both "controlled drinkers" and "behaviorally dependent" animals, whereas type III 5-deiodinase activity was inhibited, possibly to maintain physiological concentrations of T3 during abstinence. Indeed, the tissue levels of T3 were normal in the areas of the CNS, and the T4 levels were still elevated. However, the liver concentrations of T3 and T4 were significantly lower in the "behaviourally dependent" animals than in the "controlled" drinkers after 3 months of abstinence, whereas no differences were found between the T4 and T3 concentrations in the areas of the CNS investigated in the two groups exposed to ethanol. These results suggest that chronic administration of ethanol affects intracellular thyroid hormone metabolism in both rat CNS and liver in the highly complex manner. No direct evidence of ethanol-induced enhancement of tissue uptake or concentrations was obtained. However, taking into account the numerous similarities between the clinical picture of hyperthyroidism and the symptomatology of alcoholism, it may be hypothesized that ethanol may directly influence any step in the as yet unknown biochemical cascade of thyroid hormone function.

Alcoholism↗

PubMed2006

Development of an alcohol deprivation and escalation effect in C57BL/6J mice.

BACKGROUND: Relapse-like drinking has been studied through the expression of the alcohol deprivation effect (ADE), which is measured by a pronounced increase in ethanol preference and consumption after imposed abstinence. No studies have characterized the ADE in C57BL/6J (B6) mice. The present study examined the effects of length and number of deprivations on the expression of the ADE in B6 mice. METHODS: Adult male B6 mice received 24-hour continuous access to ethanol and water for 6 weeks (baseline). Experiment 1 determined the ADE in mice receiving weekly access to 15% ethanol (i.e., exposed 1 day a week and deprived during the other 6 days) for a total of 10 weeks. Experiments 2 and 3 determined the ADE after a single 2-week deprivation period in mice receiving a single concentration of 15% ethanol or multiple concentrations of 7.5, 15, and 30% ethanol, respectively, followed by weekly access to their respective ethanol solutions for 10 weeks. Experiment 4 determined the ADE after a single 2-week deprivation period, followed by daily access to 15% ethanol. Mice never deprived of ethanol (i.e., continuous access) were used as age-matched drinking controls. RESULTS: The ADE was observed after the initial 6-day deprivation period and was profoundly enhanced (i.e., escalation of the ADE) following weekly reexposure to 15% ethanol. Compared with a single concentration of 15% ethanol, concurrent access to multiple ethanol concentrations resulted in a near 2-fold increase in baseline ethanol consumption. Regardless of having access to single or multiple concentrations of ethanol, the ADE was not observed immediately after a 2-week deprivation period. The ADE was observed (although to a lesser magnitude and duration) following weekly reexposure to single or multiple concentrations of ethanol. Alternatively, following a 2-week deprivation period, mice receiving daily access to 15% ethanol showed a significant decrease in ethanol intake and preference (i.e., negative ADE). CONCLUSIONS: Short-term deprivations followed by repeated intermittent (weekly) reexposure to ethanol produces a robust ADE in B6 mice. Increasing the initial deprivation length to 2 weeks produces various opposing effects, including erasure of an initial ADE, diminished expression and magnitude of the ADE following weekly exposure, and complete reversal of the ADE following daily exposure to ethanol.

Alcohol Drinking↗