Opiate tolerance and dependence: receptors, G-proteins, and antiopiates

Despite the existence of a large body of information on the subject, the mechanisms of opiate tolerance and dependence are not yet fully understood. Although the traditional mechanisms of receptor down-regulation and desensitization seem to play a role, they cannot entirely explain the phenomena of tolerance and dependence. Therefore, other mechanisms, such as the presence of antiopiate systems and the coupling of opiate receptors to alternative G-proteins, should be considered. A further complication of studies of opiate tolerance and dependence is the multiplicity of endogenous opiate receptors and peptides. This review will focus on the endogenous opioid system--peptides, receptors, and coupling of receptors to intracellular signaling via G-proteins--in the context of their roles in tolerance and dependence. Opioid peptides include the recently discovered endomorphins and those encoded by three known genes--pro-opiomelanocortin, pro-enkephalin, and pro-dynorphin. They bind to three types of receptors--mu, delta, and kappa. Each of the receptor types is further divided into multiple subtypes. These receptors are widely known to be coupled to G-proteins of the Gi and Go subtypes, but an increasing body of results suggests coupling to other G-proteins, such as Gs. The coupling of opiate receptors to Gs, in particular, has implications for tolerance and dependence. Alterations at the receptor and transduction level have been the focus of many studies of opiate tolerance and dependence. In these studies, both receptor down-regulation and desensitization have been demonstrated in vivo and in vitro. Receptor down-regulation has been more easily observed in vitro, especially in response to morphine, a phenomenon which suggests that some factor which is missing in vitro prevents receptors from down-regulating in vivo and may play a critical role in tolerance and dependence. We suggest that antiopiate peptides may operate in vivo in this capacity, and we outline the evidence for the antiopiate properties of three peptides: neuropeptide FF, orphanin FQ/nociceptin, and Tyr-W-MIF-1. In addition, we provide new results suggesting that Tyr-W-MIF-1 may act as an antiopiate at the cellular level by inhibiting basal G-protein activation, in contrast to the activation of G-proteins by opiate agonists.     

Community studies on adolescent substance use, abuse, or dependence and psychiatric comorbidity.

A literature review on community studies of adolescent substance use, abuse, or dependence (SU/A/D) and psychiatric comorbidity yielded 22 articles from 15 studies with information on rates, specificity, timing, and differential patterns of comorbidity by gender, race/ethnicity, and other factors. Results revealed that 60% of youths with SU/A/D had a comorbid diagnosis, and conduct disorder (CD) and oppositional defiant disorder (not attention-deficit/hyperactivity disorder) were most commonly associated with SU/A/D, followed by depression. Child psychopathology (particularly CD) was associated with early onset of substance use and abuse in later adolescence. The authors suggest that available data relevant to SU/A/D and psychiatric comorbidity can be used to better address such questions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Racial factors in birth seasonality among schizophrenics: A preliminary analysis.

The records of 724 institutionalized schizophrenics were analyzed with regard to patterns of birth seasonality. A population model was derived from birth records of all people born during the same years and regions as the schizophrenics. Log-linear analyses uncovered a highly significant difference between the birth seasons of Black and White patients. Black schizophrenics were especially likely to be winter-born, while White schizophrenics had a birth peak in the fall. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Distinguishing general and specific personality disorder features and implications for substance dependence comorbidity.

Clinical and population-based samples show high comorbidity between Substance Use Disorders (SUDs) and Axis II Personality Disorders (PDs). However, Axis II disorders are frequently comorbid with each other, and existing research has generally failed to distinguish the extent to which SUD/PD comorbidity is general or specific with respect to both specific types of PDs and specific types of SUDs. We sought to determine whether ostensibly specific comorbid substance dependence-Axis II diagnoses (e.g., alcohol use dependence and borderline personality disorder) are reflective of more pervasive or general personality pathology or whether the comorbidity is specific to individual PDs. Face-to-face interview data from Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were analyzed. Participants included 34,653 adults living in households in the United States. We used hierarchical factor models to statistically partition general and specific personality disorder dimensions while simultaneously testing for specific PD-substance dependence relations. Results indicated that substance dependence-Axis II comorbidity is characterized by general (pervasive) pathology and by Cluster B PD pathology over and above the relationship to the general PD factor. Further, these relations between PD factors and substance dependence diagnoses appeared to largely account for the comorbidity among substance dependence diagnoses in the younger but not older participants. Our findings suggest that a failure to consider the general PD factor, which we interpret as reflecting interpersonal dysfunction, can lead to potential mischaracterizations of the nature of certain PD and SUD comorbidities. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Violence and risk of PTSD, major depression, substance abuse/dependence, and comorbidity: Results from the National Survey of Adolescents.

With a national household probability sample of 4,023 telephone-interviewed adolescents ages 12-17, this study provides prevalence, comorbidity, and risk-factor data for posttraumatic stress disorder (PTSD), major depressive episode (MDE), and substance abuse/dependence (SA/D). Roughly 16% of boys and 19% of girls met criteria for at least 1 diagnosis. Six-month PTSD prevalence was 3.7% for boys and 6.3% for girls, 6-month MDE prevalence was 7.4% for boys and 13.9% for girls. and 12-month SAM prevalence was 8.2% for boys and 6.2% for girls. PTSD was more likely to be comorbid than were MDE and SA/D. Results generally support the hypothesis that exposure to interpersonal violence (i.e., physical assault, sexual assault, or witnessed violence) increases the risk of these disorders and of diagnostic comorbidity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Psychiatric disorder in a birth cohort of young adults: Prevalence, comorbidity, clinical significance, and new case incidence from ages 11–21.

Mental health data were gathered at ages 11, 13, 15, 18, and 21 in an epidemiological sample using standardized diagnostic assessments. Prevalence of Diagnostic and Statistical Manual of Mental Disorders-III-Revised (DSM-III-R) mental disorders increased longitudinally from late childhood (18%) through mid- (22%) to late-adolescence (41%) and young adulthood (40%). Nearly half of age-21 cases had comorbid diagnoses; and comorbidity was associated with severity of impairment. The incidence of cases with adult onset was only 10.6%: 73.8% of adults diagnosed at age 21 had a developmental history of mental disorder. Relative to new cases, those with developmental histories were more severely impaired and more likely to have comorbid diagnoses. The high prevalence rate and significant impairment associated with a diagnosis of mental disorder suggests that treatment resources need to target the young adult sector of the population. The low new-case incidence in young adulthood, however, suggests that primary prevention and etiological research efforts need to target children and adolescents. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Psychiatric comorbidity, health status, and functional impairment associated with alcohol abuse and dependence in primary care patients: Findings of the PRIME MD-1000 study.

The psychiatric comorbidity, health, and functioning of primary care patients with alcohol abuse and dependence (AAD) was investigated in a sample of 1,000 patients. Psychiatric symptomatology was assessed with the Primary Care Evaluation of Mental Disorders (PRIME-MD) diagnostic system. Health and functional status was assessed with the Medical Outcomes Study Short Form General Health Survey (SF-20). Results indicated that use of the PRIME-MD system brought about a 71% increase in physician recognition of AAD. AAD patients were diagnosed with substantial psychiatric comorbidity, and they reported poorer health and functioning than did patients without any psychiatric disorders. However, they reported less impairment and psychiatric comorbidity than did patients with other psychiatric disorders. Results also indicated that AAD patients' health and functioning were associated with the presence or absence of psychiatric comorbidity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hyperactivity, inattention and motor control problems: prevalence, comorbidity and background factors

This paper provides a brief review of syndromes associated with activity dysregulation, inattention and motor control problems, usually referred to as attention-deficit/hyperactivity disorder, developmental coordination disorder and deficits in attention, motor control and perception. Several percent of school age children are affected by such problems. Disorders tend to overlap and show significant comorbidities. Familial and brain-damaging factors are involved in the pathogenesis and appear to impinge on specific attentional brain systems. Outcome is variable but restricted if appropriate diagnosis/intervention is not accomplished. Effective interventions are available. Given the high prevalence of these disorders and their relatively poor outcome, such interventions could constitute effective prevention in a general population health perspective.     

Opiate and cocaine addictions: challenge for pharmacotherapies

Neurobiological and behavioral studies, as well as basic and applied clinical research studies, may all contribute to the development of a pharmacotherapy for a specific addictive disease. This paper reviews recent findings from research work, primarily from one laboratory along with collaborative laboratories, that could have some relevance for the development of pharmacotherapy for cocaine dependency. The much earlier experiences of this laboratory in the development of a pharmacotherapy for opiate addiction will be addressed in the context of providing both some specific suggestions for addictive disease pharmacotherapy development and some warnings about the complexities of the introduction and implementation of a pharmacotherapy once developed. Finally, based on both the earlier perspectives and the more recent research findings, some very specific, though speculative, suggestions will be made about the development of novel pharmacotherapies for early opiate addiction, especially for cocaine abuse or addiction and prevention of relapse to cocaine use. The complex and diverse nature of the challenge for pharmacotherapy for the addictive diseases is presented, including specifically a mandate for broadening educational efforts concerning the basis of addictive diseases and the need for treatment, in parallel with the scientific efforts to develop increasingly sophisticated and targeted pharmacotherapies.     

Empathy, self-esteem, and birth order.

An experiment to measure empathy following induced identification. Empathy is defined as sharing the presumed feelings of someone with whom you have similarity. ? of 132 lower division college students were arbitrarily assigned an attribute of nonfunctional similarity (having worked on similar tasks) with a paid model. The other ? were treated differently only in this respect. ? the Ss under each of these conditions were exposed to the model's public success, the other ? to the model's public failure. Simultaneously, a 2nd measure of palmar sweat was taken. Retrospective reports of anxiety were then obtained. Anticipated differential palmar sweating among the 4 conditions was not observed. Self-reports indicated empathy when the model was similar, p     

Pedophilia, sexual orientation, and birth order

BACKGROUND/AIMS: Vagal dysfunction is reported in about 70% of patients with cirrhosis, irrespective of aetiology, as detected by cardiovascular reflex tests. We have previously shown that RR-variability on 24-h ECG is a more sensitive marker of vagal dysfunction in cirrhosis. Angiotensin II inhibits vagal function in animals, and it is elevated in cirrhosis and may be the cause of the vagal dysfunction. Our aim was to observe the effect of captopril on vagal dysfunction in cirrhosis. METHODS: Eight patients with cirrhosis (biopsy proven, male two, female six, mean age 54.25) had 24-h ECG RR-variability performed. They then received captopril 25 mg t.d.s. for 48 h. The 24-h ECG was repeated on therapy. RESULTS: Mean blood pressure remained unchanged: baseline 89.8 +/- 4.8 mmHg (mean +/- sem) versus 91.8 +/- 5.9 mmHg, p = not significant. Median baseline RR-variability was 791 (range 18-5344) counts/24 h and increased in all but one patient, with captopril, to 1548 (56-4824) p = 0.008. Three increased into the normal range. CONCLUSION: The vagal dysfunction of cirrhosis is caused by neuromodulation by angiotensin II and is not due to a neuropathy.     

Childhood-onset psychosis: evolution and comorbidity

High resolution cytogenetics, microsatellite marker analyses, and fluorescence in situ hybridization were used to define Xq deletions encompassing the fragile X gene, FMR1, detected in individuals from two unrelated families. In Family 1, a 19-year-old male had facial features consistent with fragile X syndrome; however, his profound mental and growth retardation, small testes, and lover limb skeletal defects and contractures demonstrated a more severe phenotype, suggestive of a contiguous gene syndrome. A cytogenetic deletion including Xq26.3-q27.3 was observed in the proband, his phenotypically normal mother, and his learning-disabled non-dysmorphic sister. Methylation analyses at the FMR1 and androgen receptor loci indicated that the deleted X was inactive in > 95% of his mother's white blood cells and 80-85% of the sister's leukocytes. The proximal breakpoint for the deletion was approximately 10 Mb centromeric to FMR1, and the distal breakpoint mapped 1 Mb distal to FMR1. This deletion, encompassing approximately 13 Mb of DNA, is the largest deletion including FMR1 reported to date. In the second family, a slightly smaller deletion was detected. A female with moderate to severe mental retardation, seizures, and hypothyroidism, had a de novo cytogenetic deletion extending from Xq26.3 to q27.3, which removed approximately 12 Mb of DNA around the FMR1 gene. Cytogenetic, and molecular data revealed that approximately 50% of her white blood cells contained an active deleted X. These findings indicate that males with deletions including Xq26.3-q27.3 may exhibit a more severe phenotype than typical fragile X males, and females with similar deletions may have an abnormal phenotype if the deleted X remains active in a significant proportion of the cells. Thus, important genes for intellectual and neurological development, in addition to FMR1, may reside in Xq26.3-q27.3. One candidate gene in this region, SOX3, is thought to be involved in neuronal development and its loss may partly explain the more severe phenotypes of our patients.     

Relationship between birth order, birth stress, and lateral preferences: A critical review.

Reviews the literature examining the relationship between birth order, birth stress, and lateral preferences in nonclinical samples, with special emphasis on reports since 1971. The review found no evidence to relate birth order position to deviations from right-sidedness for either sex. More direct measures of birth stress indicated that deviations from right-handedness (particularly for male subjects), and also right-eyedness, were statistically related to specific birth stressors. It should be stressed, however, that all the relationships, including the significant ones, were very weak, accounting for less that 1% of the variance. When statistical significance was achieved, it was largely due to the huge sample sizes used in the meta-analyses. Methodological and theoretical problems exist in the current literature, and we offer some suggestions to resolve them. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Schizophrenia and delusional disorder in older age: community prevalence, incidence, comorbidity, and outcome

Obesity is associated with dyslipidaemia characterised by increased fasting triglyceride and decreased high-density lipoprotein (HDL) concentrations. Causes for obesity-associated dyslipidaemia include insulin resistance, excessive caloric intake, increased free fatty acid production and disturbances in the counter-regulatory hormones. We examined the relationships between lipid parameters and obesity before and after adjustment of insulin resistance in 902 Hong Kong Chinese men. After adjustment for age, smoking and insulin resistance, increasing body mass index (BMI) and waist-to-hip ratio (WHR) remained closely associated with increased concentrations of triglyceride and apolipoprotein B (apo B), increased ratios between low-density lipoprotein (LDL) and HDL (LDL/HDL), and that between apo B and LDL (apo B/LDL), increased fasting and 2-h plasma glucose and insulin, as well as decreased concentrations of HDL, HDL2 and apolipoprotein A-I (apo A-I). On stepwise multiple regression analysis using age, BMI, WHR, insulin resistance and fasting plasma glucose as independent variables, BMI and WHR were the major determinants for the variance of triglyceride, HDL and its subfractions, LDL/HDL, apo B and apo B/LDL. Age was the most important predictor for total cholesterol and LDL. Insulin resistance only explained less than 1% of the variance in triglyceride and apo B. This was compared to a variance between 10 and 16% in these parameters as explained by BMI and/or WHR. In conclusion, obesity is associated with dyslipidaemia in Chinese men, characterised by increased plasma triglyceride, apo B, LDL/HDL, apo B/LDL, and decreased HDL, HDL2 and apo A-I concentrations. Obesity independent of insulin resistance, in particular central adiposity as reflected by increased WHR, was the most important independent variable for many of these lipid abnormalities. Our results emphasised the multifactorial linkage between obesity and dyslipidaemia.     

Alcoholism, birth order, and socializing agents.

A study of 276 female alcoholics admitted to an alcoholism clinic during the period 1951-62 showed that being born last rather than first or other born significantly relates to the absence of 1 or both natural parents during the first 5 yr. of childhood. The author concludes that besides Schachter's reduced affiliation tendency during anxiety, the absence of 1 or both natural parents during childhood is also strongly indicated as a variable meaningfully intervening between birth order and alcoholism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alcoholism, birth order, and family size.

On the basis of Schachter's findings relating affiliation during anxiety to birth order it was predicted that later borns and persons from large families should be overrepresented among alcoholics and that the number of alcoholics within each family size should increase with increasing birth order. First borns were expected to have significantly more therapeutic contacts than later borns. It was pointed out that Schachter's analyses, based on Bakan's data, lacked, among other things, a correction for family size. When this correction was employed with birth order and family size data from a sample of 242 treated alcoholics, the only hypothesis supported was that relating to an overrepresentation of persons from large families. (PsycINFO Database Record (c) 2010 APA, all rights reserved)