Energy substrate metabolism among habitually violent alcoholic offenders having antisocial personality disorder.

A large proportion of violent offences in Western countries are attributable to antisocial personality disorder (APD). Several studies have shown abnormal lipid, carbohydrate and low cerebrospinal fluid (CSF) monoamine metabolite levels in habitually violent alcoholic offenders with APD, but it is not clear how these biochemical abnormalities are related to each other in this disorder. We aimed to study energy substrate metabolism among habitually violent offenders with APD. Insulin sensitivity (euglycemic insulin clamp), basal energy expenditure (indirect calorimetry), and CSF 5-hydroxyindoleacetic acid (5-HIAA) measurements were performed on 96 habitually violent antisocial male alcoholic offenders and on 40 normal male controls. Habitually violent, incarcerated offenders with APD had significantly lower non-oxidative glucose metabolism, basal glucagon, and free fatty acids when compared with normal controls, but glucose oxidation and CSF 5-HIAA did not differ markedly between these groups. The effect sizes for lower non-oxidative glucose metabolism among incarcerated and non-incarcerated APD subjects were 0.73 and 0.51, respectively, when compared with controls, indicating that this finding was not explained by incarceration. Habitually violent offenders with APD have markedly lower glucagon and non-oxidative glucose metabolism when compared with healthy controls, and these findings were more strongly associated with habitual violent offending than low CSF 5-HIAA levels, a well-established marker for impulsive violent behavior. Follow-up studies are needed to confirm if abnormal glucose and lipid metabolism can be used to predict violent offending over the course of the APD offender's life span.

Genetic and other contributions to alcohol intake in rhesus macaques (Macaca mulatta).

BACKGROUND: The etiology of alcoholism and alcohol abuse, like many other complex diseases, is heterogeneous and multifactorial. Numerous studies demonstrate a genetic contribution to variation in the expression of alcohol-related disorders in humans. Over the past decade, nonhuman primates have emerged as a valuable model for some aspects of human alcohol abuse because of their phylogenetic proximity to humans. Long-term, longitudinal studies of rhesus macaques (Macaca mulatta) have provided much insight into environmental influences, especially early life experiences, on alcohol consumption and behavior patterns that characterize alcohol intake later in life. It is not known, however, whether there is a genetic component as well to the variation seen in alcohol consumption in rhesus macaques. A significant genetic component to variation in alcohol consumption in rhesus macaques would show for the first time that like humans, for nonhuman primates additive genetic influences are important. Moreover, their use as a model for alcohol-related disorders in humans would have even greater relevance and utility for designing experiments incorporating the expanding molecular genetics field, and allow researchers to investigate the interaction among the known environmental influences and various genotypes. METHODS: In this study, we investigate factors contributing to variation in alcohol consumption of 156 rhesus macaques collected over 10 years when subjects were adolescent in age, belonging to a single extended pedigree, with each cohort receiving identical early rearing backgrounds and subsequent treatments. To measure alcohol consumption each animal was provided unfettered simultaneous access both to an aspartame-sweetened 8.4% (v/v) alcohol-water solution, the aspartame-sweetened vehicle, and to water for 1 hour each day during the early afternoon between 13:00 and 15:00 in their home cages for a period of 5 to 7 weeks. We use multiple regression to identify factors that significantly affect alcohol consumption among these animals and a maximum likelihood program (ASReml) that, controlling for the significant factors, estimates the genetic contribution to the variance in alcohol consumption. RESULTS: Multiple regression analysis identified test cohort and rearing environment as contributing to 57 and 2%, respectively, of the total variance in alcohol consumption. Of the remaining 41% of the variance about half (19.8%) was attributable to additive genetic effects using a maximum likelihood program. CONCLUSION: This study demonstrates that, as in humans, there are additive genetic factors that contribute to variation in alcohol consumption in rhesus macaques, with other nongenetic factors accounting for substantial portions of the variance in alcohol consumption, Our findings show the presence of an additive genetic component and suggest the potential utility of the nonhuman primate as a molecular genetics tool for understanding alcohol abuse and alcoholism.

Maternal absence and stability of individual differences in CSF 5-HIAA concentrations in rhesus monkey infants.

OBJECTIVE: Early life events often lead to deficits in CNS serotonin function, which underlie a number of reoccurring psychopathological disorders. Studies using rhesus macaques have demonstrated that early maternal deprivation reduces CNS serotonin turnover, as measured by cisternal CSF 5-HIAA concentrations. In addition, individual differences in CSF 5-HIAA remain stable from the first year of life through adulthood. The purpose of this study was to assess 1) the impact of rearing environment on the early development (<6 months of age) of the serotonin system, and 2) at what stage of early development individual differences in CSF 5-HIAA concentrations stabilize. METHOD: The subjects were 256 infant rhesus macaques reared in three different conditions (mother-reared, peer-reared, and surrogate/peer-reared). Cisternal CSF was obtained at 14, 30, 60, 90, 120, and 150 days of age. RESULTS: No differences in CSF 5-HIAA concentrations were observed between peer only- and surrogate/peer-reared infants, and these groups combined exhibited lower 5-HIAA concentrations than mother-reared infants throughout early development. CSF 5-HIAA concentrations declined with increasing age regardless of rearing condition. Within each rearing condition, individual differences in CSF 5-HIAA concentrations remained stable from 14 to 150 days of age. CONCLUSIONS: Early maternal deprivation reduces CNS serotonin turnover, and individual differences in CSF 5-HIAA concentrations are trait-like and appear to stabilize in infancy.

Comparison of G-protein selectivity of human 5-HT2C and 5-HT1A receptors.

We compared the ability of human 5-HT2C and 5-HT1A receptors to couple to selected G proteins expressed in insect Sf9 cells through simultaneous infection with recombinant baculoviruses. We also examined the coupling of G proteins to these same receptors in membranes derived from the Sf9 cells using in situ reconstitution with purified G proteins. Our data show that unoccupied 5-HT2C and 5-HT1A receptors can attain an activated conformation that is stabilized by interaction with specific G proteins. While high-affinity agonist binding to the 5-HT2C receptor was increased to a greater extent by Galphaq than by Galphai2, the high-affinity agonist binding to the 5-HT1A receptor was preferentially enhanced by Galphai2 coexpression. When the two 5-HT receptors were expressed in cells also expressing G proteins, both 5-HT2C and 5-HT1A receptors appear to activate Galphai2 in preference to Galphaq. In contrast, in situ reconstitution data show that 5-HT2C receptors robustly activate Galphaq and marginally activate Galphao or Galphai, whereas 5-HT1A receptors only marginally activate Galphaq and robustly activate Galphao and Galphai. These results suggest that the overexpression of receptor and potential G-protein coupling partners in Sf9 cells may lead to erroneous conclusions as to the signaling selectivity of receptors.

On the Research Front: The NIAAA Intramural Research Program.

Intramural research at the National Institute on Alcohol Abuse and Alcoholism delves into many aspects of biological science relating to alcoholism, from the genetics of alcoholism to the imaging of alcohol-abusing patients' brains. Drawing on the unique resources within the National Institutes of Health, the Intramural Research Program plans to continue its commitment to conducting cutting-edge research.

Efeitos da buspirona e diazepam, puros ou em combinaçäo com álcool, no desempenho de habilidades e potencias evocados / Buspirone and diazepam effects alone or in association with the alcohol in abilities and e vocated menpowers

Os efeitos da buspirona 10 e 20 mg e diazepam 10 mg no desempenho de habilidades e me respostas evocadas, bem como suas interaçöes com álcool - 0.8 g/Kg, foram pesquisados em 24 homens saudáveis. O álcool causou o maior dano a atividade normal, seguido de perto pelo diazepam. Ambas as doses de buspirona causaram menores efeitos. A buspirona apresenta pricipalmente efeitos sedativos de menor duraçäo, ao passo que o diazepam prejudicou o senso de direçäo e o equilíbrio do corpo, além de ser sedativo. Ambos os ansiolíticos mostraram apenas leves interaçöes adicionais na presença da dose de álcool. Foram observados nos potenciais evocados um forte efeito das drogas, um menor, mas significativo efeito do álcool e de interaçäo droga/álcool. Os efeitos do dizepam nos potenciais evocados foram similares aos do álcool, ao passo que a buspirona em algumas circunstância pareceu reverter o efeito do álcool. A farmacocinética tanto buspirona quanto do diazepam näo foi significativamente afetada pela administraçäo de álcool. O perfil de efeitos colaterais psicomotores de uma dose ansiolítica única é preferivel ao de uma dose única de 10 mg de dizepam

Disparate Biochemical Actions of Electroconvulsive Therapy and Antidepressant Drugs.

Electroconvulsive therapy (ECT) effects on monoamine transmitter metabolites in the cerebrospinal fluid (CSF) were evaluated in three patients after completion of a course of bilateral or unilateral ECT. Each patient had earlier undergone an unsuccessful trial with an antidepressant drug. Despite the disparate nature of the basic pharmacology of the antidepressant drugs used, common chronic effects were observed in the CSF, with reductions in 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in all patients despite lack of therapeutic response. Homovanillic acid (HVA) changes were inconsistent. After ECT, however, no CSF changes were observed in the one nonresponder to that treatment. The two ECT responders showed marked increases in CSF 5-HIAA and HVA over their respective baselines, with an elevation in MHPG in one patient only. Further study of the mechanisms of action of ECT should focus on the serotonin and dopamine systems and on the differences between responders and nonresponders.

Combined Lithium and Electroconvulsive Therapy: Pharmacokinetic and Pharmacodynamic Interactions.

The combined use of lithium and electroconvulsive therapy (ECT) is currently contraindicated, due to reports of associated neurotoxicity and poor outcome. Only limited data are available to explain any pharmacological basis for an adverse interaction between the two treatments. ECT does not alter lithium distribution or kinetics. Possible drug-drug interactions between lithium and ECT premedication have been subjected to little systematic study. Despite a body of preclinical work implicating the cholinergic system in the mechanism of action of both lithium and ECT, no interaction between lithium and pre-ECT anticholinergic medication has been reported. Potentiation of barbiturate anesthetics and neuromuscular blocking agents, including succinylcholine, by lithium has been noted in the anesthesiology literature, but reports of such interaction are lacking in the context of ECT administration. Thus, no demonstrable pharmacokinetic or drug-drug interaction factors preclude combined prescription of lithium and ECT.