Low HDL cholesterol, aggression and altered central serotonergic activity.

Many studies support a significant relation between low cholesterol levels and poor impulse, aggression and mood control. Evidence exists also for a causal link between low brain serotonin (5-HT) activity and these behaviors. Mechanisms linking cholesterol and hostile or self-destructive behavior are unknown, but it has been suggested that low cholesterol influences 5-HT function. This study was designed to explore the relationship between plasma cholesterol, measures of impulsivity and aggression, and indices of 5-HT function in personality disordered cocaine addicts. Thirty-eight hospitalized male patients (age 36.8+/-7.1) were assessed with the DSM-III-R, the Buss-Durkee Hostility Inventory (BDHI), the Barratt Impulsiveness Scale (BIS) and the Brown-Goodwin Assessment for Life History of Aggression. Fasting basal cholesterol (total, LDL and HDL) was determined 2 weeks after cocaine discontinuation. On the same day 5-HT function was assessed by neuroendocrine (cortisol and prolactin) and psychological (NIMH and 'high' self-rating scales) responses following meta-chlorophenylpiperazine (m-CPP) challenges. Reduced neuroendocrine responses, 'high' feelings and increased 'activation-euphoria' following m-CPP have been interpreted as indicating 5-HT alterations in a variety of psychiatric conditions. Significantly lower levels of HDL cholesterol were found in patients who had a history of aggression (P=0.005). Lower levels of HDL cholesterol were also found to be significantly associated with more intense 'high' and 'activation-euphoria' responses as well as with blunted cortisol responses to m-CPP (P=0.033, P=0.025 and P=0.018, respectively). This study gives further support to existing evidence indicating that in some individuals, the probability of exhibiting impulsive and violent behaviors may be increased when cholesterol is low. It also suggests that low cholesterol and alterations in 5-HT activity may be causally related.

Serotonergic function in cocaine addicts: prolactin responses to sequential D,L-fenfluramine challenges.

BACKGROUND: Preclinical studies have shown that cocaine produces alterations in serotonergic function but our knowledge of the serotonergic alterations due to cocaine abuse in humans is still fragmentary. We therefore assessed the central serotonergic responsivity of cocaine addicts and control subjects by neuroendocrine challenges with the serotonin releaser and reuptake inhibitor D,L-fenfluramine (FEN). METHODS: Plasma prolactin levels following a 60 mg oral dose of FEN and placebo were studied in 25 hospitalized male cocaine addicts and 13 healthy male subjects. Control subjects underwent one set of FEN/placebo challenges and cocaine addicts two sets of challenges, during the first and third weeks following cocaine discontinuation. Patients were divided into two subgroups as a function of presence (FH+) and absence (FH-) of a paternal history of substance abuse. The following comparisons were made: 1) Control subjects versus entire patient group and versus patient subgroups; 2) entire patient group and patient subgroups responses to first versus second challenges; 3) FH+ versus FH- patients' early responses and FH+ versus FH- patients' late responses. RESULTS: The prolactin responses to FEN increased significantly in the entire patient group as time following cocaine discontinuation increased. The FH+ patients had significantly blunted early responses by comparison with FH- patients and control subjects. There was a more pronounced rebound of the responses of FH+ patients by comparison with those of FH- patients. As a result, comparisons of the late responses of FH+ and FH- patients and of FH+ patients and control subjects became nonsignificant. CONCLUSIONS: Cocaine use appears to have an effect on the serotonergic mechanisms mediating prolactin release in humans. In the present study, this effect was more pronounced in a subgroup of patients with a paternal history of alcoholism or drug abuse. The greater blunting of the prolactin response observed within days of cocaine discontinuation followed by a greater rebound of this response 2 weeks later could indicate an increased vulnerability to the disruptive effects of cocaine in these patients.

Effect of fenfluramine challenge on cocaine craving in addicted male users.

The authors studied the effects of a challenging dose of the serotonin (5-HT)-releaser/reuptake inhibitor d,l-fenfluramine (FEN) on spontaneous cocaine craving in a group of cocaine-addicted users in order to evaluate the involvement of serotonergic pathways in the modulation of craving for cocaine. Nineteen cocaine-dependent male inpatients received 60 mg of FEN or placebo (double-blind). Data were compared with those obtained in a previous study of another serotonergic probe, the partial postsynaptic agonist meta-chlorophenyl-piperazine (m-CPP). FEN significantly reduced cocaine craving and increased cortisol and prolactin when compared with placebo. When the responses to the two drugs were compared, there were no differences in the cortisol and prolactin rises, but m-CPP was a more potent inhibitor of cocaine craving than FEN. These data suggest that 5-HT releasers/reuptake inhibitors and serotonergic agents with greater postsynaptic activity should be further examined.

The meta-chlorophenylpiperazine challenge test in cocaine addicts: hormonal and psychological responses.

We report on the neuroendocrine and psychological responsivity of 31 cocaine addicts and 14 controls to the serotonergic agonist, meta-chlorophenylpiperazine (m-CPP) (0.5 mg/kg p.o.). Cocaine addicts were subdivided into subjects with aggressive tendencies and other features similar to those found in type 2 alcoholics and subjects without these features. Following m-CPP, aggressive and nonaggressive patients had a significantly blunted prolactin response compared to controls, but there was no difference between the two patient subgroups. There was no difference between the cortisol responses of nonaggressive patients and controls, but aggressive patients had a significantly blunted cortisol response compared to controls and nonaggressive patients. Both patient subgroups reported more intense "activation-euphoria" and "high" responses following m-CPP than controls. These results could indicate the existence of alterations along serotonergic pathways in cocaine addicts taken as a group. In addition, a subgroup of patients who could be described as type 2 cocaine addicts appear to be biologically different from healthy subjects and from other cocaine addicts as indicated by a greater cortisol blunting following m-CPP.

Hormonal, psychological, and alcohol craving changes after m-chlorophenylpiperazine administration in alcoholics.

To assess the serotonergic function of alcoholics, their neuroendocrine and psychological responsivities to the serotonergic partial agonist meta-chlorophenylpiperazine (m-CPP) was compared with the responsitivity of healthy subjects. The effect of m-CPP on craving for alcohol was also assessed in the alcoholics. Sixteen patients and 14 controls were tested under double-blind, placebo-controlled conditions. m-CPP (0.5 mg/kg of body weight) was given orally. Alcoholics were tested after a period of abstinence of 15 to 39 days. The two groups of subjects did not differ in their cortisol response to m-CPP, but the prolactin response of alcoholics was significantly blunted. Alcoholics reported a significantly more intense "high" feeling after m-CPP than the healthy subjects. m-CPP induced also a decreased craving for alcohol. Our data thus provide further evidence for the existence of a serotonergic dysfunction in alcoholics and a modulation of craving for alcohol by serotonergic systems.

Craving for cocaine in addicted users. Role of serotonergic mechanisms.

Very few studies have examined the role of serotonin (5-HT) in the modulation of craving for cocaine in cocaine-addicted persons. The authors evaluated whether the acute increase in serotonergic neurotransmission after the administration of a challenging dose of the 5-HT partial agonist meta-chlorophenylpiperazine (m-CPP) had an effect on spontaneous cocaine craving. Male inpatients (N = 31) who met DSM-III-R criteria for cocaine dependence completed 2 days of testing (separated by 48 hours) that involved the oral administration of m-CPP (0.5 mg/kg of body weight) or placebo in random order and under double-blind conditions. Patients' craving for cocaine was found to decrease significantly after the administration of m-CPP. These data could provide evidence for a modulation of cocaine craving by 5-HT systems.

Cerebral perfusion in early and late opiate withdrawal: a technetium-99m-HMPAO SPECT study.

The purpose of this study was to determine if cerebral blood flow (CBF) alterations are associated with discontinuation of heroin in chronic heroin users, and whether these alterations are reversible during abstinence. Ten physically healthy opioid-dependent males, hospitalized on an inpatient drug rehabilitation unit, were studied. Each patient had an initial single photon emission computed tomographic (SPECT) scan with the radiotracer technetium-99m-d,l-hexamethylpropyleneamine oxime (99mTc-HMPAO) 1 week after opiate discontinuation and a repeat scan 2 weeks later. The initial scans in 9 of the 10 subjects demonstrated significant, often discrete, perfusion defects, especially in the frontal, parietal, and temporal cortices. Two weeks later, repeat brain perfusion SPECT scans showed improvement in all nine subjects who had abnormal scans. Comparisons of the first scan with the second scan showed an increase in cortical uptake on the repeat SPECT study. All subjects had normal computed tomographic or magnetic resonance imaging scans. The results of this preliminary study suggest that the chronic use of opiates, like chronic use of cocaine, results in perfusion abnormalities without corresponding abnormalities on imaging studies of cerebral anatomy and morphology. This study also documents that these perfusion defects are partially reversible with short-term abstinence.

Admission criteria for inpatient substance abuse/dependence rehabilitation: implications for managed care.

In view of recent trends toward the replacement of traditional inpatient rehabilitation programs with nonresidential services, we examined the extent to which patients currently admitted to inpatient rehabilitation for alcohol or drug abuse/dependence met published criteria suggesting a preferential need for inpatient or residential care. Over 90% of almost 300 veterans with a primary DSM-III R diagnosis of alcohol or substance abuse/dependence, admitted to six New York Metropolitan Area Veterans Administration Medical Centers for inpatient rehabilitation, met at least one criterion dimension considered indicative of a need for such services, with over two-thirds meeting two or more dimensions. These findings suggest a continuing need for initial primary inpatient or residential rehabilitation for such patients.

Morbidity risk for alcoholism and drug abuse in relatives of cocaine addicts.

The morbidity risks for alcoholism in the first-degree relatives of a cohort of male cocaine addicts with or without alcoholism comorbidity were studied. Of the 71 patients who participated in our study, 40 (56.3%) had a history of alcoholism and 37 (59.1%) a history of opioid abuse. Twenty-two patients (30.1%) also met criteria for a lifetime diagnosis of a major psychiatric disorder. Significant increases in morbidity risks for alcoholism were found among male relatives of cocaine addicts with comorbid alcohol dependence when compared with relatives of cocaine addicts with no alcohol comorbidity. Among fathers, risks were .69 vs .32 (z = 2.98, p < .003). Among brothers, risks were .38 vs .15 (z = 2.35, p < .03). Significantly increased risks were also observed in male relatives when probands with a psychiatric diagnosis were excluded from the analyses. Among female relatives, increases in morbidity risks were found but they failed to reach statistical significance. Two interpretations are consistent with these findings. One of these interpretations is that alcoholism is a disorder distinct from other addictions and has its own mode of transmission. The second interpretation is that the transmission of substance use disorders lacks specificity and that the substances selected are influenced by sociocultural or biological factors.

Cortisol in alcoholics with a disordered aggression control.

Considerable evidence exists that the limbic system and the hypothalamus play an important role in the HPA axis disturbances found in depressive disorders. Evidence also exists that the limbic system plays a role in the modulation of aggressive behavior. Yet the HPA function of individuals with a disordered regulation of aggression has received little scrutiny. Because aggressive behavior has been observed to be extensively correlated with heavy alcohol use, we explored the HPA function of alcoholics who had had a life-long history of violence. Basal 0700h cortisol was measured in 4 consecutive wk following cessation of drinking in 19 alcoholics with a history of depression, and 17 alcoholics with a history of violent behavior, eight of whom had been incarcerated because of the severity of their violent acts. When compared with alcoholics with no problem in mood or aggression regulation, significant cortisol increases were found in the group of patients who had been incarcerated for violent acts and not in any other group. This increase persisted for 4 wk after cessation of drinking. A variety of variables, including several measures of alcohol consumption, amounts of benzodiazepines used for detoxification, and liver function tests, failed to show significant associations with cortisol. Data are interpreted as indicating that individuals displaying severe forms of violence could have a dysregulated HPA function revealed by exposure to excessive amounts of alcohol.

Duration and intensity of combat exposure and posttraumatic stress disorder in Vietnam veterans.

We assessed whether a relationship exists between posttraumatic stress disorder (PTSD) and two quantitative aspects of war trauma: the duration of exposure to combat (expressed in months) and the intensity of combat (measured by ratings on the Laufer Combat Scale). These stressor characteristics were measured in relation to PTSD prevalence and persistence. Eighty-four veterans, inducted during the Vietnam War, who attended an orthopedic clinic participated in the study. A significant association was found between duration of combat exposure and prevalence and persistence of PTSD. The longest duration of combat exposure was found in patients who still suffered from PTSD. This duration was shorter for patients in remission and still shorter for patients who had never developed PTSD. Similarly, a significant association was found between combat scale ratings and PTSD. The highest rating was observed in subjects who still had PTSD. The rating was lower in patients in remission and still lower in those who had never experienced PTSD. Having been wounded, which is one of the Laufer Combat Scale items and could be considered particularly traumatic, was strongly associated with PTSD. The findings are discussed in relation to the reliability and validity of the PTSD construct and to the contribution of factors other than stressor characteristics to PTSD symptom expression.

Are the effects of chronic ethanol administration on erythrocyte membrane mediated by changes in plasma lipids?

The effect of chronic ethanol consumption on plasma and erythrocyte membrane lipids were studied in rats fed a liquid diet containing ethanol for 4 weeks and intubated with the same diet 90 min prior to killing. Control animals underwent the same treatment, except that their liquid diet did not contain ethanol, but an isocaloric amount of carbohydrates. Plasma total cholesterol, free (unesterified) cholesterol and HDL cholesterol were higher in ethanol-fed animals than in controls. Phospholipids were also higher in the plasma of ethanol-fed animals when compared to controls so that the plasma cholesterol/phospholipid ratio (Ch/PL ratio) of the two groups did not differ significantly, regardless of the cholesterol fraction considered. Experimental and control animals did not differ either in the Ch/PL ratio of their erythrocyte membranes. In view of the fact that it has been suggested that the factor determining the direction of the cholesterol exchanges between plasma and erythrocyte membranes is the equilibrium between their respective Ch/PL ratios, these results are interpreted as being compatible with the hypothesis that the effect of chronic ethanol intake on erythrocyte membrane lipids is mediated through changes in plasma lipids.

Age of alcoholism onset. I. Relationship to psychopathology.

Numerous attempts have been made to subdivide populations of alcoholics into homogeneous subgroups. Although no consensus has been reached about the characteristics of these subgroups, a number of classification schemes have identified a subgroup of patients with a high genetic loading for alcoholism, an early onset of alcoholism, a severe course, and coexisting psychiatric problems consisting of aggressive tendencies or criminality. In a recent typology proposed by Cloninger on the basis of adoption studies, this subgroup has been classified as type 2. Another group of patients who were found to differ in their mode of inheritance and clinical characteristics was classified as type 1. The identification of etiologically homogeneous subgroups is easier in studies of adoptees than in studies of individuals who were not adopted. In an attempt to divide alcoholics into two groups of individuals presenting type 1 and type 2 characteristics, we used as a criterion the age of alcoholism onset because type 2 alcoholics as well as their fathers had been found to abuse alcohol at a younger age than type 1 patients. Patients with an onset of alcoholism before their 20th birthday were found to have a significantly higher incidence of paternal alcoholism and were twice as likely to have been incarcerated for crimes involving physical violence. We also observed other features not previously described in this patient subgroup. Patients who started abusing alcohol in their teens were three times as likely to be depressed and four times as likely to have attempted suicide as patients with a later onset of alcohol abuse.

Age of alcoholism onset. II. Relationship to susceptibility to serotonin precursor availability.

Alcoholics who start abusing alcohol early in life have been found to exhibit problems with mood and aggression control more frequently than patients with a later onset of alcoholism. Because alcohol preference and consumption, as well as mood and aggression regulation, are believed to be influenced by serotonin, relationships between tryptophan availability and mood and aggression regulation were explored in alcoholics. When studied in the entire population, the ratio of tryptophan over other amino acids competing for brain entry (which influences brain serotonin) was found to be lowest one day after cessation of drinking and to increase progressively over the following two to three weeks. When the population was divided into two groups of patients according to whether subjects started abusing alcohol before or after 20 years of age, associations between a low tryptophan ratio and depressive and aggressive tendencies were significant only in the subgroup of patients with an early onset of alcoholism. They were not significant in the rest of the population. Our data are compatible with the interpretation that patients with an early onset of alcoholism have a preexisting serotonin deficit that could manifest itself by an increased alcohol intake early in life and by an increased vulnerability to fluctuations in precursor availability.

P3 in alcoholics with disordered regulation of aggression.

Alcoholics have been found to show deficits in the P3 component of event-related potentials obtained using information-processing paradigms. However, alcoholic patients form a heterogeneous population. In a study of P3 voltages in subgroups of alcoholics with disorders in mood and aggression control, we observed significant decrements in these voltages in patients with lifelong histories of aggressive behavior. Patients with histories of incarceration for crimes involving physical violence had the lowest P3 amplitudes. The same patients also had a rate of paternal alcoholism significantly higher than that observed in the rest of the population. They could thus be classified as type 2 alcoholics, as a tendency to antisocial behavior and a high genetic loading for alcoholism have been described in this alcoholic subtype. These data could indicate that decrements in P3 amplitude characterize a subgroup of alcoholics with a disordered regulation of aggression. Alternatively, P3 deficits could be associated with some psychopathological conditions in individuals who abuse alcohol rather than with alcoholism, per se.

Increase in tryptophan oxygenase activity in alcoholic patients.

This study was conducted in order to assess whether chronic excessive alcohol consumption affects the activity of the liver enzyme tryptophan oxygenase which is rate limiting along the most important pathway of tryptophan catabolism. Five alcoholics were studied twice, once shortly after admission to an inpatient unit and the second time 1 month later. On each study day patients were given a tryptophan load of 50 mg/kg. Kynurenine in the urines (which reflects tryptophan oxygenase activity) was measured for a period of 6 hr following the load and showed a significantly enhanced activity of the enzyme shortly after cessation of drinking. This increased activity could explain the lowered tryptophan levels we have previously reported in alcoholics. The increase in enzyme activity may have been mediated by a rise in glucocorticoid hormones. In all instances, plasma cortisol measured hourly for 6 hr after the start of the experiment, was higher shortly after cessation of drinking than 1 month later.

Alterations in synaptic membrane molecular order associated with alcoholization and protein deficiency in rats.

The effects of chronic alcoholization and protein deficiency on synaptic membrane characteristics were studied in rats fed the following four liquid diets for 4 weeks: a protein-deficient diet containing alcohol, a protein-deficient diet containing no alcohol, a non-protein-deficient diet containing alcohol and a non-protein-deficient diet containing no alcohol. A fluorescent probe, diphenylhexatriene (DPH), was used to estimate the fluidity of synaptic membranes and their sensitivity to the fluidizing effect of ethanol added in vitro, in concentrations ranging from 50 mM to 800 mM. Prior to in vitro addition of ethanol, the difference between the fluidity of synaptic membranes of alcoholized and non-alcoholized animals was significant for the two groups of protein-deficient animals but not for the two groups of non-protein-deficient animals. After in vitro addition of ethanol, the differences between the fluidity of synaptic membranes of the alcoholized and non-alcoholized animals were larger and more frequently significant for the protein-deficient animals than for the non-protein-deficient animals. In view of previous observations that rats fed a protein-deficient diet experience more severe withdrawal symptoms following alcoholization than rats fed a nutritionally adequate diet, the results of the present experiment lend additional support to the hypothesis that tolerance and dependence may be mediated by alterations in biomembrane characteristics.