Joseph Thavundayil

Nicotine and Behavioral Markers of Risk for Schizophrenia: A Double-Blind, Placebo- Controlled, Cross-Over Study

We investigated the effect of nicotine on three behavioral markers of risk for schizophrenia: sustained attention (using the Continuous Performance Task (CPT)), antisaccade performance, and smooth pursuit. Smooth pursuit was investigated in two conditions, one in which attention was enhanced (monitoring target changes) and one in which attention was not enhanced (no monitoring). Patients with schizophrenia (n = 15) and controls (n = 14) were given a 14-mg nicotine patch in a double-blind, placebo-controlled, crossover design and plasma nicotine concentrations were monitored. Nicotine concentrations were similar in both groups. A Group × Drug interaction (p < .02) on CPT hits indicated that nicotine improved sustained attention in patients but not in controls. Nicotine significantly decreased antisaccade errors (p < .01) in both groups. A Drug × Monitoring condition interaction (p < .01) on pursuit gain indicated that nicotine significantly increased pursuit gain in the no-monitoring condition in patients and controls equally, but did not improve pursuit in the monitoring condition. Thus, improvement in pursuit may have been mediated via an effect on attention rather than by an effect on oculomotor function per se. In patients, the magnitude of improvement in attention on nicotine was correlated with the improvement on eye movement tasks. Thus, nicotine improves performance on both attention and oculomotor markers of risk for schizophrenia, possibly via common mechanisms.

Different pituitary ß-endorphin and adrenal cortisol response to ethanol in individuals with high and low risk for future development of alcoholism

The purpose of the present studies was to investigate the activity of the adrenal gland and the pituitary beta-endorphin system in individuals from families with a 3 generation history of alcoholism, High Risk group, or from families without history of alcoholism, Low Risk group. All subjects had a medical examination, a drinking behavior personal interview and the Michigan Alcoholism Screening Test. Individuals with medical problems or excessive drinking were not included in the study. On the day of testing, a blood sample was taken at 9:00 a.m., then the subject drank a placebo drink or an ethanol solution (0.5 g ethanol/kg B.Wt.). Additional blood samples were taken at 15, 45 and 120 minutes post-drink. Results indicated that individuals of the High Risk group had lower basal levels of beta-endorphin like immunoreactivity (beta-EPLIR) than individuals of the Low Risk group. The dose of 0.5 g ethanol/kg B.Wt. induced an increase in the plasma content of beta-EPLIR of the High Risk group, but not of the Low Risk group. In the Low Risk group ethanol did not induce an increase above the 9:00 a.m. levels, however, it attenuated the beta-endorphin decrease overtime, observed following the placebo drink. Analysis of beta-endorphin-like peptides in the plasma of the High Risk group, with Sephadex G-75 chromatography indicated that the major component of the plasma beta-EPLIR was beta-lipotropin. Plasma cortisol levels, following ethanol intake, presented a small increase in the High Risk group but not in the Low Risk group. Both groups presented similar blood alcohol levels. The basal levels of immunoreactive cortisol and beta-endorphin in the plasma of individuals who were alcoholics, but had been abstinent for at least six months prior to testing were similar to the levels of the High Risk group. Thus there are differences both in the basal levels and in the response of the cortisol and the pituitary beta-endorphin system to an acute ethanol challenge between the two groups.

Plasma melatonin—An index of brain aging in humans?

We investigated the age-related changes in the circadian rhythm of plasma melatonin as a potential index of brain aging in man. The subjects were 5 young men aged 19-25 years, 11 older men aged 51-65 years, 6 elderly men aged 66-89 years, 7 young women aged 19-25 years, 5 premenopausal women aged 45-50 years, 8 postmenopausal women aged 51-65 years, and 5 elderly women aged 66-75 years. They were all physically and psychiatrically normal. Serial blood samples were drawn from 8:00 AM until 8:00 AM on the next day, with the indoor illumination set at 300 Lux from 7:00 AM until 4:00 PM and at 50 Lux thereafter. Plasma melatonin was estimated by radioimmunoassay. The results show that there is a significant negative correlation between age and 24-hr secretion of plasma melatonin (r = -0.952, p less than 0.0001), between age and peak levels of plasma melatonin (r = -0.937, p less than 0.00001), and between age and the lag in time from sunset to the onset of significant elevation of plasma melatonin over daytime values (r = 0.916, p less than 0.0001). It is concluded that study of the circadian rhythm of plasma melatonin may prove to be a useful index of the aging process.

Apomorphine-induced penile tumescence in impotent patients — preliminary findings

Apomorphine (Apo), a short acting dopamine (DA) receptor agonist induces penile erections in normal subjects. The erectile response to one or more doses of Apo HCl (0.25, 0.5, 0.75, 1.0 mg sc) or placebo was investigated in eight impotent subjects and penile tumescence monitored using a mercury strain gauge and strip chart recording. Four patients showed a full erection with Apo and one a partial response. Distressing side effects (nausea, sweating) were associated with non-response or partial response. Three responders to Apo were treated with low doses of the long acting DA receptor agonist, bromocriptine (2.5-3.75 mg/d po); all three showed complete recovery of erectile function within two weeks. A subgroup of impotent patients may have impaired central DA function. Testing with Apo may provide a diagnostic and predictive test to identify such patients who may respond to treatment with low doses of bromocriptine or other DA receptor agonist.

Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects

Apomorphine HCl (Apo) (0.25, 0.5 or 0.75 mg sc), a dopamine (DA) receptor agonist, induced penile erections (PEs) (monitored by mercury strain gauges and continuous recording on paper strip charts) in 7 out of 9 normal subjects and placebo in 1 of these 9 (p less than 0.05). Apo-induced PEs recurred in each of the 6 subjects retested. Benztropine (2 mg iv) had no effect on Apo-induced penile tumescence (PT). These data suggest (a) DA mechanisms play a role in normal erectile function (b) DA-mediated PT is not modulated by cholinergic systems (c) evaluation of the erectile response to Apo may provide a simple ancillary test to the investigation of impotence and a way of identifying a subpopulation of impotent subjects with impaired DA function who may respond to long-acting DA agents (d) Apo-induced PT may provide a novel way of studying DA function in man.

Implication of the endogenous opioid system in excessive ethanol consumption

Numerous human and animal studies suggest that certain genetic factors may increase an individuals vulnerability to excessive alcohol consumption. Human and animal studies suggest that some of the reinforcing effects of ethanol may be mediated by the endogenous opioid system. In human studies, plasma levels of subjects genetically at high risk for excessive alcohol consumption showed lower basal activity of beta-endorphin, and more pronounced release of beta-endorphin in response to ethanol. In animal studies, the hypothalamus of mice bred for ethanol preference showed high basal activity of beta-endorphin and more pronounced release of beta-endorphin in response to ethanol than control mice. An important factor in the development of excessive ethanol consumption is the increase in opioidergic activity shortly after individuals begin drinking ethanol. Increased opioidergic activity could mediate the rewarding effects of ethanol, reinforce the act of drinking, and increase ethanol consumption. Human and animal studies, in which the administration of the opioid antagonists naloxone and naltrexone decreased ethanol consumption both by ethanol-preferring animals and by recovering alcoholics, support this hypothesis.

Response of the Hypothalamic-Pituitary-Adrenal Axis to Stress in the Absence and Presence of Ethanol in Subjects at High and Low Risk of Alcoholism

Both genetic and environmental factors, such as stress, are important in determining alcohol consumption. Furthermore, both stress and alcohol influence the activity of the hypothalamic-pituitary-adrenal (HPA)-axis. Thus, the present studies investigated the response of the HPA axis to stress and the effect of ethanol on the stress response, in subjects at high (HR) and low (LR) risk of alcoholism as determined from their family history. Twenty HR and 20 LR subjects performed a stress-inducing task 30 min following the ingestion of either a placebo drink or a low dose of ethanol. The levels of plasma adrenal corticotropic hormone (ACTH) and cortisol were measured prior to and for four hours following initiation of the treatment. Changes with time in the plasma hormone levels following ingestion of either a placebo or an ethanol drink, without the performance of the stress task, served as controls to compare the stress-induced changes. Neither the placebo nor the ethanol drink altered the plasma ACTH and cortisol concentrations. High risk subjects presented lower basal ACTH, but not cortisol, levels and a lower stress-induced increase in plasma ACTH concentration than LR subjects. Furthermore, the HR subjects presented a delayed poststress recovery of the plasma ACTH and cortisol levels. Ethanol consumption prior to the stress task attenuated (ACTH) or abolished (cortisol) the stress-induced increase in the plasma hormone concentrations of both LR and HR subjects. Thus, there are quantitative differences on the response of the HPA-axis to stress between HR and LR subjects, while ingestion of low amounts of ethanol prior to the performance of the stress task had a similar effect on HR and LR individuals.

Apomorphine: clinical studies on erectile impotence and yawning.

1. The erectile response to the short-acting dopamine (DA) receptor agonist, apomorphine (Apo) HCl (0.25, 0.5, 0.75 and 1.0 mg sc), and placebo was evaluated in 28 impotent patients and penile circumference monitored using a mercury strain gauge and strip chart recording. 2. A full erection (increment in penile circumference greater than 2 cm and lasting at least one minute) occurred in 17 patients with Apo; no erection developed after placebo. An erection occurred in 6/8 patients with impaired glucose tolerance, 2/6 patients with diabetes mellitus and in both patients on lithium. 3. Nine patients who responded to Apo were treated in an open trial with bromocriptine; 6 reported improvement in potency. 4. Impairment in DA function may play a role in idiopathic impotence and in impotence associated with impaired glucose tolerance and diabetes mellitus. 5. An erectile response to Apo may predict therapeutic response to bromocriptine or other long acting dopaminergic agents. 6. Lithium, which inhibits DA-sensitive adenylate cyclase, does not prevent Apo-induced erections. This provides further support indicating that Apo induces erections by an effect on D2 receptors. 7. The yawning response to placebo and four doses of Apo HC1 (3.5, 5.0, 7.0, and 10.5 ug/kg sc) was evaluated in five normal men using a polygraphic technique. The yawning response was also assessed in normal young (less than 30 yrs; N = 16) and elderly (greater than 60 yrs; N = 12) volunteers. 8. Under experimental conditions of study, placebo induced spontaneous yawning. This was antagonized by 3.5 and 5.0 ug/kg Apo HC1 but increased by 7.0 ug/kg Apo HC1. These observations are compatible with the view that Apo HC1 in doses of 3.5-5.0 ug/kg stimulates presynaptic DA receptors whereas 7.0 ug/kg stimulates postsynaptic DA receptors. 9. Spontaneous and Apo-induced yawning were significantly decreased in the elderly which suggests that D2 receptor function declines with normal aging.

Response of the HPA-axis to alcohol and stress as a function of alcohol dependence and family history of alcoholism

Dysfunction of the hypothalamic-pituitary-adrenal (HPA)-axis has been observed in chronic alcoholics and in non-alcoholic sons of alcoholic parents, while genetic and environmental factors, such as stress, may play a significant role in the development of alcoholism. The present study was designed to investigate the response of the HPA-axis to alcohol and stress as a function of family history of alcoholism and chronic alcohol abuse. We determined changes in plasma adrenal corticotrophin (ACTH) and cortisol concentrations in response to a placebo or an alcohol (0.50g ethanol/kg body wt) drink and to a stress task performed 30 min following ingestion of either the placebo or the alcohol drink in social and heavy drinkers with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism. Thus, four groups of healthy male individuals, low risk with no alcohol-dependence diagnosis (LRNAD), high risk with no alcohol-dependence diagnosis (HRNAD), low-risk alcohol dependent (LRAD) and high-risk alcohol dependent (HRAD), participated in the four experimental sessions given in random order. Basal plasma ACTH levels of LRNAD participants were higher from those of the other three groups of participants. Basal plasma cortisol levels of HRAD participants were higher from those of LRNAD and HRNAD but not of LRAD participants. The stress-induced increases of plasma ACTH and cortisol concentrations were more pronounced in LRNAD participants. The alcohol drink prevented the stress-induced increases in plasma ACTH and cortisol of all groups of participants. The self-ratings of anxiety were attenuated in LRNAD and LRAD participants in the alcohol only session and in HRNAD and HRAD participants in the alcohol plus stress session. In conclusion, there are differences in the activity of the HPA-axis as a function of family history and alcohol dependence, while the effect of an alcohol drink on the self-rating of anxiety may be influenced by both family history and stress.

Endorphins in Individuals with High and Low Risk for Development of Alcoholism

Alcohol is both a nutrient and a dangerous drug depending on the amount consumed and the duration of its consumption. Prolonged ingestion of large amounts of alcoholic beverages leads to the development of alcoholism. Presently, alcoholism may be considered as the most prevalent type of drug-addiction and is characterized by the development of tolerance and physical dependence, symptoms which are also found in other addictions including addiction to opiates. Furthermore, it is known that several behavioral and pharmacological effects of ethanol (E) are similar to those produced by opiates (Kalant, 1977), and cross-tolerance develops between E and morphine with respect to some of these effects (Khanna, Kalant & Leblanc, 1979; Ross, 1976). However, in contrast to opioids, which act through specific receptors, E is believed to have nonspecific effects on lipid components of cellular membranes (Goldstein, Chin & Lyon, 1982; Harris & Schroeder, 1981). The effects of E on membrane-lipids may in turn influence the activity of proteins which reside within the lipid environment of the membranes (receptors, enzymes) as well as the rate of release of certain cellular products (hormones, neurohormones and neurotransmitters). In fact, it has been proposed that E exerts its reinforcing effect by such interactions at neural and endocrine sites.