Nancy K. Mello

Drinking patterns during work-contingent and noncontingent alcohol acquisition.

&NA; Drinking patterns of alcoholics were compared under conditions which allowed unrestricted access to alcohol (N = 18), and where it was necessary to perform a simple operant task in order to obtain both alcohol and cigarettes (N = 8). Work‐contingent alcohol acquisition was characterized by alternations between drinking episodes of 3‐6 days, and relatively abstinent work periods of 2‐3 days which were usually associated with partial withdrawal signs and symptoms. Subjects given unrestricted access to alcohol (32 ounces/day) maintained stable levels of blood alcohol (between 150 and 200 mg/100 ml) over drinking periods of 8‐15 days. No subject in either group drank all the alcohol available. Subjects showed little fluctuation in body weight, even though daily caloric intake from food and alcohol averaged between 4000 and 5000 calories per day. The role which the pattern of alcohol consumption plays in determining its behavioral and biologic effects is discussed.

Age-related Reduction in Functional MRI Response to Photic Stimulation

Many functional imaging studies have demonstrated age-related alterations in cerebral blood flow during the resting state. However, few studies have addressed possible differences in functional response to cerebral activation. We assessed the response of visual cortex to photic stimulation in 9 normal elderly subjects and 17 normal younger subjects with blood oxygenation level dependent functional magnetic resonance imaging. We found that the amplitude of response in elderly subjects was significantly decreased compared to younger subjects (2.5 +/- 1.0% versus 4.0 +/- 1.6%, p = 0.01), suggesting a reduction in functional activation or an age-related alteration in the coupling of blood oxygenation to focal activation. NEUROLOGY 1997;48: 173-176

Effects of naltrexone on mood and neuroendocrine function in normal adult males

Abstract (1) A significant increase in integrated plasma luteinizing hormone (LH) levels occurred following oral administration of 50 mg of naltrexone to seven healthy adult males who had no past history of opiate use or abuse. (2) All subjects were able to identify naltrexone from placebo in a double-blind study. (3) All subjects reported that naltrexone produced dysphoric effects including fatigue, sleepiness, light-headedness, nausea, sweating and occasional feelings of unreality. (4) Three subjects reported recurrent spontaneous penile erections following naltrexone administration. (5) No dysphoric side effects or penile erections occurred following placebo administration. (6) These findings indicate that naltrexone affects both mood states and sexual function in adult males who have no history of opiate abuse and suggests that these effects may be mediated by hypothalamic and pituitary mechanisms which also subserve LH secretory activity.

A new device for administering placebo alcohol

Placebo alcohol administered via a new device induced intoxication in 7 of 10 healthy adult males. Intoxication levels reported after placebo alcohol was 36% of intoxication ratings after real alcohol when peak blood alcohol values reached 84 mg/dl. Since expectancy about alcohol effects may contribute significantly to perceived intoxication, the new device should facilitate alcohol administration studies which would benefit from a placebo control.

Effects of Low- and High-Nicotine Cigarette Smoking on Mood States and the HPA Axis in Men

The acute effects of smoking a low- or high-nicotine cigarette on hypothalamic–pituitary–adrenal (HPA) hormones, subjective responses, and cardiovascular measures were studied in 20 healthy men who met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for nicotine dependence. Within four puffs (or 2 min) after cigarette smoking began, plasma nicotine levels and heart rate increased significantly (P<0.01), and peak ratings of ‘high’ and ‘rush’ on a Visual Analogue Scale were reported. Reports of ‘high,’ ‘rush,’ and ‘liking’ and reduction of ‘craving’ were significantly greater after smoking a high-nicotine cigarette than a low-nicotine cigarette (P<0.05). Peak plasma nicotine levels after high-nicotine cigarette smoking (23.9±2.6 ng/ml) were significantly greater than after low-nicotine cigarette smoking (3.63±0.59 ng/ml) (P<0.001). After smoking a low-nicotine cigarette, adrenocorticotropin hormone (ACTH), cortisol, dehydroepiandrosterone (DHEA), and epinephrine did not change significantly from baseline. After high-nicotine cigarette smoking began, plasma ACTH levels increased significantly above baseline within 12 min and reached peak levels of 21.88±5.34 pmol/l within 20 min. ACTH increases were significantly correlated with increases in plasma nicotine (r=0.85; P<0.0001), DHEA (r=0.66; P=0.002), and epinephrine (r=0.86; P<0.0001). Cortisol and DHEA increased significantly within 20 min (P<0.05) and reached peak levels of 424±48 and 21.13±2.55 ng/ml within 60 and 30 min, respectively. Thus cigarette smoking produced nicotine dose-related effects on HPA hormones and subjective and cardiovascular measures. These data suggest that activation of the HPA axis may contribute to the abuse-related effects of cigarette smoking.

Cocaine’s Effects on Neuroendocrine Systems: Clinical and Preclinical Studies

This review examines the effects of cocaine on the neuroendocrine system and summarizes findings from clinical studies of cocaine abusers and preclinical studies in rodents and rhesus monkeys. The effects of acute and chronic cocaine administration on anterior pituitary, gonadal, and adrenal hormones are described, and the functional consequences of chronic cocaine exposure are discussed. Many of cocaines acute effects on the endocrine system are consistent with its actions as a monoamine reuptake inhibitor. Acute cocaine administration stimulates release of gonadotropins, ACTH, and cortisol or corticosterone and suppresses prolactin levels. It has been difficult to detect changes in basal levels of most hormones or alterations in hormone responsiveness to a challenge dose of cocaine or other agents after chronic cocaine treatment. Interpretation of clinical data is often complicated by polydrug abuse involving opiates and alcohol as well as cocaine. However, preclinical studies of the effects of chronic cocaine exposure on integrated neuroendocrine function have revealed disruptions of the estrous cycle in rats and the menstrual cycle in rhesus monkeys. Furthermore, the menstrual cycle disorders observed in rhesus monkeys parallel those reported in women who abuse cocaine. Much remains to be learned about cocaines interactions with the endocrine system and the consequences of cocaine abuse for reproductive function.

Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys

Effective treatment of opioid dependence with methadone and of tobacco dependence with nicotine illustrates the potential usefulness of agonist medications for drug abuse treatment. The monoamine-releaser d-amphetamine is one drug under consideration as an agonist pharmacotherapy for cocaine dependence. To assess the concordance between preclinical evaluations and ongoing clinical trials, the present study examined the effects of chronic treatment with saline or d-amphetamine on cocaine- and food-maintained responding in rhesus monkeys. Cocaine injections and food pellets were available under a second-order schedule during alternating daily sessions of cocaine and food availability. d-Amphetamine (0.01-0.1 mg/kg per h i.v. for 7 consecutive days) dose-dependently decreased self-administration of a unit dose of cocaine (0.01 mg/kg per injection) at the peak of the cocaine self-administration dose-effect curve. d-Amphetamine (0.032-0.1 mg/kg per h for 7 days) also decreased self-administration of a broad range of cocaine doses (0.0032-0.1 mg/kg per injection) and produced rightward and downward shifts in the cocaine dose-effect curve. Food-maintained responding was usually decreased less than cocaine self-administration, and few signs of toxicity were noted. To evaluate the effects of a longer treatment regimen, d-amphetamine (0.1 mg/kg per h) was administered for 28 consecutive days. d-Amphetamine nearly eliminated self-administration of cocaine (0.01 mg/kg per injection) throughout this treatment, whereas food-maintained responding returned to baseline levels after approximately 9 days. These preclinical findings are concordant with recent clinical studies and suggest that chronic d-amphetamine may selectively decrease cocaine-taking behavior in rhesus monkeys, possibly by producing a selective decrease in the reinforcing effects of cocaine.

Reduction in BOLD fMRI response to primary visual stimulation following alcohol ingestion

The physiology of alcohols effects on brain function is poorly understood. Emission tomographic imaging has revealed both acute and chronic alterations in resting cerebral hemodynamics and metabolism following alcohol ingestion. However, cerebral functional integrity under these conditions has received less attention. Functional magnetic resonance imaging (fMRI) offers a non-invasive method for assessing brain functional activation. In order to assess its utility for studying the effect of alcohol on brain function, we performed fMRI with photic stimulation before and after administration of either 0.7 mg/kg alcohol (N = 12) or placebo (N = 5), resulting in peak breath alcohol levels averaging 0.069 g/dl. We found that the amplitude of visual cortical activation in response to photic stimulation was significantly reduced by approximately 33% following alcohol administration (4.0 +/- 1.7% vs. 2.7 +/- 1.3%, P = 0.02), but not following placebo (4.2 +/- 1.5% vs. 4.1 +/- 1.4%, P = 0.7). The results also suggest that the baseline right hemispheric predominance of activation in response to photic stimulation may be reduced following alcohol, suggesting a greater effect on the right hemisphere, consistent with previous studies and alcohols known effects on visuospatial processing. In addition, through the course of each activation session, there was a progressive reduction in response following alcohol. These data demonstrate that the cerebral effects of alcohol intoxication can be studied with fMRI, and that the effects on brain function of even moderate alcohol intoxication may be widespread, may be lateralized, and may include the visual system.

Interactions between kappa opioid agonists and cocaine. Preclinical studies.

Abstract: Kappa opioid agonists inhibit dopamine release from mesolimbic dopaminergic neurons and attenuate some behavioral effects of cocaine in rodents. Evidence that kappa opioid agonists may act as functional antagonists of cocaine led us to examine their interactions with cocaines abuse‐related effects in rhesus monkeys. In cocaine self‐administration studies, four arylacetamides (U50,488, enadoline, (−) spiradoline and PD117302) and four benzomorphans (ethylketocyclazocine [EKC], bremazocine, Mr2033 and cyclazozine) each were administered as continuous infusions over 10 days. EKC, Mr2033, bremazocine, U50,488 and enadoline produced significant dose‐dependent and sustained decreases in cocaine self‐administration and also decreased food‐maintained responding at some doses. Emesis and sedation were occasionally observed during the first two days of kappa agonist treatment, but tolerance developed rapidly to these effects. Cyclazocine, PD117302 and spiradoline did not significantly alter cocaine self‐administration. The behavioral effects of EKC and U50,488 were antagonized by both the kappa opioid antagonist nor‐binaltorphimine and the non‐selective opioid antagonist naloxone. In general, compounds with mixed activity at both kappa and mu opioid receptors (e.g. EKC, Mr2033) decreased cocaine self‐administration more consistently and with fewer or less severe undesirable side effects than more selective kappa agonists (e.g. U50,488, spiradoline). Although several kappa agonists decreased cocaine self‐administration, EKC and U50,488 did not consistently block the discriminative stimulus effects of cocaine in monkeys trained to discriminate cocaine from saline. The extent to which kappa agonist‐induced decreases in cocaine self‐administration reflect an antagonism of cocaines abuse‐related effect remains to be determined.

EXPERIMENTAL ANALYSIS OF DRINKING BEHAVIOR OF CHRONIC ALCOHOLICS

Almost all studies of drinking behavior, whether focused upon the individual or selected ethnic-socioeconomic groups, have been based upon the retrospective reports of alcoholic individuals that were made during intervals of sobriety. However, the validity of inferences based solely upon a patient’s retrospective report of a drinking experience may be affected both by deliberate or unintentional distortions and by his inability to recall and adequately verbalize his reactions. Most clinicians report that alcoholic patients are unable to specify the circumstances which lead to the onset of a drinking spree or to describe the factors which contribute to the termination of drinking. Patients with alcohol-related problems tend to give vague descriptions of changes in feeling states produced by alcohol. Although most patients report some initial reduction in tensions, they are seldom able to accurately recall their thoughts and feelings during prolonged periods of drinking. Despite the difficulties associated with adequately characterizing an alcoholic’s behavior on the basis of retrospective reports, there has been little critical examination of the diffuse concepts of “alcoholism” which prevail in the literature. According to the voluminous psychiatric literature on this subject, the effects of alcohol are: anxiety reduction, transient alleviation of depression, and facilitation of overt psychopathological behavior. However, systematic observation and recording of these phenomena in inebriated alcoholic subjects has rarely occurred, and some experimental data (Mendelson, et al. 1964) indicates that alcohol may increase anxiety and depression in alcoholics. It is unfortunate that the majority of hypotheses advanced to account for the behaviors associated with chronic alcoholism have never been experimentally verified; yet these provide the basis of many of the assumptions which are implicit in the various therapeutic programs developed for the treatment of alcohol-related illnesses. Details of those tacit assumptions about determinants and psychopathology of alcoholism that are currently in vogue have been critically reviewed elsewhere (Mendelson et al. 1964). During the past five years, we have been concerned with examining some behavioral and metabolic components of alcohol addiction in a laboratory situation. We have completed a series of studies on experimentally induced intoxication and withdrawal of alcohol in alcoholic volunteers (Mendelson, 1964; Mendelson etal . 1965). Although the resutling data have not supported a number of the hypotheses advanced by investigators who have studied alcoholics in a clinical setting, one major difficulty associated with comparing our findings with existing clinical data, is that most of our experiments have involved programmed administration of alcohol. This procedure involves administering a