D.R. Cherek

Drug Excretion in Human Breast Milk

SummaryThe excretion of drugs in human breast milk is reviewed with regard to milk production, composition, feeding patterns and mechanisms of drug transfer into milk. Fundamental principles of breast milk excretion are used to construct a pharmacokinetic approach useful for the study of most drugs. An infant-modulated 3-compartment open model is proposed for drug distribution and elimination in the breast feeding woman. Milk/plasma drug concentration ratios are projected on the basis of pH partitioning. While some studies confirm these projections, other studies demonstrate a need to consider additional factors such as lipid solubility and protein binding characteristics of a drug in milk.Data are lacking for most drugs and hence dosing via milk or risk to the infant remains speculative. Very few pharmacokinetic studies of both milk and infant plasma were found. A review of selected drug classes cites available information as a basis for future studies. Few drugs are contraindicated in breast feeding women, but supportive data for either proscriptions or permissive statements are often lacking. A neglected but potentially serious infant risk — impaired behaviour and development — is discussed from the standpoint of emerging animal data.Conceptually valid and comprehensive studies on drug excretion in breast milk are needed if this valuable nutrient for infants is to be made available safely.

Effects of smoking different doses of nicotine on human aggressive behavior

A new methodology was employed to study the effects of drugs on human aggressive behavior in a laboratory situation. The effects of not smoking, smoking a low nicotine dose (0.42 mg/cigarette), and smoking a high nicotine dose (2.19 mg/cigarette) on human nonaggressive and aggressive responding was determined. A nonaggressive response, which resulted in the accumulation of money, was continuously available to the subject. Two different aggressive responses were also available: the ostensible subtraction of money from, and the ostensible presentation of a 1-s blast of white noise to a (fictitious) person. Aggressive responding was elicited by subtracting money from the research subjects, which was attributed to a fictitious person paired with the research subject randomly each day. Nicotine, administered with experimental cigarettes, produced dose-dependent decreases in both types of aggressive responding elicited by low or high frequency subtractions of money attributed to another person. Generally, the more aggressive response option, i.e., subtraction of money from another person, decreased more following nicotine administration. Smoking the same doses of nicotine increased nonaggressive monetary reinforced responding. This indicates that the suppressant effect of nicotine on aggressive responding was not due to a nonspecific depressant action.

Biogenic monoamine turnover in discrete rat brain regions is correlated with conditioned emotional response and its conditioning history

The content and turnover of dopamine, norepinephrine and 5-hydroxytryptamine (serotonin), and the content of their respective major metabolites were evaluated in 19 discrete brain areas of rats exposed to conditioned emotional response (CER), and in control groups which received either equivalent yoked shock (shock only) or compound stimulus presentation (tone only). On test day, CER animals suppressed responding and exhibited forms of emotional behavior after presentation of the conditioned stimulus (CS); while shock only and tone only control groups, and CER animals which received an acute dose of diazepam prior to testing, did not suppress. Few changes were observed in content of the biogenic amines or their metabolites, suggesting that the behavioral manipulations were acting within normal physiological limits. On the other hand, numerous changes were observed in the utilization of the 3 biogenic monoamines, which were correlated with the conditioning-anxiety (comparisons of CER vs shock only) and the shock history (comparison of shock only vs tone only). These observations are consistent with putative neural pathways in the frontal cortex, septum, nucleus accumbens, amygdala, striatum, hippocampus and brain stem (which utilize specific monoamines), and with discrete brain areas which have been implicated in classical conditioning and CER-related phenomena. These observations suggest roles for biogenic monoamines in mediating or responding to the classical conditioning and emotional components of the paradigm.

Effects of provocation and alcohol on human aggressive behavior

Effects of provoking stimuli on human aggressive behavior and on the relationship between alcohol and aggressive behavior were measured. Four adult males manipulated pushbuttons that produced points on their own counters (redeemable for money) or ostensibly subtracted points (money) from the counters of fictitious persons described as participating in the same study at other locations. During five 10-min components, frequency and intensity of point subtractions, ostensibly controlled by another person, were manipulated. Each subject was repeatedly exposed to alcohol doses (0.25, 0.5 and 0.75 g/kg of 95% ethanol) over time using a repeated measures design. Aggressive responding was affected by provocation intensity and frequency. The highest dose of alcohol produced selective increases in aggressive responding; however, no interactions between alcohol effects and provocation conditions were observed.

Changes in biogenic amine and benzodiazepine receptors correlated with conditioned emotional response and its reversal by diazepam

Groups of littermate rats were trained to respond for food reinforcement on a variable interval one-min (VI 1) schedule, after which they were classically conditioned to associate a conditioned stimulus (CS) with footshock (conditioned emotional response; conditioned suppression; CER). Two control groups received yoked footshock (no CS) or the visual-auditory stimulus only (no footshock). On test day, a group of the CER conditioned animals received injections of either vehicle or diazepam prior to exposure to the VI 1 food-reinforced schedule. After 30 min of the VI 1 schedule, the CS was presented continuously for 15 min, after which the animals were decapitated, the brains removed, membranes prepared and in vitro receptor binding evaluated. During the CS, the CER animals suppressed responding and exhibited conditioned fear (emotional) behavior, while the control groups, and animals given acute diazepam, maintained normal responding. [3H]Diazepam binding was reduced in the CER animals, yet acute benzodiazepine administration did not effect this binding. [3H]QNB binding was reduced by CER and increased by diazepam administration. Adrenergic, serotonergic and dopaminergic systems were also evaluated. Traditional biogenic amine systems may respond to CER and diazepam administration in some compensatory manner.

Schedule-induced cigarette self-administration.

Cigarette self-administration was studied in a controlled laboratory setting by automated recording of the various components of smoking behavior. The effects of intermittent scheduled monetary reinforcement presentation on cigarette smoking was determined in an attempt to demonstrate schedule-induced cigarette self-administration. Schedule-induced cigarette self-administration was indicated by changes in some of the topographical components of cigarette smoking behavior, e.g., puff frequency and mean puffs per cigarette, as a function of changes in the fixed interval value of a monetary reinforcement schedule. While the number of cigarettes smoked changed only slightly following changes in the FI value of the monetary reinforcement schedule, other components of cigarette smoking behavior, particularly puff frequency and mean puffs per cigarette, were significantly altered. Cigarette puffs were most likely to occur immediately following monetary reinforcement presentation or in the initial segment of the next fixed interval. The demonstration of schedule-induced self-administration in human adds another common factor found to influence infrahuman and human drug self-administration.

Effects of d-amphetamine on human aggressive behavior

Male research subjects were administered placebo and three doses of d-amphetamine (5, 10 and 20 mg/70 kg) in a laboratory situation which provided both aggressive and non-aggressive response options. The non-aggressive response was button pressing maintained by presentation of points exchangeable for money at the end of the session. The aggressive response was button pressing on a separate manipulanda which ostensibly subtracted points from a fictitious partner. Aggressive responding was elicited by subtracting points from the research subjects which was attributed to the fictitious partner. d-Amphetamine increased both aggressive and non-aggressive responding, particularly at 5 and 10 mg/70 kg. At the highest dose (20 mg/70 kg), aggressive responding decreased to levels similar to those observed during placebo sessions, while monetary reinforced responding remained elevated.

Amino acid neurotransmitter utilization in discrete rat brain regions is correlated with conditioned emotional response

The content and utilization of amino acid neurotransmitters were evaluated in discrete brain areas of rats exposed to a conditioned emotional response (CER) procedure and in control groups which received either equivalent yoked shock history (shock only) or compound stimulus presentation (tone only). On test day, CER animals suppressed responding and exhibited anxious behavior after presentation of the CS, while shock only and tone only control groups, or CER animals which received an acute dose of diazepam prior to testing, did not suppress. Few changes were observed in the content of amino acids, suggesting that the behavioral manipulations were acting within normal physiological limits. On the other hand, numerous changes were observed in the utilization (turnover, metabolism) of the amino acid neurotransmitters. The effects of a history of shock presentation (shock only versus tone only) were persistent long after the conditioning sessions were terminated, and resulted in decreased turnover of the amino acids in many areas. CER conditioning-emotion (CER versus shock only) produced an increase in the turnover of aspartate and glutamate in many structures, while changes in GABA turnover were generally limited to decreases in limbic areas. If CER represents an animal model of anxiety, these observations may suggest roles for neurons which utilize amino acids in mediating or responding to emotional components of the paradigm.

Reinforcer interactions under concurrent schedules of food, water, and intravenous morphine

Responding by six rats was maintained under a concurrent chained fixed-ratio 1, fixed-ratio 9 schedule (conc chain FR1 FR9) of food, water, and morphine presentations. The subjects had continuous access to the schedule contingencies on a reversed 12-h light-dark cycle. Local rates and temporal patterns were very similar for responding maintained by the three reinforcers with food and water intake occurring predominantly during the dark cycle, while morphine infusions were evenly distributed. Food and water extinction (24-h duration) decreased the number of ratios completed on both the food and water levers. Moreover, food extinction resulted in a large increase in I.V. morphine self-administration. Morphine extinction increased responding on the morphine lever while almost eliminating responding on the water lever. Changes in the dose of morphine (2.5–40 mg/kg/injection) did not significantly affect food and water intake, but were inversely related to responding on the morphine lever. Saline substitutions resulted in effects similar to those observed during morphine extinction. The schedule used in this study provides a method for examining the specificity of a number of pharmacological and neurochemical manipulations.

Effects of cigarettes on saliva cortisol levels

We determined the effects of cigarette deprivation and smoking on saliva cortisol levels in the presence and absence of an operant, monetarily reinforced work task. Subjects were randomly exposed to the following four experimental conditions over successive sessions: no smoking, smoking, no smoking + work, and smoking + work. Measurements of cortisol levels in saliva were determined before and after each daily session. Saliva Cortisol levels declined from the beginning to the end of sessions and the end‐of‐session saliva Cortisol levels were not affected by any of the four experimental conditions. Increased cigarette smoking in the presence of the work task also did not affect saliva cortisol levels. Our data do not support: reports of increased cortisol levels as a consequence of smoking or theories relating cortisol and endorphin release to nicotine habituation.