Toxicology of Antidepressant Drugs: Tricyclic Antidepressants

Animal Toxicity General Toxicology The LD 50 values for a number of tricyclic antidepressants, when administered to mice and rats in single oral or parenteral doses, are listed in Table Acute LD50 valuesa of some tricyclic antidepressants. Acute poisoning by tricyclic antidepressants usually leads to symptoms of central excitation followed at the higher and lethal dose levels by central inhibition. The symptomatology includes muscular weakness, twitching, stupor, respiratory disorders, ataxia, and tonic-clonic convulsions. Table Acute LD50 valuesa of some tricyclic antidepressants Imipramine Doxepine Nortriptyline Viloxazine Maprotiline Mouse i.v. p.o. 35 666 15- 20 148-178 26 327 60 1000 31 660- 900 Rat i.v. p.o. 22 625 13- 19 346-460 22 502 60-77 2000 38- 52 760-1050 a The values given are for LD50, single administration, in mg/kg body weight It is evident from Table Acute LD50 valuesa of some tricyclic antidepressants or from the reports of Pluviage () and of Ueki et al. () that no major differences in the acute toxicity of tricyclic antidepressants are apparent. Information on animal studies relating to the tolerance of tricyclic antidepressants Read more […]

Differential Drug Effects as a Function of the Controlling Consequences

One of the central themes during the initial period in the development of behavioral pharmacology was the issue of whether motivational factors influence the effects drugs have on behavior. Though seemingly a straightforward question, the translation of this problem into an experimentally addressable form was, and continues to be, somewhat difficult. Motivational concepts almost inevitably pose formidable experimental problems, and studies designed to resolve those problems have often yielded equivocal results. Typically, however, the question has been approached experimentally by comparing the effects of various drugs on behavior controlled by different types of events, e.g., food presentation and escape from electric shock. Presumably, different events and the behavioral consequences associated with them engendered different motivational states. The influence of motivational factors as determinants of drug action should then be reflected by differential changes in overt behavior when the organism is given certain drugs. This approach had one rather substantial problem that was not always recognized. Behavioral consequences are important in several different ways, not only when they differ on some hedonic dimension, Read more […]

Drug effects on behavior maintained by food, electric-shock presentation and stimulus-shock termination

Although early experiments did not find differences in drug effects depending on the type of event, more recent studies have reported several instances in which the maintaining event appeared to influence the effects of several drugs on behavior. For example, morphine, methadone, and the narcotic antagonists naloxone and nalorphine decreased responding maintained under 5-minute fixed-interval food-presentation schedules at doses that increased responding comparably maintained by the presentation of an electric shock (). Under similar schedule conditions, both amphetamine () and cocaine () increased responding maintained by these two events. However, appropriate doses of pentobarbital, ethanol, and chlordiazepoxide increased responding maintained by food, while only decreasing responding under shock-presentation schedules (). These findings suggested that there were several conditions under which certain drugs appeared to affect similar performances maintained under comparable schedules in an event-dependent manner. Further, as shown in Figure Effects of chlordiazepoxide on different control rates of responding under S-minute fixed-interval schedules of food or shock presentation. The event pen was defected downward Read more […]

Sedatives

An assessment of the relationship between sedatives and driving accidents requires the survey of literature dealing with: (1) the effects of sedatives on actual driving behaviors, (2) the epidemiological studies of sedatives and traffic accidents, and (3) the physiological, psychological, and behavioral effects of sedatives on factors related to driving. Only a few studies have tested the effects of sedatives either in a simulator or in the field. Loomis and West () tested eight subjects in a driving simulator from 1 to 6 hours after they were given various drugs. The simulator consisted of an automobile steering wheel and brake accelerator pedals arranged as in a standard automobile. The steering wheel operated a model car placed on a moving belt 150 ft. long and 30 in. wide with an opaque l-in. strip running down it lengthwise, which simulated the road bed. The strip was shifted randomly, moving smoothly from side to side as the belt advanced. Accelerator and brake pedals actuated and controlled the rate of belt movement, and the steering wheel controlled the position of the model car. A light source placed 14 in. above the car was capable of producing an amber, red, or green light. The subject was required to Read more […]

Internal Stimulus Control and Subjective Effects of Drugs

For many years psychotropic drugs have been characterized and classified using methods designed to measure their subjective effects in humans (). This research approach has two principal purposes: 1) to investigate the efficacy of a drug in attenuating unwanted subjective states in patients (e.g., pain, anxiety, depression), 2) to investigate the abuse potential of new drugs by comparing their subjective effects in experienced drug abusers to those produced by known drugs of abuse. In regard to the latter, such methods have been used to determine whether there are any common subjective states produced by all drugs of abuse (e.g., euphoria). Systematic studies of subjective methods for drug classification have been conducted at the Addiction Research Center (ARC) in Lexington, Kentucky, now part of the National Institute on Drug Abuse. A major mission of the ARC has been to evaluate new analgesic compounds to determine whether they produced morphine-like effects. The subjective effects of morphine and related compounds were an important aspect of this evaluation. The research demonstrated that morphine and related narcotic analgesics produced a unique spectrum of subjective effects that can be reliably discriminated Read more […]

History of Drug Exposure as a Determinant of Drug Self-Administration

The purpose of this paper is to review how a drug’s effectiveness in initiating and maintaining self-administration can be influenced by a subject’s past experience with drugs. Drug self-administration by humans and laboratory animals is considered an instance of operant behavior (), controlled by the subject’s genetic constitution, past history, and the current circumstances of drug availability (of Skinner, 1938). The influence of history of drug exposure on current drug-maintained behavior may be controlled, in turn, by the particular drugs and doses employed and the conditions under which the drug is administered. This discussion will focus on the ways in which a history of drug exposure can control later drug self-administration in laboratory animals. Effects of history of drug exposure on initiation of drug self-administration In order to study drug self-administration by laboratory animals, an experimenter must set up a situation in which subjects are exposed to some contingency between the occurrence of a specific response and delivery of a particular drug. For many drugs, no explicit behavioral or pharmacologioal history is necessary for the drug to maintain behavior. In one initial study, for example, Read more […]

Administration of Amphetamines to Rodent Subjects

As mentioned above, ethical concerns preclude the use of humans in many experimental situations; however, we can understand many features of the human central nervous system by understanding the brains of other animals. The animal most widely used in the area of amphetamine experimentation is the rodent, which has an analogous, rather than homologous, brain structure to humans. In the following sections, we examine the modification of aggressive behavior in rodents by amphetamines. The various aspects of aggressive behavior include the tendency for provoked attack, the influence of environment on behavior, social factors, and the neurological basis of aggression. Behavioral Observations When using nonhuman subjects to study aggressive behavior, the typical research methodologies most usually employed by experimenters include pain-, isolation-, and brain stimulation-induced aggression. However, when making a comparison between animals of different species the outcomes of these tests yield varying and somewhat contradictory results, which in turn hampers one’s ability to generalize to the human population. Additionally, it has been found that the most important aspects of amphetamine-stimulated aggressive and defensive Read more […]

Amphetamines and Their Effects on Dominance Hierarchy in Primates

Humans are primates, as are monkeys and apes. Evolution tends to be very conservative and so the brains of humans are very similar to our cousins. In fact, genetically we are about 98% the same as our primate cousins. Although research that involves monkeys demonstrates the same dose-dependent effects of amphetamine as shown with rodent subjects, the resultant effects on aggressive behavior favor a positive rather than negative relationship (). Primarily, the effects that amphetamine has on primates’ dominance rank have been examined. Analysis has suggested that these effects are a function of social status and group dynamics (). Differences of Effects between Ranks The behavior of dominant animals differs drastically from that of subordinate animals (). We tend to categorize dominant styles of behavior as aggressive and subordinate styles of behavior as defensive. Dominant and subordinate animals also differ from each other neurochemically and hormonally. We can identify the rank of a primate within its hierarchy by observing behavior. When amphetamine is administered to monkeys of different social status within an established colony, the subjects express behavior dependent on their position in the hierarchy. For Read more […]

Amphetamines and Their Effects on Human Aggressive Behavior

Because the possession, use, and distribution of amphetamine are illegal and because the compound causes brain damage, ethical concerns have prevented experimental research on the behavioral effects of amphetamine. Thus, the available literature on the effects of amphetamine in human participants is all correlational. Although there have been reports of high correlations between violent crime and amphetamine use, these studies may be confounded because other drugs such as alcohol are often involved and users that commit these acts sometimes have aggressive tendencies beforehand (). The existing literature does give some indication regarding the effects of various doses and the possible predictions one can make concerning the long-term effects on mental health, but until more research can be performed we are limited in our understanding the relationship of amphetamine with human aggressive behavior. Subjective Analysis The advantage of experiments involving human subjects is that people have the ability to describe their immediate emotional states and report their feelings and thoughts. However, these subjective analyses can sometimes be inaccurate, and in a sense become “contaminated” because of participants’ biases Read more […]