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 […]

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 […]

Benzodiazepines in the Treatment of Alcoholism

This post comprises three sections that cover the main aspects of benzodiazepines and alcohol: (1) the basic pharmacology of benzodiazepines; (2) use of benzodiazepines in the treatment of withdrawal; and (3) the use of benzodiazepines in treating alcoholics. The basic studies suggest that a major site of action of alcohol may be the GABA/benzodiazepine receptor complex and that compensatory alterations in this complex may underly withdrawal. In the section on alcohol withdrawal, interactions between the GABA/benzodiazepine receptor complex, sympathetic nervous system, and hypothalamic-pituitary-adrenal axis are discussed. Use of benzodiazepines in the treatment of the alcohol withdrawal syndrome are reviewed, including the possibility that the benzodiazepines may prevent withdrawal-induced “kindling”. Lastly, we review indications for, and efficacy of, benzodiazepines in long-term treatment of patients with alcoholism. Benzodiazepines are not indicated for the treatment of alcoholism. Furthermore, they have very few indications in alcoholics and their dependency-producing potency has to be appreciated when they are used in patients with alcoholism. The benzodiazepines () are a group of compounds that were first Read more […]


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 […]

Buprenorphine, Heroin, and Methadone: Comparison of Relative’ Reinforcing Properties

Buprenorphine is a partial agonist of the morphine type. It is both a long-acting opiate antagonist, like naltrexone, and a potent opiate agonist with respect to analgesia, physiological and subjective reactions in man (). However, buprenorphine does not induce physical dependence in several species and appears to produce only minimal physical dependence in man (). Buprenorphine’s positive morphine-like agonist effects combined with its antagonist potency, low toxicity, and minimal capacity for producing physical dependence, suggested that it should be valuable for the treatment of opiate addiction (). Clinical studies have shown that buprenorphine maintenance (8 mg/ day s.c.) significantly suppressed self-administration of heroin (21 to 40.5 mg/day) by male heroin addicts over 10 days of heroin availability in comparison to buprenorphine placebo (). Buprenorphine (0.282 to 0.789 mg/kg/day i.v.) also significantly suppressed opiate self-administration in the rhesus monkey drug self-administration model (). Recent clinical studies have shown that sublingual administration of buprenorphine (1-2 mg) should be suitable for daily maintenance for the treatment of narcotic addiction (). The opiate agonist effects of Read more […]

Benzodiazepines: Drug Discrimination and Physiological Dependence

The benzodiazepines are among the most widely used of all prescribed drugs. Concern about abuse of these drugs has prompted the development of preclinical methods for assessing various pharmacological effects of diazepam-like drugs which are relevant to their abuse and dependence liability. This abstract describes results from a series of ongoing experiments to assess discriminative stimulus effects and physiological dependence-producing properties of benzodiazepines. Drug discrimination: In drug discrimination procedures, animals are trained to respond differentially depending on the nature of drug pretreatment. The procedure can provide information analogous to a human testing situation in which subjects categorize drugs with respect to their subjective effects. In ongoing drug discrimination experiments, four baboons were trained to discriminate lorazepam (1.0 mg/kg) and two baboons were trained to discriminate pentobarbital (5.6 mg/kg) in a two-lever drug versus no-drug discrimination procedure. Food delivery depended on 20 consecutive responses on one lever in sessions preceded by an intramuscular injection of the training drug (60-min pretreatment time), and on 20 consecutive responses on the other lever Read more […]

Endocrine Effects of Marijuana in the Male: Preclinical Studies

The research efforts of many investigators in the recent past have made it abundantly clear that exposure to marijuana has significant effects upon the reproductive system and the effects of cannabinoid treatment are equally significant on both male and female reproductive systems. Among the effects of cannabinoid treatment on the male reproductive system that have been reported arc altered testicular function, in the form of depressed male hormone secretion, and changes in both the quantity and quality of the sperm produced by the seminiferous tubules. There have been changes reported in the weight and in certain of the enzymes associated with the reproductive organs. Much research effort focused on the ability of THC to depress the secretion of the gonadotropins from the pituitary that are responsible for stimulating testosterone production by the Leydig cells of the testis and the action on the hypothalamus to depress gonadotropic releasing hormone (GnRH). Maintenance and regulation of normal reproductive capacity in the male is a complex and highly integrated phenomenon. It requires proper nutritional and hormonal support, not only by the hormones directly involved in reproduction, hut also by the synergistic Read more […]

Effect of marijuana the adrenal gland

Cortical Hormones Exposure to stressful situations elicits a prompt secretion of adrenocortical steriods which help the organisms to counteract the stress. The adrenal cortex responds to acute cannabinoid treatment with a prompt rise in corticosterone levels in the plasma. Exposure to a wide range of dosages of THC ranging fran 2 to 50 mg/ kg body weight produced increased corticosterone levels in the plasm of both the rat and the mouse. Dewey et al. () showed that ascorbic acid, which is inversely correlated to adrenal cortical hormne secretion, was depleted fran the adrenal cortex of laboratory rats. Maier and Maitre () demonstrated that. the increased corticosterone in plasma of rats pretreated with THC was accompanied by a decrease in adrenal cortical cholesterol, a precursor to adrenal cortical hormones, and an increase in unesterified fatty acids; however, the rabbit did not respond to THC with a similar increase in wrtisol. Birmingham and Bartova () showed that the response of elevated plasma corticosterone to THC disappeared after 8 days of treatment with a dose of 3 mg/kg body weight. Pertwee () also showed that tolerance developed to the effect of THC on corticosterone levels in muse plasm and did so without 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 […]