RESUMO
The general anesthetic ketamine (Ketalar, Ketaject, Vetalar) (KET) is used in human and veterinary medicine for induction of anesthesia for short surgical procedures and routine veterinary examination. Its illicit use by teenagers in rave parties has been reported, and it has recently been identified as a substance associated with sexual assault. One aim of this paper was to study the elimination of KET and its major metabolite norketamine (NKET) in urine collected from five nonhuman primates that received a single dose (5 mg/kg, I.M.) of KET and to study elimination patterns to determine how long after drug administration KET and NKET can be detected. Another aim of this study was to develop and validate a highly sensitive negative ion chemical ionization-gas chromatography-mass spectrometry (NCI-GC-MS) method for the simultaneous quantitation of KET and its major metabolite NKET in urine and to analyze urine samples collected from the animals. The last aim of this study was to apply and evaluate a newly developed ELISA screening methodology for detection of KET and its metabolites in the same urine samples collected from primates which received a single dose of KET. In two monkeys, KET was detected in urine up to 3 days after drug administration (32-7070 ng/mL); in one monkey, it was detected up to 4 days (65-13,500 ng/mL); in one monkey, it was detected only on days 1 and 2 (4000 and 70 ng/mL, respectively); and in one monkey, it was detected 10 days after KET injection (22-35,000 ng/mL). NKET concentrations ranged from 63 pg/mL to 1.75 microg/mL, and it remained in the urine throughout the entire 35-day study period in 4 out of 5 animals. In one monkey, NKET was detected up to 31 days after KET administration. Urine analysis using ELISA revealed that KET and NKET can be easily detectable at 25 ng/mL. In one monkey, KET and its metabolites were detected in urine up to 4 days after drug administration, up to 7 days in two monkeys, up to 11 days in one monkey, and 16 days after KET injection in one monkey. Urine extraction followed by screening using ELISA methodology allowed for significant extension of the detection period in all animals from the study. It is believed that the KET elimination in urine of nonhuman primates is slightly faster than in humans. We propose that NCI-GC-MS be employed to detect NKET as a target compound in urine in toxicological investigations of drug-facilitated sexual assault when KET use by the perpetrator is suspected.
Assuntos
Ketamina/análogos & derivados , Ketamina/urina , Detecção do Abuso de Substâncias/métodos , Animais , Ensaio de Imunoadsorção Enzimática/instrumentação , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Cromatografia Gasosa-Espectrometria de Massas/instrumentação , Cromatografia Gasosa-Espectrometria de Massas/métodos , Injeções Intramusculares , Ketamina/administração & dosagem , Macaca , Masculino , Modelos Animais , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fatores de TempoRESUMO
Stress-related effects can often interfere with studies of behavioral pharmacology in animals. This is known to occur where frequent dosing is required as in the study of drugs of abuse. A depot system capable of eliciting a pharmacodynamic response over an extended period would circumvent the need for frequent dosing. Cocaine hydrochloride was incorporated in 4.2 microns median diameter (geometric standard deviation 1.7) poly(L-lactide) microspheres at a concentration of 20% w/w. Seventy percent of the drug load was released in the period from 1-8 h. Studies of the locomotion of rats (n = 10/group) in an open field demonstrated a baseline movement of approximately 0.1 m/h after the intraperitoneal administration of microspheres in saline, or saline alone. Ten milligram of cocaine in saline increased the movement of rats to > 3 m/h for a period of 1 h following injection. The distance travelled by rats after administration of 10 mg of cocaine in microspheres was > 3 m/h for a period up to 6 h. Cocaine delivered in microspheres significantly increased the drug action (0.022 < p < 0.032). Particulate carriers were used to deliver small quantities of drug that overcame the need for multiple dosing of experimental animals to achieve extended behavioral effects.
Assuntos
Cocaína/farmacologia , Locomoção/efeitos dos fármacos , Animais , Masculino , Microscopia Eletrônica de Varredura , Microesferas , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
BMY 14802 was identified as a potential antipsychotic drug in traditional model systems, and this identification was confirmed in modern behavioral and electrophysiological systems. The drug appears to be atypical as an antipsychotic in its lack of activity in models predictive of the potential to produce extrapyramidal side effects and tardive dyskinesia. Indeed, this suggestion is corroborated by clinical findings to date. The atypical profile of BMY 14802 extends to its neurochemical actions and appears to find its basis in regionally selective, indirect modulation of the dopamine system. Furthermore, BMY 14802 exhibits interactions with sigma binding sites in vitro and in vivo, a notion supported by data from neurophysiological, behavioral, and biochemical investigations. BMY 14802 also appears to be neuroprotective in some model systems and may have utility in the treatment of stroke (Boissard et al. 1991). BMY 14802 appears to interact with 5-HT1A receptors, but this interaction does not seem to contribute significantly to the potential antipsychotic actions of the drug. Moreover, the formation of active metabolites of BMY 14802 does not appear to occur in animals or humans to an extent of physiological or behavioral relevance. If clinically efficacious, BMY 14802 may treat the symptoms of schizophrenia by a mechanism novel for antipsychotic drugs: regionally selective, indirect modulation of dopaminergic systems by specific interaction at sigma sites.
Assuntos
Psicotrópicos/farmacologia , Pirimidinas/farmacologia , Receptores sigma/efeitos dos fármacos , Animais , Sítios de Ligação , Química Encefálica/efeitos dos fármacos , Humanos , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Receptores sigma/metabolismoRESUMO
The present study examined the effect of structural analogs of clonidine on feeding in both rabbits and monkeys. In rabbits, lofexidine and tizanidine either did not influence or decreased food intake in contrast to clonidine, which stimulated food intake. Lofexidine elicited easily observed decreases in motor behavior with several of the doses used in the study. Changes in motor behavior induced by tizanidine were more subtle. Conversely, lofexidine and tizanidine significantly increased feeding behavior in Stumptail macaque monkeys, as did clonidine. The results suggest that, in contrast to rabbits, Stumptail monkeys are more useful in searching for an 'orectic' effect of clonidine analogs.
Assuntos
Clonidina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Animais , Clonidina/administração & dosagem , Clonidina/análogos & derivados , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Feminino , Macaca , Masculino , Coelhos , Cloreto de Sódio/administração & dosagem , Cloreto de Sódio/farmacologiaRESUMO
Two new arylpiperazine derivatives, the 4-(1-piperazinyl)thieno- and -furo[3,2-c]pyridine ring systems, have been synthesized and appended via tetramethylene chains to various imide rings. Target compounds from each series were found to have significant activity in the blockade of apomorphine stereotypy and apomorphine-induced climbing, the Sidman avoidance response, and the conditioned avoidance response. In addition, while potent affinity for serotonin 5-HT1 and 5-HT2 receptors was observed for both the thieno- and furo[3,2-c]pyridine derivatives, the interaction of these molecules with the dopamine D2 receptor was weak. Electrophysiological studies of the lead prototypes from each series, involving compounds 22 and 33, indicate these two molecules have distinctively different effects on dopamine neurons in areas A9 and A10. Despite the similarity these molecules share in their behavioral indices of antipsychotic activity, it is likely that the thieno- and furo[3,2-c]pyridine rings employ different mechanisms to achieve this convergence of biological effects.
Assuntos
Piperazinas , Transtornos Psicóticos/tratamento farmacológico , Piridinas , Tiofenos , Anfetaminas , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Ligação Competitiva , Catalepsia/induzido quimicamente , Fenômenos Químicos , Química , Dioxanos/metabolismo , Feminino , Furanos/síntese química , Furanos/farmacologia , Furanos/uso terapêutico , Macaca , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Psicoses Induzidas por Substâncias/tratamento farmacológico , Piridinas/síntese química , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Espiperona/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacologia , Tiofenos/uso terapêuticoRESUMO
A series of 3-substituted 2-pyridinyl-1-piperazine derivatives have been appended to cyclic imide groups and evaluated for their potential antipsychotic activity. The dopamine receptor affinities of these target molecules, as well as their ability to block apomorphine-induced stereotypy or reverse neuroleptic-induced catalepsy, was dependent on the lipophilic and electronic characteristics of the substituent situated on the pyridine ring. Groups with + omega and - phi values were most consistent with the desired biological profile of the target molecules, the cyano moiety being the optimum choice. Evaluation of compound 12 in a monkey model of amphetamine psychosis, and the regional selectivity it expresses for the A10 dopaminergic cell bodies in electrophysiological experiments, suggest this compound would be an atypical antipsychotic agent with few side effects.
Assuntos
Antipsicóticos/síntese química , Piperazinas/síntese química , Animais , Apomorfina/antagonistas & inibidores , Catalepsia/induzido quimicamente , Dioxanos/farmacologia , Eletrofisiologia , Haplorrinos , Piperazinas/farmacologia , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The alpha 2-adrenergic agonist clonidine has been reported to increase feeding in several species. This study evaluated the effects of clonidine (500-700 micrograms/day), administered per os, to four treatment-resistant anorexia nervosa patients in a long-term placebo-controlled crossover trial. All patients increased their body weight significantly. Clonidine administration, however, did not influence the rate of weight gain, nor did clonidine affect hunger or satiety sensations. Similarly, 24-hour urinary 3-methoxy-4-hydroxyphenylglycol levels and levels of anxiety and depression were unchanged by clonidine. By contrast, clonidine showed significant hemodynamic effects; clonidine lowered systolic and diastolic blood pressure, reduced pulse rate, and produced sedation. Discontinuation of clonidine was associated with a small but significant weight loss compared to a small weight increase during the initiation of clonidine treatment. The results suggest that clonidine may not be indicated in the treatment of anorexia nervosa.
Assuntos
Anorexia Nervosa/tratamento farmacológico , Clonidina/uso terapêutico , Adulto , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ensaios Clínicos como Assunto , Emoções/efeitos dos fármacos , Feminino , Humanos , Fome/efeitos dos fármacos , Metoxi-Hidroxifenilglicol/urina , Placebos , Resposta de Saciedade/efeitos dos fármacos , Fases do Sono/efeitos dos fármacosRESUMO
Previous studies support an interaction between noradrenergic and opiate systems in the control of food intake. For example, in both rats and rabbits, food intake stimulated by the noradrenergic agent clonidine is reduced by opiate antagonists. The purpose of the present study was to determine whether or not clonidine stimulated the food intake of non-food-deprived hamsters, a species which appears to lack an opiate-sensitive feeding system. Hamsters fed a chow diet did not increase their food intake when injected with clonidine in doses ranging from 0.05 to 0.25 mg/kg. Furthermore, the animals did not increase their intake of sunflower seeds, a preferred diet for hamsters.
Assuntos
Clonidina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Animais , Cricetinae , Ingestão de Energia/efeitos dos fármacos , Preferências Alimentares , Masculino , Mesocricetus , Especificidade da EspécieRESUMO
An animal model for studying the actions of hallucinogenic drugs using primate social colonies is presented. Although hallucinogens induce a number of behavioral changes in this paradigm, one emergent behavior, limb jerks, appears to be selectively induced by three classes of hallucinogens in doses which correlate with those reported to be hallucinogenic in humans. Several non-hallucinogenic congeners of hallucinogens failed to significantly elicit this response. Other behavioral changes induced by hallucinogens in monkeys such as ptosis and social withdrawal may be useful in studying aspects of hallucinogen intoxication other than hallucinations, or psychosis in general. Upon daily administration, tolerance developed to all hallucinogens tested except two, as is seen in humans. Moreover, cross-tolerance between hallucinogens could be demonstrated. Further experiments with the hallucinogen 5-methoxy N,N-dimethyltryptamine revealed that although certain individual behaviors could be antagonized by serotonin antagonists, dopamine antagonists, and physostigmine, no drug completely reversed the behavioral abnormalities induced by this hallucinogen. It is suggested that this paradigm, which offers an hallucinogen-induced behavior which correlates well with the human hallucinogen response and permits observation of a wide variety of other potentially relevant behaviors in primates, may be useful in developing and testing theories of hallucinogenic drug action. It may be especially valuable in view of the present difficulties of conducting hallucinogen research in humans.
Assuntos
Comportamento Animal/efeitos dos fármacos , Alucinógenos/farmacologia , Animais , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Macaca , Mescalina/farmacologia , Modelos Neurológicos , Comportamento Social , Fatores de TempoRESUMO
The present study examined the effect of opiate antagonists on clonidine-induced feeding in rabbits. The change in food intake induced by clonidine was blocked by naltrexone. The active (-)-isomer of the antagonist 5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan had an effect similar to naltrexone. Similar doses of the (+)-isomer were inactive, except at the highest dose used in the study. The results suggest that opiate antagonists block feeding elicited by a specific noradrenoreceptor agonist and that this inhibition is due to a direct interaction with opiate systems.
Assuntos
Clonidina/antagonistas & inibidores , Comportamento Alimentar/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Animais , Benzomorfanos/farmacologia , Relação Dose-Resposta a Droga , Masculino , Naltrexona/farmacologia , Coelhos , EstereoisomerismoAssuntos
Comportamento Animal/efeitos dos fármacos , Alucinógenos/farmacologia , N,N-Dimetiltriptamina/farmacologia , Meio Social , Triptaminas/farmacologia , Animais , Nível de Alerta/efeitos dos fármacos , Tolerância a Medicamentos , Feminino , Macaca , Contração Muscular/efeitos dos fármacos , Comportamento SocialAssuntos
Modelos Animais de Doenças , Transtornos Psicóticos , Animais , Dextroanfetamina , Feminino , Alucinógenos , Humanos , Macaca , FenciclidinaRESUMO
Evidence gathered from several experiments where stimulant drugs were given to selected members of adult Stumptail macaque social colonies is presented which suggests that dopamine systems play an important part in the mediation of submissive behavior in this species. Chronic administration of d-amphetamine, 3.2 mg/kg/day, for 12 days, induced a significant increase in submissive gestures displayed by some treated monkeys despite the lack of a significant concurrent increase in aggressive gestures directed toward these animals. This behavioral change was antagonized by haloperidol and pimozide, two agents with preferential dopamine receptor blocking properties. The dopamine receptor agonist apomorphine induced a large dose-dependent increase in submissive gestures displayed by treated monkeys. Repeated administration of apomorphine, 1.0 mg/kg/day, for 12 days, induced a significant increase in submissive gestures comparable to amphetamine in monkeys who had previously received chronic d-amphetamine treatment. In addition, it appears that the significant increase in submissive gestures by monkeys treated with the hallucinogen 5-methoxy N,N-dimethyltryptamine is also mediated through dopamine systems since the preferential dopamine receptor blockers haloperidol and trifluoperazine antagonized this response while the serotonin antagonists cinanserin, methysergide, metergoline, and cyproheptadine all failed to antagonize or even potentiate this behavioral change. These results have important implications in the study of animal behavior and may have relevance to drug-induced and endogenous psychopathologies in humans as well.
Assuntos
Dominação-Subordinação , Receptores Dopaminérgicos/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Predomínio Social , Anfetamina/farmacologia , Animais , Apomorfina/farmacologia , Feminino , Haloperidol/farmacologia , Macaca , Masculino , Metoxidimetiltriptaminas/farmacologia , Pimozida/farmacologia , Trifluoperazina/farmacologiaRESUMO
The mechanism of clonidine-induced hyperphagia and weight gain in monkeys was studied in 11 Stumptail macaques. Clonidine induced a significant increase in food intake over baseline levels and a significant weight gain after the 3-day treatment period. Both changes induced by clonidine were antagonized by the alpha 2-noradrenergic antagonist yohimbine, but not by prazosin, an alpha 1-noradrenergic antagonist. These results suggest that clonidine-induced hyperphagia and weight gain in monkeys are mediated through alpha 2-noradrenergic receptors.
Assuntos
Clonidina/farmacologia , Transtornos da Alimentação e da Ingestão de Alimentos/induzido quimicamente , Hiperfagia/induzido quimicamente , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos/fisiologia , Animais , Interações Medicamentosas , Humanos , Macaca , Norepinefrina/fisiologia , Simpatomiméticos/farmacologiaRESUMO
The acute and chronic effect of 5-methoxytryptamine (5-MeOT), a structural analogue of known tryptamine hallucinogens and a substance found in mammalian brain, on nonhuman primate behavior was studied in a social colony of four Stumptail macaques. In the first study, dose-dependent behavioral changes induced by 5-MeOT were determined with the administration of seven acute doses to each animal. At higher doses, 10-20 mg/kg, 5-MeOT induced two abnormal or "emergent" behaviors, body shakes and limb jerks. 5-MeOT also induced a dose-dependent reduction in normal social and solitary behavior of treated animals suggesting that this drug has sedative properties. The second study examined the effect of once daily administration of 5-MeOT, 10 mg/kg, for 5 days. During this time, tolerance developed to both 5-MeOT-induced body shakes and limb jerks, but failed to develop to the reduction in social and solitary behaviors. Since body shakes and limb jerks are behaviors characteristically induced in this species by hallucinogens, these results suggest that 5-MeOT may possess hallucinogenic properties. However, this effect may be weak and may only occur after large doses since large doses of 5-MeOT were required to induce a relatively small number of body shakes and limb jerks in monkeys when compared to potent hallucinogens such as LSD and 5-MeODMT.
Assuntos
5-Metoxitriptamina/farmacologia , Comportamento Animal/efeitos dos fármacos , Triptaminas/farmacologia , 5-Metoxitriptamina/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Feminino , Asseio Animal/efeitos dos fármacos , Macaca , Masculino , Atividade Motora/efeitos dos fármacos , Transtornos dos Movimentos/induzido quimicamente , Mioclonia/induzido quimicamente , Comportamento Social/efeitos dos fármacos , Fatores de TempoRESUMO
The effect of six acute doses of the dopamine receptor agonist apomorphine on non-human primate social and individual behaviour was studied in a social colony of four adult Stumptail macaques. Apomorphine was administered intramuscularly to 2 monkeys/day in doses ranging from 0.05 to 3.00 mg kg-1 15 min bfefore a 1 h observation period. Apomorphine induced hyperactivity, hypervigilance, and stereotyped behaviour at doses of 0.50 mg kg-1 and greater in all 4 monkeys. In addition it also caused a dose-dependent disruption of normal behavioural patterns. Social grooming was eliminated while the submissive gestures were significantly increased. It also induced an increase in vocalizations and suppression of food forage behaviours. The results demonstrate the role of dopamine systems in the mediation of affiliative behaviour as well as motor behaviour in a primate species. Also, since similar behavioural changes are induced in this species during chronic (+)-amphetamine treatment, it is suggested that dopamine systems play a predominant role in amphetamine-induced behaviour in primates.
Assuntos
Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Asseio Animal/efeitos dos fármacos , Haplorrinos , Humanos , Macaca , Masculino , Receptores Dopaminérgicos/efeitos dos fármacos , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacosRESUMO
The effect of the alpha-noradrenergic receptor agonist, clonidine, on food intake and weight was examined in ten adult Stumptail macaque monkeys. An intramuscular injection of 0.1 mg/kg of clonidine HCl for seven consecutive days significantly increased food intake from baseline levels throughout treatment. All but two monkeys gained weight during clonidine treatment with seven animals gaining from 5--15% of their original body weight by the end of 1 week.