抗运动病药物研究进展

运动病是一种常见病。运动病的防治措施主要有药物防治和适应性训练。适应性训练具有可逆性等局限,相对而言,药物防治具有更好的应用价值。本文主要综述应用较广泛的4类抗运动病药物及其相应药理作用特点,同时展望抗运动病药物的药效评价动物模型和技术体系方面的进展。     

Unusual metabolism of caffeine in the squirrel monkey

The chronic toxicity of caffeine observed with the squirrel monkey appears to be related to the long plasma half-life of caffeine in this species. A half-life of 11 hr was found following the administration of 5 mg/kg compared to 2.4 hr in the rhesus monkey (5 hr or less have previously been reported for the mouse, dog and man). The methylxanthines found in the tissues and urine of the squirrel monkey following caffeine administration were the same as those reported for other species. No difference in the metabolism of caffeine by a squirrel monkey showing a toxic response to 25 mg/kg/day and a monkey tolerating this dose could be determined. The squirrel monkey appears to have a unique deficit in its ability to catabolize caffeine to metabolites which can be effectively excreted.     

Effects of amphetamine and methylphenidate on fixed-interval responding in the squirrel monkey.

The effects of oral doses of d-amphetamine and methylphenidate on a fixed-interval operant response were studied in four young male squirrel monkeys. A fixed-interval of 80 sec with a limited hold of 20 sec was used. Methylphenidate produced no observable changes in behavior, while d-amphetamine produced dose related changes in both the rate of responding and the temporal patterning of responses. Since dose levels used included, and exceeded, human clinical dosages, the present findings may have implications for future research involving the clinical use of these drugs.     

Benactyzine increases alarm call rates in the squirrel monkey

The effects of benactyzine (0.01–3.0 mg/kg) were examined on the frequency of alarm calls of squirrel monkeys in a laboratory setting. Under baseline conditions, few calls occurred, and neither saline nor a low dose (0.01 mg/kg) of benactyzine increased calling. Higher doses (0.03–3.0 mg/kg) of benactyzine significantly increased call rate (to 1–2 calls per s) in a dose-dependent manner. The rate-increasing effect of benactyzine on alarm calls appears to be related to a central antimuscarinic effect, as it could be partially blocked by 0.01 mg/kg physostigmine, completely blocked by 0.1 mg/kg physostigmine, but was not blocked at all by 0.1 mg/kg neostigmine. Neither of these cholinomimetics increased call rates when given alone. These findings show that benactyzine can increase alarm call rates in squirrel monkeys under defined laboratory conditions, and may serve as a useful pharmacological probe to study neurochemical mechanisms mediating the production of this type of vocalization. In the squirrel monkey, one such mechanism apparently involves a cholinergic substrate.Preliminary results were presented at the 15th Annual Meeting of the Society of Neuroscience, Dallas, TX     

Phencyclidine-like discriminative stimulus properties of opioids in the squirrel monkey

The opioids SKF 10047, dl-cyclazocine, and dextrorphan have been shown to have phencyclidine (PCP)-like discriminative stimulus properties in the rat. In order to extend the generality of this observation, the stimulus effects of these and other opioids were evaluated in squirrel monkeys trained to discriminate between IM injections of saline and 0.25 mg/kg of PCP in a two-choice discrete-trial avoidance paradigm. Stimulus control of behavior was characterized by the reliable completion of at least 22 trials of a 25-trial session on the appropriate choice lever after an injection of saline or PCP. In tests of stimulus generalization, SKF 10047, d-cyclazocine, dextrorphan, normetazocine, dl-cyclazocine, l-cyclazocine, and dextromethorphan occasioned dose-related increases in PCP-appropriate responding. The first four of these compounds and, under some conditions, l- and dl-cyclazocine, produced stimulus control of behavior comparable to that produced by the PCP training dose. Six other opioids occasioned responding only on the saline-appropriate lever: ethylketocyclazocine, ketocyclazocine, levorphanol, levallorphan, pentazocine, naltrexone. Naltrexone (1.0 or 4.0 mg/kg) attenuated slightly the PCP-like stimulus effects of SKF 10047 and dextrorphan, but increased PCP-appropriate responding with l- and dl-cyclazocine and levorphanol by enabling higher doses of these drugs to be tested without disruption of responding. The PCP-like stimulus effects of certain opioids appear to be mediated at neuronal substrates acted upon by PCP rather than at sites typically associated with opiate activity. These neuronal sites of action common to opioids and PCP may correspond to the sigma opiate receptor.     

Behavioral effects of d-amphetamine and caffeine in the squirrel monkey

Four Squirrel monkeys were trained on a bar-press response with reinforcement available every 80 sec. The effects of d-amphetamine and caffeine upon this response were studied in both light and dark. In addition to differential drug effects it was found that both illumination and sex of the subjects were important variables.     

A study of the chronic toxicity of inhaled disodium cromoglycate in the squirrel monkey.

A chronic inhalation toxicological study of disodium cromoglycate (cromolyn sodium, intal) was performed in the squirrel monkey, Saimiri sciureus. Each of five experimental groups consisted of three male and three female monkeys. Groups I and II were exposed 6 hr/day, 7 days/week, for 1 year to aerosols containing a disodium cromoglycate blend in approximate concentrations of 0.5 and 0.05 mg/liter of air, respectively. Group III was similarly exposed to an aerosol containing 0.01 mg of lactose/liter of air. Group IV animals served as chamber controls, and the room controls (Group V) were maintained in the animal holding room throughout the study. A comprehensive toxicological evaluation of the monkeys was carried out prior to and throughout the study. At appropriate intervals observations were made of physical appearance, behavior, weight gain, and ophthalmoscopic appearance; electrocardiograms, systolic blood pressure measurements, hemograms, blood biochemical profiles, and urinalyses were also obtained. At termination, necropsies were conducted, and organ weights were determined. A variety of staining techniques was employed in the histopathological examination of tissues. Special attention was given to heart, kidney, and lung structures and to vascular and nerve tissues. Bone marrow smears and the distribution and morphology of mast cells in the lung were studied. Ultrastructural studies, using the electron microscope, were made of the lungs. No changes that could be attributed to the action of disodium cromoglycate were seen in any parameter. A special absorption study in five monkeys showed that the Group I animals absorbed about 60 times the recommended human dose.     

Maternal responsiveness in the squirrel monkey following chronic administration of delta 9-THC.

Mother squirrel monkeys were orally administered gradually increasing doses of delta 9-THC (from 0.5 to 5.0 mg/kg) 5 days/wk from 2 wk to approximately 6 mo after birth. After having received a dose of 5.0 mg/kg for an average of 3.5 mo, drug-treated mothers were then compared with control mothers in terms of theri responsiveness both to their own and to unrelated infants. In contrast to the control mothers whose response pattern clearly showed differentiation of their own and other infants, the mothers that received delta 9-THC responded in much the same manner to the alien infant as they did to their own infant. The results show that the behavior of the THC-exposed mothers was not attributed simply to a general reduction in their responsiveness toward their offspring or to an overall reduction in their own state of arousal. Rather, the results suggest that chronic ingestion of delta 9-THC caused the mothers to be less disturbed by separation from their infants and/or produced degree of perceptual distortion that prevented them from responding selectively to the different infants.     

Effects of combinations of phencyclidine and pentobarbital on schedule-controlled behavior in the squirrel monkey.

Three squirrel monkeys trained on a variable interval schedule of food presentation were used to examine the interaction between phencyclidine (PCP) and pentobarbital (PB). First, dose-response curves for each drug given alone were obtained. PCP caused small response rate increases at low doses, and a dose-dependent decrease in responding at higher doses. PB caused only dose-dependent decreases in responding. The PB dose-response curve was then redetermined in the presence of four doses of PCP. Little support was found for the hypothesis that PCP enhances the depressant properties of PB. In fact, most dose combinations caused less disruption of responding than expected from simple addition of the effects of each drug given alone. These results are discussed in terms of species differences, measurement of different dipendent variables and rate-dependency.     

Differential behavioral effects of sulpiride in the rat and squirrel monkey

Despite its clinical efficacy as an antipsychotic agent, sulpiride differs from other neuroleptics in that it has been reported to exert erratic effects in several animal models. The effects of sulpiride were investigated on Sidman avoidance responding by the rat and squirrel monkey. At 100 mg/kg i.p. or orally, sulpiride failed to impair rat Sidman avoidance responding appreciably while exerting marginally toxic effects, but at 30 mg/kg orally, this drug strongly impaired Sidman avoidance responding by the squirrel monkey. This effect, which manifested delayed onset, was reversed by benztropine, indicating that dopamine receptor blockade was most likely responsible for the impairment of responding. The gross behavioral effects of sulpiride in the squirrel monkey resembled those of haloperidol, and dyskinetic postures induced by haloperidol could be mimicked by sulpiride in some instances. It is concluded that the behavioral effects of sulpiride in the rat may not be representative of its action in primates or in the clinic.     

Effects of d-amphetamine and methylphenidate upon auditory threshold in the squirrel monkey

The effects of d-amphetamine sulfate and methylphenidate hydrochloride on auditory thresholds in ten squirrel monkeys were examined using a 4.2 kHz stimulus in a free field. The results indicated that d-amphetamine raised auditory thresholds but methylphenidate did not alter the thresholds. The elevation of sensory thresholds by d-amphetamine was in agreement with previous studies suggesting that the drug acts as a behavioral depressant in diurnal animals.     

Oral ethanol intake and levels of blood alcohol in the squirrel monkey

Oral alcohol ingestion and blood alcohol levels were examined in adult female squirrel monkeys to assess the feasibility of using this primate as a model for fetal alcohol effects, In one experiment, alcohol intake was evaluated in nonpregnant animals under conditions in which the concentration of ethanol, length of ethanol exposure, and degree of liquid deprivation were varied. In another experiment blood alcohol levels were measured in pregnant animals of two subtypes that had been drinking ethanol. In a third experiment, time-dependent blood alcohol levels and behavior were evaluated in nonpregnant monkeys following intubation of specific doses of ethanol. Results showed that nonpregnant monkeys drank ethanol at concentrations of 5 to 10%, and that the amount of ethanol consumed was related to the concentration and length of time ethanol was available. When given access to a 5% ethanol solution, pregnant animals drank quantities that varied between individuals and subtypes, with maximum blood levels, measured up to 6 hr after presentation, ranging from 1 to 196 mg%. Intubation of ethanol resulted in blood alcohol levels and incoordination scores that were linearly related to dose, with maximum effects occurring 1 hr after administration. Elimination of ethanol from the blood at levels above 50 mg% occurred at a rate of about 35 mg%/hr, while the rate of clearance from the body was calculated to be approximately 250 mg/kg/hr.     

Effects of dopamine uptake inhibitors on schedule-controlled behavior in the squirrel monkey

Squirrel monkeys responded under a multiple fixedinterval (FI) fixed-ratio (FR) schedule of stimulus-shock termination. Benztropine mesylate (0.03–1.7 mg/kg), bupropion HCl (0.3–5.6 mg/kg), mazindol (0.01–0.3 mg/kg), and nomifensine maleate (0.1–1.0 mg/kg) markedly increased responding under the FI schedule, but not under the RR schedule. Mazindol was about three-times more potent than nomifensine and ten-times more potent than bupropion. Benztropine and mazindol were about equal in potency. The order and relative magnitude of potency differences for mazindol, nomifensine, and bupropion are similar to those reported by others for in vitro inhibition of dopamine uptake in rat striatum, but the relative potency of benztropine was greater in these behavioral experiments than expected from its potency in inhibiting dopamine uptake.     

Discriminative stimulus properties of phencyclidine and five analogues in the squirrel monkey

Squirrel monkeys were trained to discriminate 0.16 mg/kg of 1-(1-phenylcyclohexyl) piperidine (PCP) from saline in a two-lever drug discrimination task on a fixed-ratio 32 schedule of food presentation. Intramuscular injections were given 5 min pre-session in a double alternation pattern. After reliable discriminative control of lever choice was established, dose-response determinations for generalization to the training dose of PCP were made with several doses of PCP, N-ethyl-1-phenylcyclohexylamine (PCE), 1-[1-(2-thienyl) cyclohexyl] piperidine (TCP), 1-(1-phenylcyclohexyl) morpholine (PCM), 1-(1-phenylcyclohexyl) pyrrolidine (PHP), and ketamine. All drugs produced dose-dependent PCP-appropriate responding. For each analogue, a dose was found which produced stimulus control of responding comparable to that of the PCP training dose. ED50 values were determined for each drug for percent drug-lever appropriate responding and for suppression of operant responding during test sessions. The relative potency for producing drug-lever appropriate responding was: TCP>PCP=PCE>PHP>PCM>ketamine. The relative potency for suppression of operant responding was: PCP=TCP>PHP>PCE>PCM>ketamine. In all cases, the dose necessary to suppress operant responding to fifty percent of vehicle rates was three to five times larger than the ED50 dose for drug-lever appropriate responding. The results of this study indicate marked similarities in the behavioral effects of these six arylcyclohexylamines.     

Stress modification of the toxicity of antimotion sickness drugs and aspirin.

The effect of environmental temperature on the toxicity of cyclizine, trimethobenzamide, and Aspirin were studied in mice. LD50s were compared at 30 degrees C (warm), 22 degrees C (normal), and 15 degrees C (cool). At 30 degrees C the toxicity of all three drugs increased, with that to aspirin being affected most. Cooling decreased the toxicity of cyclizine and had no significant effect on that of trimethobenzamide or Aspirin. These findings indicate that alterations in environmental temperature markedly affect drug toxicity. They emphasize that such alterations, and particularly increases in temperature, do not have to be particularly drastic, but that "mild' variations in the environment are effective in altering an animal's sensitivity to a drug.     

Pharmacological interactions between serotonin and dopamine on behavior in the squirrel monkey

 The behavioral effects of GBR 12909, a selective dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of IV drug self-administration. Intermediate doses of GBR 12909 increased FI response rate markedly, and the highest dose decreased response rate below control values. The 5HT uptake inhibitors, alaproclate and fluoxetine, and the 5HT agonist, quipazine, attenuated the behavioral-stimulant effects of GBR 12909, whereas the 5HT_2A/2C antagonist, ritanserin, enhanced the behavioral-stimulant effects of the lowest dose. GBR 12909 reliably maintained self-administration, and ritanserin increased response rate maintained by the highest dose. The dopamine agonist, quinpirole, increased FI response rate in only one of three subjects, and ritanserin enhanced the behavioral-stimulant effects of quinpirole in that subject. The dopamine agonist, apomorphine, only decreased FI response rate, and ritanserin did not alter its behavioral effects. The pharmacological profile of GBR 12909 administered alone and in combination with selective 5HT drugs in the present study was similar to that obtained previously with cocaine, further demonstrating that 5HT can reliably modulate the behavioral effects of psychomotor stimulants with prominent dopaminergic actions. Received: 9 July 1996 / Final version: 22 November 1996