Charles W. Schindler

Pharmacological mechanisms in cocaine's cardiovascular effects

The squirrel monkey is a reliable model for the cardiovascular effects of cocaine in that it mimics the human response to cocaine; low to moderate doses of cocaine produce a sustained pressor effect and tachycardia. Pretreatment experiments have indicated the importance of alpha-1 and beta-1 adrenoceptor mechanisms in mediating the pressor and tachycardiac effects of cocaine, respectively. Little support for a role of dopaminergic mechanisms in the hemodynamic effects of cocaine has been found. Toxicity to cocaine is often observed hours after its administration, pointing to a potential role of the cocaine metabolites. Studies on the direct effects of a variety of cocaine metabolites indicate that their cardiovascular effects do not necessarily mimic those produced by cocaine, and therefore these differing effects of the metabolites should be considered when evaluating the cardiovascular toxicity of cocaine. Further, as these metabolites are present in the body for long periods of time, these results suggest a role of the metabolites in producing toxicity long after cocaine administration. Finally, studies using both dopaminergic and calcium channel antagonists indicate that the pharmacological mechanisms involved in the cardiovascular effects of cocaine are not the same as those involved in its behavioral effects.

Effects of cocaine, cocaine metabolites and cocaine pyrolysis products on the hindbrain cardiac and respiratory centers of the rabbit ag

Hemodynamic and respiratory effects of vertebral artery or i.v. administration of cocaine, cocaine metabolites and cocaine pyrolysis products were measured in anesthetized rabbits. Vertebral artery administration of 1 mg of cocaine produced decreases in blood pressure and heart rate and respiratory arrest. Cocaethylene (1 mg), a cocaine metabolite produced following co-administration of cocaine and ethanol, had comparable effects except that the respiratory arrest following cocaethylene had a longer duration of action than did cocaine. A decrease in blood pressure was also observed following 1 mg of norcocaine; however, unlike cocaine, norcocaine did not affect respiration. Acute tolerance was not observed to any of the effects of 1 mg of cocaine, cocaethylene or norcocaine following vertebral artery administration. None of these compounds had significant effects following i.v. administration of the same dose. The cocaine metabolites benzoylecgonine and ecgonine methyl ester were without effect by either route in doses up to 3 mg. In contrast to cocaine, the cocaine pyrolysis products anhydroecgonine methyl ester (3 mg) and noranhydroecgonine methyl ester (3 mg) produced similar effects via both routes of administration. Both compounds produced decreases in blood pressure and heart rate and an increase in respiratory rate. Anhydroecgonine ethyl ester (3 mg), a metabolite hypothetically formed from the cocaine pyrolysis product in individuals co-administering ethanol, had effects similar to the other pyrolysis products, although its effects were not as prominent via the i.v. route of administration. Acute tolerance was observed upon administration of the cocaine pyrolysis products. These results indicate that the cocaine pyrolysis products do not share a common mechanism of action with either cocaine or the cocaine metabolites.

Cocaine and cardiovascular toxicity

Over the past 10 years a great deal has been learned about the cardiovascular effects of cocaine. In particular, the acute effects of cocaine have been studied extensively. Upon acute administration cocaine increases blood pressure and heart rate, primarily through an action on the sympathetic nervous system. Cocaine also suppresses the baroreflex response and vagal tone, further contributing to its effects on heart rate. At the same time cocaine is increasing the work‐load on the heart it induces coronary artery vasoconstriction, potentially leading to cardiac ischemia. At higher doses cocaine can depress ventricular function and slow electrical conduction in the heart. Both these effects appear to be mediated by cocaines local anesthetic action. The effects of cocaine mediated by the sympathetic nervous system are greatly reduced in anesthetized animals. Further, when cocaine is administered repeatedly over a short period of time, acute tolerance can develop to the sympathomimetic effects of cocaine. In contrast, the effects of cocaine mediated by its local anesthetic action do not appear blunted by anesthesia or susceptible to acute tolerance. With chronic administration, higher doses appear to induce tolerance while lower doses may induce sensitization to cocaines sympathomimetic effects. Cocaine also induces a variety of pathological changes in the heart, including myocardial contraction band necrosis and ventricular hypertrophy. These effects of cocaine on the heart can all contribute to potentially lethal cardiovascular events. In addition to the effects of cocaine alone, the metabolites of cocaine may also contribute to cocaines cardiovascular toxicity, and both licit and illicit drugs used in combination with cocaine might potentially alter its cardiovascular effects.

Interaction of haloperidol and SCH 23390 with cocaine and dopamine receptor subtype-selective agonists on schedule-controlled behavior of squirrel monkeys

Involvement of D1 and D2 dopamine receptors in the effects of cocaine on schedule-controlled behavior was evaluated in squirrel monkeys responding under a multiple fixed-interval 5-min, fixed-ratio 10 schedule (mult FI FR) of food delivery. Cocaine and the D2 agonist quinpirole increased responding under the FI at certain doses and disrupted the temporal patterning of behavior. Higher doses of these drugs decreased responding. In contrast, the D1 agonist SKF 38393 was devoid of behavioral activity up to 10 mg/kg where response suppression was obtained without significant modification of the temporal distribution of responding. The D2 antagonist haloperidol (0.001–0.03 mg/kg) did not alter the behavioral effects of cocaine up to doses that had pronounced behavioral effects on their own. However, haloperidol attenuated the behavioral effects of quinpirole. In contrast, the D1 antagonist SCH 23390 partially attenuated the response rate-suppressant effects of cocaine without blocking cocaine-induced disruptions of temporal response patterning. SCH 23390 did not antagonize the behavioral effects of SKF 38393. These results suggest that independent stimulation of either D1 or D2 receptors alone does not play a major role in the effects of cocaine on schedule-controlled behavior of squirrel monkeys.

Asymmetric uptake of 2-deoxy-d-[14C]glucose in the dorsal cochlear nucleus during Pavlovian conditioning in the rabbit

Uptake of 2-deoxy-D-[14C]glucose was measured during Pavlovian conditioning of the rabbits nictitating membrane response by both qualitative autoradiography and by quantitative measurement of radioactivity in samples of brain tissue. Conditioning was accomplished by pairing a tone stimulus delivered to both ears with an air-puff stimulus delivered to the right eye. Infusion of 2-deoxy-D-[14C]glucose during the first day of conditioning when there was no evidence of acquisition or during the 7th day of conditioning when animals demonstrated 68% conditioned responses resulted in a significantly greater uptake of radioactivity by the caudal portions of the left as compared with the right dorsal cochlear nucleus. Similar changes were not observed in other auditory and non-auditory nuclei. Rabbits that had acquired conditioned responses across 6 days of training and were exposed only to the tone-conditioned stimulus on the 7th day of testing exhibited 69% conditioned responses but no asymmetry in the uptake of 2-deoxy-D-[14C]glucose. Control animals receiving unpaired presentations of tone and air puff or no stimulation did not acquire conditioned responses and did not demonstrate asymmetric uptake of radioactivity in the dorsal cochlear nucleus. These results indicate that the asymmetric uptake of radioactivity by the dorsal cochlear nucleus did not result from the effects of stimulation per se or the prior occurrence of learning but was due to the explicit pairing of the tone stimulus with the asymmetric delivery of the air puff. It would appear that the caudal dorsal cochlear nucleus not only serves as a signal transducer for auditory stimuli but also receives inputs from other sensory systems thus allowing it to both recognize when an auditory stimulus is followed by a biologically significant event and to transmit such information to other brain regions that are, in turn, responsible for learning.

Evaluation of deprenyl for cocaine-like discriminative stimulus effects in rats

The antiparkinsonian agent l-deprenyl is metabolized to l-methamphetamine and l-amphetamine and, at higher doses, can facilitate the release and inhibit the reuptake of dopamine. Since l-deprenyl can affect dopamine release and reuptake it was important to evaluate it for cocaine-like discriminative stimulus effects. Male Fisher rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-lever, operant-conditioning procedure using schedules of food-delivery or stimulus-shock termination. l-Deprenyl (17 mg/kg, i.p.) produced full generalization to cocaine under the food-delivery schedule but this or higher doses produced only partial generalization to cocaine under the stimulus-shock termination schedule. d-Deprenyl produced full generalization to cocaine under both schedules at i.p. doses of 5.6 to 10 mg/kg. These cocaine-like discriminative stimulus effects occur only at doses that are well above the clinically relevant dose range for l-deprenyl.

Acquisition of a nose-poke response in rats as an operant

Acquisition of a nose-poke operant response was investigated in rats. The baseline level of this response was high and acquisition with food reinforcement occurred rapidly, particularly when compared with a leverpress operant response. A variety of control procedures clearly indicated that this response was acquired due to the contingency between nose pokes and food reinforcement.The response was also sensitive to manipulations of delay of reinforcement and food-deprivation level. Acquisition was slowed with longer delays of reinforcement and with decreases in deprivation level. Therefore, the nose-poke response appears to be particularly useful for the study of the acquisition of operant responses.

Integrating control generated by positive and negative reinforcement on an operant baseline: Appetitive-aversive interactions

The interaction of opposing motivational states was measured within a design in which rats barpressed for food in one stimulus and to avoid shock in another. Tone and light discriminative stimuli (Sds) were counterbalanced over incentive conditions. Extinction eliminated responding when neither Sd was present. To minimize the influence of competing peripheral operants or reinforcer-elicited behaviors during appetitive-aversive interactions, contingency parameters were manipulated to generate similar rates and patterns of barpressing in both Sds and stimulus-compounding tests were administered in extinction. On these tests, rates in tone, light, and tone plus light (T+L) were equivalent. In contrast, when the same reinforcer (i.e., food or shock avoidance) maintained comparable training rates in tone and in light, in testing, T+L controlled double the rates of the single stimuli—strong additive summation. These results were strikingly similar to those of single-incentive experiments concerned with the contribution of excitatory and inhibitory incentive states to the results of stimulus compounding. Simultaneously presenting two Sds whose implicit stimulus-reinforcer (S-Sr) contingencies were arranged to make them, respectively, conditioned appetitive and aversive exciters (present experiment) produced test results comparable to those of two Sds whose implicit S-Sr contingencies were arranged to make them both conditioned inhibitors. Reciprocal antagonism between these two motive states more than neutralizes them. It appears to produce a negative (i.e., an inhibitory) motive state.

Cardiovascular effects of cocaine: underlying mechanisms

At the 1993 annual meeting of the College on Problems of Drug Dependence in Toronto Canada, a symposium entitled ‘Cardiovascular effects of cocaine: Underlying mechanisms’ was presented. The purpose of this symposium was to present a wide range of state-ofthe-art research on the cardiovascular effects of cocaine, including both animal and human studies. The timeliness of this symposium is supported by the continued upward trends in the mentions for cocaine in the Drug Abuse Warning Network (DAWN) surveys of both emergency rooms and medical examiners. Increases in cocaine mentions have occurred in both of these surveys in each of the last two years for which data are available (1991- 1992). Undoubtedly, the cardiovascular effects of cocaine played some role in these increasing trends. The papers that follow grew out of four presentations at that symposium. The paper by Gillis et al. (1995) reviews their extensive animal research on locus of action for cocaine in producing its sympathetic nervous system mediated effects. They conclude that rather than having a central nervous system origin, the sympathetic mediated cardiovascular effects are primarily due to actions of cocaine in the periphery. While contradicted by other studies using more indirect measures of sympathetic nervous system function which have pointed to a central origin for the cardiovascular effects of cocaine (e.g., Wilkerson, 1988), the techniques used by Gillis et al. to directly measure sympathetic nerve activity presents a strong case for a peripheral site of action for cocaine. The research reviewed in the paper by Schindler et al. (1995) utilized more traditional techniques to explore the pharmacological basis for the cardiovascular effects of co

Chapter 3 - Classical conditioning

Publisher Summary nThis chapter provides an overview of classical conditioning concept in learning behavior. While classical conditioning is often thought of as a simpler form of learning than operant conditioning; in fact, the complexity of classical conditioning from a procedural viewpoint rivals that of operant conditioning. It is generally agreed that classical conditioning, along with operant conditioning, constitutes the majority, if not all, of the learned behaviors. In general, classical conditioning involves the pairing of two stimulus events, typically a neutral conditioned stimulus (CS), and an unconditioned stimulus (US). That an association between these two events is learned is reflected in the acquisition of a conditioned response (CR) to the CS. The CR is usually topographically similar in the form to the unconditioned response (UR) to the US, although this is not universally the case. However, for classical conditioning the CR in no way changes the CS–US stimulus arrangements. One area where classical conditioning has been used extensively is in the study of drug effects on learning or acquisition. Classical conditioning procedures hold a number of advantages over operant conditioning in the study of learning.