Stereoselective behavioral effects of cocaine and a phenyltropane analog.

Intramuscular injections of the stereoisomers of cocaine and of its phenyltropane analog were compared for their effects on schedule-controlled behavior of squirrel monkeys. Monkeys responded by pressing a lever under a multiple schedule with alternating fixed-interval and fixed-ratio components; responding was maintained by presentation of food in some monkeys and by termination of a stimulus associated with electric shock in other monkeys. The levorotatory isomers, (-)-cocaine (0.09-2.7 mg/kg) and WIN 35,065-2 (0.006-0.2 mg/kg), had qualitatively similar effects which depended primarily on the type of component schedule (fixed-interval or fixed-ratio) that maintained responding. In the fixed-interval components, intermediate doses of each drug increased responding, whereas higher doses decreased responding. In the fixed-ratio components, each drug only decreased responding in a dose-related manner. The minimal effective dose of (-)-cocaine was about 10 times that of WIN 35,065-2. Although the dextrorotatory isomers, (+)-cocaine and WIN 35,065-3, also increased responding in the fixed-interval components and decreased responding in the fixed-ratio components in some monkeys, the doses required were 100 to 622 times the minimal effective doses of their enantiomers. The results show a high degree of stereoselectivity in the behavioral effects of both cocaine and its phenyltropane analog.

Behavioral effects of clozapine: comparison with thioridazine, chlorpromazine, haloperidol and chlordiazepoxide in squirrel monkeys.

The behavioral effects of the antipsychotic drug, clozapine, were compared with those of thioridazine, chlorpromazine, haloperidol and chlordiazepoxide. Behavior of squirrel monkeys was controlled by different consequences of a lever-pressing response (presentation of food, presentation of electric shock or termination of a stimulus associated with electric shock) under different schedules of reinforcement (a fixed-interval schedule or a multiple schedule with alternating fixed-ratio and fixed-interval components). The effects of thioridazine (0.2-24.6 mumol/kg), chlorpromazine (0.03-2.8 mumol/kg) and haloperidol (0.001-0.08 mumol/kg) were largely independent of the type of schedule or the type of consequent event that maintained responding: each drug produced dose-related decreases in responding under all conditions in which they were studied. Clozapine (0.1-9.2 mumol/kg) and chlordiazepoxide (0.9-167.4 mumol/kg) also only decreased responding under most schedule conditions; however, intermediate doses of either drug markedly increased responding maintained by presentation of food under the fixed-interval schedule (whether programmed singly or as a component of the multiple schedule). Only clozapine increased responding maintained by presentation of electric shock under the fixed-interval schedule. Thus, the behavioral effects of clozapine differed qualitatively from those of representative antipsychotic and antianxiety drugs.

Fixed-ratio responding under second-order schedules of food presentation or cocaine injection.

Squirrel monkeys pressed a key under second-order schedules in which every nth response resulted in a 2-sec visual stimulus (n-response fixed ratio; n = 10, 20 or 30); after a minimum fixed-interval of time elapsed (second-order t-min fixed-interval; t = 5 or 60), the completion of a fixed-ratio resulted in both the brief stimulus and either presentation of food or i.v. injection of cocaine. Under a second-order 5-min fixed-interval schedule with 15 intervals per session, rates of responding increased to a maximum and then decreased with increases in the amount of food (from 250 to 4000 mg/presentation) or cocaine (from 25 to 400 micrograms/kg/injection). Cocaine injections maintained higher maximal rates of responding than food presentation. When the brief stimuli were omitted during the 5-min intervals, average rates of responding maintained by cocaine decreased, but those maintained by food presentation did not. The presession administration of cocaine (0.3-1.0 mg/kg i.m.) increased rates of responding maintained by food to about the same level as those maintained by cocaine; these elevated rates did not decrease when the brief stimuli were omitted. Under a second-order 60-min fixed-interval with one interval per session, both food and cocaine maintained relatively high rates of responding even with large amounts of food (7.5-14 g/presentation) or cocaine (375-1500 micrograms/kg/injection). When the brief stimuli were omitted during the 60-min interval, rates of responding maintained by either food or cocaine decreased. Thus, the brief-stimulus presentations were essential for maintaining performance under the second-order 60-min fixed-interval schedule.

Self-administration of cocaine derivatives by squirrel monkeys.

Lever pressing by squirrel monkeys was maintained under a 5-min fixed-interval schedule of drug self-administration; the first response after 5 min elapsed produced an i.v. injection of cocaine (2.7-267.7 micrograms/kg), the phenyltropane analog of cocaine, WIN 35,065-2 (0.6-64.3 micrograms/kg) or their respective N-demethylated derivatives, norcocaine (3.0-1,000.0 micrograms/kg) and WIN 35,981 (0.8-245.5 micrograms/kg). As the dose per injection was increased, responding maintained by each drug first increased and then decreased. When saline was substituted for the drugs, responding occurred irregularly and at low rates. The drugs were equally effective in maintaining responding, but WIN 35,065-2 was 3 to 10 times more potent than cocaine; cocaine and WIN 35,065-2 were each 3 to 10 times more potent than their N-demethylated derivatives, norcocaine and WIN 35,981. There was a high degree of stereoselectivity in the effects of the phenyltropane analogs; the (-)-isomer, WIN 35,065-2, was the most potent drug studied, yet its enantiomer, WIN 35,065-3, did not maintain responding at any dose tested (0.6-6427.7 micrograms/kg/injection). These structure-activity relations correspond to those observed previously for the effects of cocaine derivatives on schedule-controlled responding by pigeons and squirrel monkeys, suggesting that the reinforcing and other behavioral effects of these drugs reflect common pharmacological actions.

Pharmacological studies of behavioral influences on cardiovascular function.

Squirrel monkeys, prepared with chronic arterial and venous catheters, responded (pressed a key) under fixed-ratio schedules of termination of a stimulus associated with electric shock or under fixed-ratio schedules of food presentation. Although there was no necessary correlation between schedule-controlled responding and cardiovascular changes, pronounced elevations in both heart rate and blood pressure occurred during and just after brief periods of fixed-ratio responding. These episodic increases in blood pressure and heart rate were as marked under schedules of food presentation as under schedules of stimulus-shock termination. Thus, these episodic changes appear to be more dependent upon the schedule-controlled behavior than upon the type of event maintaining the behavior. Pharmacological studies indicated that under the conditions of the behavioral experiments the squirrel monkey has a relatively high degree of cardiac sympathetic tone; however, blood pressure elevations produced by administration of 1-norepinephrine were associated with an increased parasympathetic tone and decreased heart rate. The reflex bradycardia induced by 1-norepinephrine was inhibited during periods of schedule-controlled responding, suggesting that environmental and behavioral factors can not only modulate the parameters of physiological variables but also modulate this basic cardiovascular control system.

Behavioral effects of self-administered cocaine: responding maintained alternately by cocaine and electric shock in squirrel monkeys.

Squirrel monkeys responded under a fixed-interval schedule of intravenous cocaine injection that alternated with a fixed-interval schedule of either presentation of electric shock or termination of a stimulus associated with electric shock. As the dose of cocaine was increased from 10 to 1000 microgram/kg/injection, responding maintained by cocaine injection or alternately by electric shock first increased and then decreased. The lowest doses of cocaine that reliably maintained self-administration often increased responding maintained by electric shock; the highest doses of cocaine that continued to maintain self-administration often decreased responding maintained by electric shock. When saline was substituted for cocaine, responding that had previously been maintained by cocaine injection occurred irregularly and at very low rates, whereas rates and patterns of responding maintained by electric shock were characteristic of fixed-interval schedules. When the fixed-interval schedule of cocaine injection was replaced by intravenous injections that occurred without regard to antecedent responding, the effects of cocaine on responding maintained by electric shock were found to be independent of the way in which cocaine was administered.

Synthesis and biological activity of cocaine analogs I: N-alkylated norcocaine derivatives.

N-Allylnorcocaine, N-dimethylallylnorcocaine, and N-cyclopropylmethylnorcocaine were prepared and examined for cocaine-like activity. The compounds were prepared by alkylation of norcocaine, which was obtained by demethylation of cocaine with 2,2,2-trichloroethyl chloroformate followed by zinc--acetic acid reduction. The compounds were evaluated by comparison with cocaine in causing disruption of milk intake in rats, behavioral modification in squirrel monkeys, and inhibition of 3H-serotonin uptake by rat synaptosomes. The compounds showed cocaine-like activity less potent than cocaine in the latter two tests and were inactive in the milk intake test.

Fixed-interval responding under second-order schedules of food presentation or cocaine injection.

Squirrel monkeys operated a key under second-order schedules in which every tenth completion of a 5-minute fixed interval resulted in either presentation of food or intravenous injection of cocaine. When a 2-second light was presented at the completion of the component fixed-interval schedules, positively accelerated responding developed and was maintained in each component. Over a tenfold range of doses of cocaine(30 to 300 microgram/kg/injection) and amounts of food (0.75 to 7.5 g/presentation); the second-order schedule of cocaine injection maintained higher average rates of responding than the second-order schedule of food presentation. Substituting saline for cocaine or eliminating food presentation decreased average rates of responding. When no stimulus change occurred at the completion of the first nine component fixed-interval schedules, but the 2-second light and food presentation or cocaine injection still occurred after the tenth component, only low and relatively constant rates of responding were maintained in each component. Patterns of responding characteristic of 5-minute fixed-interval schedules were maintained by the 2-second light paired with either cocaine injection or food presentation, though the maximum frequency of cocaine injection or food presentation was less than once per 50 minutes.

Some effects of cocaine and two cocaine analogs on schedule-controlled behavior of squirrel monkeys.

The behavioral effects of two phenyltropane derivatives of coaine were compared with those of cocaine. Squirrel monkeys responded under multiple fixed-interval, fixed-ratio schedules of either stimulus-shock termination or food presentation or under a fixed-ratio schedule of food presentation. The effects of the three drugs were independent of the type of event that maintained responding. Under the fixed-interval schedules, some doses of each drug increased responding, whereas larger doses generally decreased responding. Maximal increases in responding were similar with each drug. Appropriate doses of each drug increased low response rates, which occurred during the initial segments of the fixed intervals, but had little effect on or decreased higher response rates, which occurred during the later segments of the fixed intervals. Under the fixed-ratio schedules, each drug decreased responding in a dose-related manner. Decreases in fixed-ratio responding resulted both from increased periods of no responding at the beginning of the fixed ratios and from decreased rates of responding once responding began. Each cocaine analog had a slower onset of effect and longer responding began. Each cocaine analog had a slower onset of effect and a longer duration of effect than cocaine. The behavioral effects of the two cocaine analogs were qualitatively similar to those of cocaine, but each was 3 to 10 times more potent than cocaine.

Behavior controlled by scheduled injections of cocaine in squirrel and rhesus monkeys.

Rates and patterns of key-press responding maintained under schedules in which responding resulted in intravenous injections of cocaine were studied in squirrel monkeys and rhesus monkeys. Each injection was followed by a 60- or 100-sec timeout period. Schedule-controlled behavior was obtained at appropriate cocaine doses in each species. Under FR 10 or FR 30 schedules, performance was characterized by high rates of responding (usually more than one response per second) in each ratio. Under FI 5-min schedules, performance was characterized by an initial pause, followed by acceleration of responding to a final rate that was maintained until the end of the interval. Under multiple fixed-ratio fixed-interval schedules, rates and patterns of responding appropriate to each schedule component were maintained. Responding seldom occurred during timeout periods under any schedule studied. At doses of cocaine above or below those that maintained characteristic schedule-controlled behavior, rates of responding were relatively low and patterns of responding were irregular. Characteristic fixed-interval responding was maintained over a wider range of cocaine doses than characteristic fixed-ratio responding. Complex patterns of responding controlled by discriminative stimuli under fixed-ratio or fixed-interval schedules can be maintained by cocaine injections in squirrel monkeys and rhesus monkeys.