Min Presession Research Articles

Self-administration in baboons and the discriminative stimulus effects in rats of bupropion, nomifensine, diclofensine and imipramine

The behavioral effects of the antidepressants nomifensine, diclofensine, bupropion, and imipramine were examined using a cocaine substitution drug self-administration procedure in baboons and a cocaine drug discrimination procedure in rats. Intravenous self-administration of the antidepressants was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a fixed-ratio 80-response or 160-response schedule of intravenous injection. Each drug injection was followed by a 3-h time-out allowing a maximum of eight injections per day. The antidepressants or their vehicles were substituted for cocaine for a period of 15 days, followed by a return to the cocaine baseline. Nomifensine, diclofensine and bupropion all maintained self-administration behavior at levels above those maintained by their respective vehicles. Some doses of nomifensine, diclofensine, and bupropion maintained levels of behavior similar to those maintained under baseline cocaine conditions. High doses of imipramine maintained levels of behavior above those maintained by its vehicle, but the amount of behavior maintained under these conditions was extremely small. In a second experiment rats were trained to discriminate 32 mumol/kg cocaine (IP 10 min presession) from no drug in a two-lever food reinforced drug discrimination procedure in which responding on one lever was reinforced following ten consecutive responses when the session was preceded by cocaine administration, while responding on the other lever was similarly reinforced in the absence of cocaine pretreatment. Cocaine, nomifensine, diclofensine, and bupropion all dose-dependently occasioned cocaine-appropriate responding. Imipramine did not occasion cocaine-appropriate responding over a range of behaviorally active doses.

Evaluation of the interaction between D1 and D2 receptors in a drug discrimination paradigm

Recent research has suggested that there is a synergistic interaction between D1 and D2 dopamine (DA) receptors and that D1 stimulation by endogenous DA is necessary for the expression of some D2-mediated behavioral effects. The purpose of the present experiment was to examine further the interactions between D1 and D2 receptors using drug discrimination (DD), a behavioral paradigm that is sensitive and selective for D1 and D2 agonist and antagonist activity. Two groups of male Sprague-Dawley rats (N = 8/group) were trained to discriminate the D2 agonist quinpirole (QUIN; either 0.05 or 0.012 mg/kg, ip, 10 min pre-session) from saline (1.0 ml/kg, ip, 10 min pre-session) in a two-lever, food-reinforced DD paradigm. QUIN (0.0015-0.1 mg/kg) produced a dose-related increase in QUIN-appropriate responding in both groups of rats. The D1 agonist SKF 38393 (SKF; 6.4-12.8 mg/kg, ip) given alone did not substitute for QUIN in either of the two training dose groups. The administration of SKF 30 min before QUIN had no effect on the QUIN dose-response function in either group of rats. These results indicate that stimulation of D1 receptors failed to potentiate a behavioral effect mediated by D2 receptors. The D1 antagonist SCH 23390 (SCH; 0.0015-0.05 mg/kg, ip) partially substituted for QUIN in the group trained with the 0.05 dose of QUIN, and to a larger extent in the group trained with the 0.012 dose of QUIN. SCH did not alter the effect of the training dose of QUIN except at a dose high enough to virtually eliminate lever pressing in the group trained to discriminate the high dose of QUIN. The failure of SCH to block QUIN suggests that D1 receptor stimulation by endogenous DA is not necessary for this D2 effect to be expressed. These results may be accounted for by assuming a presynaptic site of action for QUIN in the QUIN discrimination. Further, they demonstrate that the interaction between D1 and D2 receptors cannot be simply characterized as synergistic.

Evalutation of the pharmacological similarities between phenlpopanolamine andamphetamine: Effects on schedule‐controlled behavior

In an effort to determine the degree to which the repeated administration of phenylpropanolamine (PPA) results in the development of tolerance to its disruptive effects on operant responding as well as cross-tolerance to the effects of acutely administered amphetamine, water-deprived rats were first trained on a fixed-ratio 5 (FR-5) schedule for water presentation. Dose-response curves for the effects of PPA and amphetamine (administered IP, 15 min presession) were then determined (ED50 = 35.0 and 2.6 mg/kg, respectively) followed by the chronic administration of 40.0 mg/kg PPA (administered IP, 15 min prior to each session). When responding returned to prechronic rates, the dose-response curves were redetermined for both PPA (ED50 = 220 mg/kg) and amphetamine (ED50 = 4.8 mg/kg). In a second set of rats, trained under similar conditions, it was observed that pretreatment with alpha-methyltyrosine (AMT, 100 mg/kg IP, 2 h presession) antagonized the disruptive effects of both PPA and amphetamine, whereas pretreatment with reserpine (0.31 mg/kg, IP, 12 h presession) antagonized the disruptive effects of PPA, but exacerbated the disruptive effects of amphetamine. In a separate experiment, the repeated administration of PPA 100 mg/kg or 200 mg/kg IP resulted in no long-lasting depletions of rat striatal dopamine, serotonin, or 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations. These observations indicate that PPA and amphetamine share a similar mechanism of action to the degree that cross-tolerance develops, but which is nonetheless dissociable with respect to their differential sensitivity to antagonists and their neurotoxic efficacy.

Investigations of amitraz neurotoxicity in rats: I. Effects on operant performance

Amitraz (AMZ) is a formamidine pesticide which is often compared to chlordimeform (CDM). The effects of AMZ (6.25–75 mg/kg) and CDM (5–20 mg/kg) on the schedule-controlled performance of rats were examined using a multiple fixed-ratio (FR) 10 fixed-interval (FI) 300-sec schedule of milk reinforcement. Following dose-effect determinations, rats received three daily doses of AMZ (50 mg/kg). Low to intermediate doses of AMZ (6.25-25 mg/kg), administered 20 min presession, significantly decreased FI responding but not FR responding. In contrast, CDM appeared to decrease responding similarly under both components. Both compounds disrupted the temporal pattern of responding within the interval; AMZ had only a moderate influence at all effective doses but CDM produced a marked dose-dependent disruption of temporal response patterning. The effects of the high doses of AMZ (50–75 mg/kg) were more pronounced 24 hr after dosing, whereas the rats had recovered from lower doses at this time. Performance was progressively disrupted and the rats' health rapidly deteriorated during the course of three daily injections of AMZ (50 mg/kg). Operant performance recovered more quickly than did the general health of the rats. Thus AMZ produced effects on multiple-schedule performance that were distinct from the effects of CDM. Moreover, the signs of intoxication and the effects on schedule-controlled behavior following a high dose (50 mg/kg) were augmented and persistent with short-term repeated administration.

Differential effects of formamidine pesticides on fixed-interval behavior in rats

Chlordimeform (CDM), amitraz (AMZ), and formetanate (FMT) are members of the formamidine class of pesticides. To date, effects on operant behavior have been determined only for CDM. This experiment compared the effects of CDM, AMZ, and FMT on schedule-controlled responding. Nine male Long-Evans rats were trained during 1-hr sessions to lever-press under a multiple fixed-interval (FI)-1-min FI-5-min schedule of milk reinforcement. Dose-effect determinations for each compound administered ip, 20 min presession, were carried out in each subject. The dose ranges were: CDM HCl, 0.3–20 mg/kg; FMT HCl, 0.03 – 0.75 mg/kg; and AMZ, 5–75 mg/kg. Under baseline conditions response rates were higher under the FI-1-min than under FI-5-min, and index of curvature (IOC) values (a measure of within-interval response patterning) were generally higher under FI-5-min. All compounds produced dose-dependent decreases in response rate. CDM significantly decreased only FI-1-min response rates; a similar effect of AMZ was seen only at an intermediate dose. FMT decreased responding to the same extent in both components. CDM produced pronounced changes in the pattern of responding in both components, with IOC decreased more under FI-5-min than under FI-1-min. AMZ produced significant decreases in IOC only under FI-5-min. FMT did not appreciably decrease IOC in either component. High doses of AMZ produced general signs of poor health that persisted for several days. In addition, a greater effect on response rates and IOC in both components was obtained when AMZ (75 mg/kg) was given more than 10 days following another dose compared to when it was given 7 days or less after another dose. Formamidine pesticides produce differential effects on FI schedule-controlled behavior that are in turn modulated by the parameter value of the FI schedule.

Effects of a D1 and a D2 dopamine antagonist on the self-administration of cocaine and piribedil by rhesus monkeys.

Rhesus monkeys were surgically prepared with chronic intravenous catheters and allowed to self-administer the indirect dopamine (DA) agonist cocaine (0.03 or 0.1 mg/kg/inj) or the direct D2 agonist piribedil (0.1 or 0.2 mg/kg/inj) on a fixed-ratio 10 schedule of drug delivery during daily 2 hour experimental sessions. When responding was stable, they were injected IV with SCH 23390, a selective D1 antagonist (0.003-0.3 mg/kg, 30 min pre-session) or pimozide, a selective D2 antagonist (0.003-0.3 mg/kg, 2 hours pre-session). Intermediate doses of pimozide generally increased self-administration of cocaine or piribedil, though increases in piribedil self-administration were more reliable. In contrast, intermediate doses of SCH 23390 either did not affect or decreased cocaine and piribedil self-administration. High doses of each antagonist decreased the rate of self-administration of each compound and produced catalepsy. The selective increase in responding maintained by cocaine or piribedil following pimozide pretreatment suggests a role for a D2-like receptor in psychomotor stimulant self-administration.

Alteration of response patterning by d-amphetamine on repeated acquisition in rats

The acute effects of d-amphetamine on response patterning in a repeated acquisition baseline were investigated with rats. Each session the animals acquired a different four-member response sequence on three levels. Each sequence (trial) completion produced a food pellet. Errors produced a brief timeout that was reset by responses made during the timeout. Acute doses of d-amphetamine (0.5–4.0 mg/kg) and saline were administered 30 min presession. The response patterns analyzed were perseverative responses to a single lever (runs), and a response to each lever in either a left-to-right or right-to-left direction (tranerses). The trial position, frequency, and lever location of error and timeout responses that occurred in the context of runs and traverses were studied. In contrast to control sessions, higher doses of d-amphetamine produced increases in the number of error and timeout responses emitted. The majority of these responses occurred as runs; traverse responding did not exceed control levels. Furthermore, the run error and timeout responding tended to occur early in the session and on a siingle response lever. The results are consistent with the view that d-amphetamine disrupts stimulus control and produces perseverative responding which may account for previous reports of disruption in repeated acquisition tasks following d-amphetamine administration.

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.

Effects of cocaine and fenfluramine on progressive-ratio performance

Pigeons obtained food on a progressive-ratio schedule that required 8 additional responses for each successive reinforcement. The number of responses in the final completed ratio of the session was defined as the breaking point. When cocaine was administered (IM, 5 min presession), the breaking point increased and then decreased as a function of increasing doses (0.3–10 mg/kg). In contrast, across the same range of doses of fenfluramine, the breaking point only decreased. At doses of each drug that decreased the breaking point, the high running rate of responding was interrupted by pauses. At doses of cocaine that increased the breaking point, the running rate was also disrupted, but the disruption was characterized by lower, irregular rates rather than pausing. The increases in breaking point observed at 3 mg/kg of cocaine were no longer seen when fenfluramine was administered at the same time.

Time course for the effects of cocaine on fixed-ratio water-reinforced responding in rats.

Four male rats performed during 35-min sessions under a schedule that arranged water delivery (0.04 ml) after every fortieth response. Cocaine (1.0-16.0 mg per rat, i.p.) was administered 15 min, 30 min, 60 min or 120 min prior to a session. When given 15 min prior to a session, cocaine (1.0-8.0 mg) in all rats produced dose-related decreases in responding. The largest dose, when given 15 min pre-session to two rats, almost completely suppressed responding. Lengthening the time between drug injection and test session attenuated the rate-decreasing effects of cocaine (1.0-8.0 mg), but did not affect the almost complete suppression of performance seen with the largest dose. Small doses (1.0-4.0 mg) had no effect on the pause in responding that occurred after water delivery. The 8.0-mg dose lengthened the pause by approximately 9000% and 650% when given 15 and 30 min prior to a session, respectively, but by less than 50% when given 60 or 120 min pre-session. Cocaine effects depend on the dose as well as the time of its administration prior to testing.

Performance influence on the development of tolerance to amphetamine

This experiment was performed to determine whether performance of a behavior in the drug state was necessary for behavioral tolerance to the effects of that drug to occur. Eight rats trained on a DRL 17.5-sec schedule received daily injections of 1.5 mg/kg d-amphetamine sulfate; four received amphetamine 30 min presession, and four received amphetamine 30 min postsession. Amphetamine given presession initially resulted in a disruption of timing behavior, an increase in response rate, an increase in short IRTs and a decrease in the number of reinforcements received. With continued administration of presession amphetamine the rats developed a partial tolerance to these disruptive effects. Postsession amphetamine had no effect on performance. When tolerance developed in rats receiving presession amphetamine, they were switched to postsession amphetamine; rats receiving postsession amphetamine were switched to presession amphetamine. Amphetamine produced the same disruption of performance in the rats switched to presession amphetamine as was observed in the initial pressession amphetamine group, indicating that tolerance did not develop to amphetamine given postsession. In addition changes in the pattern of responding were observed when amphetamine was initially administered presession.

Effects of d-amphetamine on the “breaking point” of progressive-ratio performance

When d-amphetamine was administered intramuscularly to pigeons 30 min presession, the “breaking point” of their progressive-ratio performance increased as the dose increased from 0.5 to 2 mg/kg and then decreased to below control values at the largest dose (4 mg/kg). The maximum increase in breaking point induced by d-amphetamine was substantially less than that found with the optimal dose of phenobarbital (40 mg/kg). An attempt to mimic the large disruptive effect of the 4-mg/kg dose of d-amphetamine by prefeeding the Ss 60 g of grain produced only a small decrease in breaking point compared to the drug condition.