Effects of MDMA, methamphetamine and methylphenidate on repeated acquisition and performance in rats.

Repeated-acquisition procedures that include performance controls for effects not specific to acquisition permit the assessment of drug effects on learning on a within-subject, within-session basis. Despite the advantages of this methodology, few studies have examined effects of psychomotor stimulants on repeated acquisition in rodents. The purpose of the present study was to investigate the effects of methylenedioxymethamphetamine (MDMA, 0.3-10mg/kg), methamphetamine (MA, 0.1-3mg/kg) and methylphenidate (MPD,1-17 mg/kg) using repeated-acquisition procedures with performance controls in rats using a touch-screen apparatus. Rats were presented a 2x3 array of stimuli using a computer touch-screen and nose-pokes to target locations within the array were reinforced. In the acquisition component, the correct location changed across sessions, whereas during the performance component, the correct location was constant across sessions. All three drugs reduced accuracy of responding to target locations in a dose-dependent fashion. None of the compounds enhanced learning at any dose. MPD and MA produced significant disruptions of acquisition accuracy only at doses that also disrupted performance, but the 3mg/kg dose of MDMA impaired acquisition of target responding without affecting performance. The selective impairment of acquisition found in the present study adds to the evidence of learning and memory disruption produced by acute MDMA administration and raise questions about the mechanisms for these actions.

Chlordiazepoxide and dizocilpine, but not morphine, selectively impair acquisition under a novel repeated-acquisition and performance task in rats.

RATIONALE: Some classes of drugs can selectively affect learning (i.e., acquisition of behavior) at doses that do not affect performance (i.e., previously learned behavior). Some drugs (e.g., benzodiazepines) show selective effects on acquisition across a wide variety of tasks. Other drugs [e.g., N-methyl-D-aspartate (NMDA) antagonists and opiate agonists], however, show selective effects under some tasks, but not others. OBJECTIVES: The purpose of this study was to examine the effects of the NMDA-antagonist dizocilpine (0.01-0.3 mg/kg), the opiate-agonist morphine (1.0-17.0 mg/kg), and the benzodiazepine chlordiazepoxide (3.0-30.0 mg/kg) in rats under a novel repeated-acquisition and performance task. METHODS: Nose pokes to a correct location within a 2x3 stimulus array on a computer touch screen were reinforced with food. In the acquisition component, the correct location changed across sessions but remained constant within sessions; in the performance component, the correct location was constant both across and within sessions. RESULTS: Both chlordiazepoxide and dizocilpine selectively impaired accuracy in the acquisition component at doses that did not affect accuracy in the performance component or overall response speed. Morphine, however, did not affect acquisition without affecting performance or response speed. CONCLUSIONS: These results with rats resembled those previously obtained for response-sequence learning in primates, rather than those previously reported for spatial learning in rats. Therefore, previous discrepancies in results for NMDA antagonists and opiate agonists across tasks probably were not a function of the species studied, but, rather, they more likely were a function of unique variables controlling acquisition within each task.

Effects of positive GABA(A) modulators on a multiple-component, repeated-acquisition test of spatial learning.

The purpose of this study was to determine the effects of the benzodiazepines, midazolam and chlordiazepoxide, and the barbiturate, pentobarbital, on spatial learning, in a within-subject, repeated-acquisition and performance procedure adapted to the Morris Swim Task. In the presence of one stimulus arrangement, rats learned to swim to a hidden escape platform that was always in the same location in a swimming pool (performance component). In the presence of a second stimulus arrangement, the platform moved to a different place in the pool for each daily session (acquisition component). All subjects completed six training trials in both components during each daily training session, alternating between the two components within each session. Relatively direct paths to the platform and short escape latencies in the performance component, and steep within-session learning curves in the acquisition component, demonstrated that behavior under each component was controlled by the discriminative stimuli. All three GABA(A) modulators increased swim distances, escape latencies, and slowed swim speed in a dose-dependent manner. Midazolam and chlordiazepoxide, but not pentobarbital, produced selective impairments of swim distances and escape latencies in the acquisition component. Benzodiazepines disrupted acquisition at doses that did not disrupt steady-state performance. Pentobarbital impaired acquisition only at doses that also disrupted behavior during the performance component and reduced swimming speeds.

Clocinnamox antagonism of the antinociceptive effects of mu opioids in squirrel monkeys.

The opioid agonists morphine, etorphine, buprenorphine and U50,488 were examined alone and in combination with the insurmountable opioid antagonist clocinnamox (C-CAM) in squirrel monkeys responding under a schedule of shock titration. In this procedure, shock intensity increased every 15 sec from 0.01 to 2.0 mA in 30 increments. Five lever presses during any given 15-sec shock period produced a 15-sec timeout, after which shock resumed at the next lower intensity. When given alone, each of these agonists increased the median intensity at which the monkeys maintained shock [median shock level (MSL)]. At the highest dose examined alone, each agonist produced maximal increases in MSL and, except buprenorphine, decreased response rates. C-CAM dose-dependently antagonized the effects of morphine, etorphine and buprenorphine on MSL. In the presence of the higher C-CAM doses, etorphine, morphine and buprenorphine did not produce maximal effects on MSL. The effects of U50,488 were not systematically altered when tested in combination with the highest C-CAM dose. In general, C-CAM was more potent and the duration of antagonism was slightly longer against buprenorphine than against morphine and etorphine. Quantitative analysis of these data according to an extended model of yielded the following apparent affinity and efficacy estimates, respectively: etorphine (0. 085 mg/kg, 117); morphine (49 mg/kg, 24) and buprenorphine (0.62 mg/kg, 7.1). Determination of the individual q values over time indicated that the receptor population recovers more quickly after C-CAM antagonism of etorphine than from C-CAM antagonism of either morphine or buprenorphine. These data suggest that C-CAM functions as a long-lasting antagonist of mu opioid agonist actions in a shock titration procedure and yields estimates of relative intrinsic efficacy with the rank order of etorphine > morphine > buprenorphine.

Naturalistic conceptions of moral maturity.

By examining naturalistic conceptions of moral maturity, this project sought a more comprehensive understanding of moral excellence than is evident in dominant theories of moral development. Studies 1 and 2 involved different samples of 120 adults (17-25, 35-55, and 65+ years). Study 3 involved a sample of 180 undergraduates. In Study 1, a free-listing procedure was used to generate the attributes of a highly moral person as well as those for two related person-concepts. In Study 2, a rating procedure for these attributes was used to generate a prototype of the moral person-concept. In Study 3, a similarity-sorting task was used to uncover people's implicit typology of moral maturity. The findings indicate that naturalistic notions of moral excellence not only contain themes of principled reasoning but also reference aspects of moral character and virtue that enlarge our understanding of the psychological functioning of the mature moral agent.

Tolerance and cross tolerance to the accuracy- and rate-decreasing effects of mu opioids in rats responding under a fixed-consecutive-number schedule.

The purpose of the present investigation was to examine the development of tolerance to the effects of morphine and other mu opioids in rats responding under a fixed-consecutive-number (FCN) schedule of food presentation. To this end, five rats were trained under an FCN schedule and subsequently tested with a variety of mu opioids both before and during chronic exposure to a 0.4 mg/ml morphine drinking solution. Morphine, fentanyl, buprenorphine, butorphanol and nalbuphine produced dose-dependent decreases in both accuracy and response rate when tested prior to the chronic regimen. In most instances, doses of these drugs that decreased accuracy also decreased response rate. During chronic treatment, tolerance developed to the effects of morphine and cross-tolerance was conferred to the effects of fentanyl, buprenorphine and butorphanol. A greater degree of tolerance was conferred to the effects of butorphanol than to the other opioids examined, and the degree of tolerance conferred to butorphanol's rate-decreasing effects was greater than the degree of tolerance conferred to its accuracy-decreasing effects. Doses of naloxone that had no effect prior to morphine treatment produced large decreases in accuracy and response rate when tested during the chronic regimen. In contrast to the other opioids examined, the potency of nalbuphine was not altered by chronic morphine administration. These data emphasize the importance of both pharmacological and procedural variables in the development of tolerance and cross tolerance to the behavioral effects of opioids.

Opioids and rate of positively reinforced behavior: differential antagonism by naltrexone.

Lever pressing by rats was maintained under a fixed-ratio 30 schedule of food presentation. The response rate-decreasing effects of several opioid compounds that vary in selectivity for, and activity at, µ, kappa, and non-opioid receptors, were examined alone and in combination with the opioid antagonist naltrexone. Naltrexone (0.01-1.0mg/kg) produced dose-dependent and generally parallel rightward shifts in the dose-effect curves for morphine, fentanyl, butorphanol and nalbuphine. Apparent pA(2) values for naltrexone against these agonists ranged from 7.05 to 7.29, and the slopes of the regression lines fitted to the Schild plots approximated theoretical unity (-1.0), suggesting a competitive interaction at µ-opioid receptors. In contrast, although at least one dose of naltrexone (0.01-10.0mg/kg) antagonized the response rate-decreasing effects of bremazocine, U50,488, (-)-pentazocine and nalorphine, suggesting some opioid activity, these effects differed from those of the µ agonists in that: (a) they were less sensitive to naltrexone antagonism; (b) maximal rightward shifts were smaller; (c) antagonism patterns were not directly related to naltrexone dose and, in some cases, were influenced by the response rate-decreasing effects of the larger naltrexone doses; and (d) there were considerable between-subjects differences in sensitivity to naltrexone antagonism. Naltrexone (0.1-10.0mg/kg) did not antagonize the effects of the non-opioid control compound pentobarbital. The present results suggest that patterns of naltrexone antagonism can provide a basis for making inferences about receptor activity related to the effects of some opioids on rate of schedule-controlled behavior. With some opioids, however, such inferences are limited by the direct response rate-decreasing effects of naltrexone itself and by differences in patterns of antagonism across subjects.

Cocaine and food deprivation: effects on food-reinforced fixed-ratio performance in pigeons.

Key pecking by 6 pigeons was maintained by a fixed-ratio 30 schedule of food presentation while body weights were 80% of free-feeding weights. Acute administration of cocaine (0.3 to 13.0 mg/kg, i.m.) dose-dependently decreased response rates. Dose-effect curves were shifted to the right when 3 of the 6 pigeons were maintained at 70% of free-feeding weights and were shifted to the left when the other 3 pigeons were maintained at 90% of free-feeding weights. Then a dose of cocaine that initially decreased response rates by more than 95% of control rates was administered before each daily session. Comparable degrees of tolerance to these rate-decreasing effects developed in the two groups. The rate at which responding recovered was relatively rapid for pigeons in the 70% free-feeding-weight group and was slower for 2 of the 3 pigeons in the 90% free-feeding-weight group. When body weights were then increased from 70% to 80% or were decreased from 90% to 80% of free-feeding weight, performance was disrupted initially only for pigeons whose weight went from 70% to 80% of free feeding. In the present experiment the degree of deprivation may have indirectly influenced the degree of tolerance that developed to cocaine's response rate-decreasing effects because it directly influenced the dose chosen to be administered chronically. The degree of deprivation appeared to have a more direct influence on the rate at which tolerance developed.

Effects of reinforcement amount on attack induced under a fixed-interval schedule in pigeons.

Key pecking by pigeons was maintained on a chained fixed-interval 4-min (12-min for 1 subject) fixed-ratio 1 schedule of food presentation. Attacks toward a restrained and protected conspecific were recorded. In the first experiment, the amount of food presented per interval was manipulated across phases by varying the number of fixed ratios required in the terminal link of the chain. Measures of attack for all pigeons during the fixed-interval component increased monotonically as a function of food amount. In the second experiment, two different food amounts alternated within each experimental session under a multiple schedule. For both pigeons in this experiment, measures of attack were higher during the component that delivered the larger food amount per interval. The differences in levels of attack induced by the two food amounts in Experiment 2, however, were not as great as in Experiment 1; apparently this was because attack during the first interval of each component was controlled in part (P-5626) or entirely (P-7848) by the reinforcement amount delivered at the end of the previous component. Attack was also a function of the location of the interfood interval within the session. For both pigeons, attack tended to decrease throughout the session. The results of both experiments suggest that attack is an increasing function of reinforcement amount under fixed-interval schedules, but that this function may be influenced by the manner in which reinforcement amount is manipulated, by the duration of the interfood interval, and by the location of the interfood interval within the experimental session. In general, these results are compatible with theories of induced attack and other schedule-induced behavior that emphasize aversive after-effects of reinforcement presentation.

Antinociceptive and response rate-altering effects of kappa opioid agonists, spiradoline, enadoline and U69,593, alone and in combination with opioid antagonists in squirrel monkeys.

Effects of the kappa opioid agonists, spiradoline (U62,066), enadoline (CI-977) and U69,593, were examined alone and in combination with the opioid antagonists quadazocine and beta-funaltrexamine in squirrel monkeys that responded under a schedule of shock titration. When given alone, each of these agonists increased the intensity at which the monkeys maintained shock 50% of the time (median shock level, MSL). Lower doses of spiradoline, enadoline and U69,593 increased response rates in some monkeys and higher doses decreased response rates in all monkeys. When given in combination with the opioid antagonist quadazocine, the dose-effect curves of each agonist, both for MSL and response rates, were shifted to the right in a dose-related and parallel manner. The slopes for the regression lines of the Schild plots for each agonist-quadazocine interaction approximated unity and apparent pA2 values for quadazocine in combination with these agonists ranged between 6.68 and 6.81 for MSL and between 6.63 and 6.87 for response rate. The effects of these agonists were not changed by an 8.0 mg/kg dose of beta-funaltrexamine that markedly antagonized the effects of morphine. These results parallel those previously obtained with other kappa agonists, such as bremazocine and U50,488 and suggest that the antinociceptive effects of spiradoline, enadoline and U69,593 in the shock-titration procedure in squirrel monkeys relate to activity at non-mu, probably kappa, opioid receptors.

Effects of ethanol on punished and nonpunished responding under conditions of equated reinforcement rates and similar response rates.

Lever pressing by pairs of rats was maintained under random-ratio (first subject) and yoked-interval (second subject) schedules of food presentation. The inter-reinforcement intervals generated under the ratio schedule comprised the interval values for the second (yoked) subject. This arrangement yielded nearly equivalent rates of food presentation for each subject pair. For the first rat of each pair a random-ratio schedule of shock presentation was added to the ratio schedule of food presentation. This manipulation resulted in similar rates of punished (first rat) and nonpunished (second rat) responding within subject pairs. Ethanol administration (0.25-1.5 g/kg) generally resulted in dose-related decreases in both punished and nonpunished responding. In general, punishment-specific effects were not obtained. These results suggest that ethanol may not be as effective as chlordiazepoxide or pentobarbital in increasing punished responding even when the effects of baseline response and reinforcement rates are controlled.

Preference for less frequent shock under fixed-interval schedules of electric-shock presentation.

Lever pressing by 2 squirrel monkeys was maintained under fixed-interval 6-min and fixed-interval 2-min schedules of electric-shock presentation. Preference for these schedules was assessed during three experimental phases. In all phases, responses on one lever produced shock according to one or the other fixed-interval schedule, and responses on a second, changeover, lever switched between schedules. The opportunity to change over was presented during separate choice periods (during which the fixed-interval schedules did not operate) that followed the first through fourth shocks in each schedule. If no changeover occurred during those choice periods, a changeover automatically occurred following the fifth shock. In Phase I, durations of the choice periods were fixed. In Phase II, the choice periods equaled a proportion of their respective fixed interval. During Phase III (completed with 1 monkey) a response on the changeover lever during a given choice period reinstated the most recent fixed interval, and a failure to respond resulted in a changeover. During each of these phases, distinct preferences developed for the 6-min schedule. These results suggest that the maintenance of lever pressing by fixed-interval presentation of electric shock may not be an example of positive reinforcement, and that the response-maintaining characteristics of shock presentation may derive from other properties of the schedule.