Dose-related Decreases In Response Rates Research Articles

Effects of antipsychotic drugs on operant responding after acute and repeated administration.

The current generation of atypical antipsychotic drugs represents an improvement over traditional ("typical") antipsychotics in many respects. However, a theoretical framework and adequate preclinical models have not yet been developed to predict or explain differences among the atypical antipsychotics, a necessary component of future development. The purpose of the present set of experiments was to identify differences between the acute and subchronic effects of several atypical antipsychotic drugs and the typical antipsychotic haloperidol on operant responding in rats. The effects of haloperidol and the atypical antipsychotics clozapine, olanzapine, risperidone, sertindole, quetiapine, remoxipride, and thioridazine were determined in rats trained to respond for food reward under a multiple fixed ratio 30/fixed interval 60 s schedule. A profile of the acute effects of each drug on response rates, response durations, and within-session effects were determined. Next, the dose of each drug that produced 75% suppression of response rates was administered for 16 consecutive days to determine whether or not tolerance would develop to the rate-suppressing effects of that dose. All drugs produced dose-related decreases in response rates. Only haloperidol and risperidone produced significant increases in response duration, while only haloperidol and remoxipride displayed within-session response decrements. Tolerance was evident for clozapine and to a lesser extent thioridazine. These results illustrate that the current generation of atypical antipsychotics are a heterogeneous group and that operant procedures may be useful for identifying differences preclinically. Specifically, clozapine appears to possess properties that distinguish it from other atypical antipsychotics, particularly after repeated dosing.

Comparison of the effects of full and partial allosteric modulators of GABAA receptors on complex behavioral processes in monkeys

Two baselines involving a repeated acquisition task were used to assess the effects of bretazenil, imidazenil, and triazolam. The first baseline was a multiple schedule of repeated acquisition and performance of conditional discriminations. In the first component, the subject acquired a four-response chain by responding sequentially on three keys in the presence of different combinations of colors and geometric forms displayed on a center key. Acquisition of the discrimination was defined by a decrease in errors as the session progressed. In the performance component, the four-response chain was the same each session. Incorrect responses in either component produced a 5s time out during which responding had no programmed consequence. The second procedure, which has been used to evaluate the effects of drugs on memory, involved the acquisition of a discrimination, followed by a 1h delay and a retest of the same discrimination to assess retention. Triazolam (0.32 and 0.56mg/kg) administered alone, produced dose-related decreases in response rate in each component. In addition, triazolam also produced a dose-related increase in percentage errors in acquisition with no effect in performance. Triazolam (0.32mg/kg) eliminated retention (0 percent savings) in the memory task. Bretazenil (0.1-5.6mg/kg) or imidazenil (0.1-1.8mg/kg) administered alone had little or no effect on either rate of responding or accuracy in either component. Furthermore, bretazenil but not imidazenil disrupted retention at the higher doses tested. The combination of imidazenil or bretazenil with triazolam produced dose-related attenuation of the disruptive effects of triazolam on both behavioral baselines. These data suggest that the disruptive effects of benzodiazepines on learning and memory may be a function of the intrinsic efficacy of these compounds at different GABA(A) receptor subtypes.

Triazolam and ethanol effects on human matching-to-sample performance vary as a function of pattern size and discriminability

The effects of placebo, triazolam (2.0, 4.0 and 8.0 μg/kg) and ethanol (0.25, 0.5, 1.0 g/kg) on perceptual-motor performance were examined using a visual pattern matching-to-sample procedure in which pattern size and comparison stimulus discriminability were systematically varied. Baseline response rates and accuracy increased as the discriminability of the comparison stimuli increased. At the highest dose, both drugs decreased response accuracy. This disruption of accuracy was attenuated by increasing the discriminability of non-matching stimuli. Triazolam produced dose-related decreases in response rate while ethanol produced only slight decreases at the highest baseline rates of responding. Thus, triazolam produced response rate slowing at relatively lower doses than ethanol.

Benzodiazepine-induced impairment of matching-to-sample performance in humans

The effects of benzodiazepines on a visual pattern matching-to-sample (MTS) task were examined in nine healthy male volunteers. The MTS task employed randomly generated checkerboard-like stimuli presented on a video display. The sample and two comparison stimuli were simultaneously presented. Nonmatching comparison stimuli were randomly generated to be 3.125, 6.25, 12.5, 25.0, 37.5, or 50.0 percent different from the sample. Subjects responded on left or right button manipulanda to identify the matching comparison stimulus. The nonmatching stimulus condition was maintained constant for a 60-sec component and the percentage difference of the nonmatching stimuli was systematically varied across multiple components. The effects of triazolam (2.25–9.0 μg/kg) and lorazepam (7.5–45 μg/kg) were examined in a within-subjects, double-blind, placebo-controlled study. Under placebo conditions, response rates and accuracy were a positive function of the nonmatching stimulus discriminability. Triazolam produced dose-related decreases in response rate at nonmatching stimulus conditions ⩾25%. Only the 9.0 μ/kg dose of triazolam decreased accuracy and this occured across all nonmatching stimulus conditions. Lorazepam effects were qualitatively similar but less robust than those of triazolam.

Central and peripheral muscarinic actions of physostigmine and oxotremorine on avoidance responding of squirrel monkeys

The involvement of central and peripheral muscarinic cholinergic receptors in the behavioral effects of the cholinesterase inhibitor physostigmine was evaluated by comparing the ability of atropine and methylatropine to reverse the effects of physostigmine, the muscarinic agonist oxotremorine, or their quaternary analogs neostigmine and oxotremorine-M. Avoidance behavior was maintained under a schedule in which every lever press postponed delivery of electric shock for 20 s; shock occurred every 5 s in the absence of responding. Cumulative doses of physostigmine or oxotremorine produced dose-related decreases in response rates, and increases in response durations and rates of shock delivery. Similar effects occurred with neostigmine and oxotremorine-M. Methylatropine completely prevented the behavioral and parasympathetic effects of neostigmine and oxotremorine-M without having any behavioral effects of its own. However, methylatropine did not alter the behavioral effects of physostigmine or oxotremorine. Atropine prevented the peripheral manifestations as well as the behavioral effects of physostigmine and oxotremorine even though atropine decreased avoidance responding when given alone. These results suggest that in squirrel monkeys, central and peripheral muscarinic receptors may function in a redundant manner to control agonist-induced decrements in avoidance. When physostigmine or oxotremorine was given in conjunction with atropine, rates of avoidance responding were increased to 180% of control levels. Response rate increases after administration of oxotremorine or physostigmine in monkeys treated with atropine may reflect a non-muscarinic action of atropine, unmasked by the presence of cholinomimetics.

Tolerance to effects of cocaine on schedule-controlled behavior: effects of fixed-interval schedule parameter.

Tolerance to the effects of cocaine on key pecking by pigeons, maintained by differently valued fixed-interval schedules of food presentation, was studied. Key pecking was established on a multiple fixed-interval 5-sec fixed-interval 30-sec fixed-interval 120-sec schedule. Cocaine (1.0-10.0 mg/kg) was administered acutely and then chronically (i.e., before each session) in 5.6 mg/kg doses. Acute cocaine administration produced dose-related decreases in response rates under all three schedules. When cocaine was administered chronically, response rates either recovered fully, or increased to the extent that no reinforcers were missed during the sessions. The development of tolerance was not systematically related to the schedule value. Considered in relation to previous research, these results indicate that different control rates of reinforcement, within the schedules and parameters studied, do not contribute to tolerance to cocaine's behavioral effects.

Opioid receptor subtype-specific cross-tolerance to the effects of morphine on schedule-controlled behavior in mice.

Key-press responding of mice was maintained under a fixed-ratio (FR) 30-response schedule of food presentation. Successive 3-min periods during which the experimental chamber was illuminated and the schedule was in effect were preceded by 10-min time-out (TO) periods during which all lights were out and responses had no scheduled consequences. Intraperitoneal (IP) injections of saline or of cumulative doses of drugs were given at the start of each TO period. Successive saline injections had little or no effect on response rates, whereas the mu-opioid agonists morphine (0.1-10.0 mg/kg) and levorphanol (0.1-3.0 mg/kg), the kappa-opioid agonist ethylketazocine (0.03-3.0 mg/kg), the mixed mu-/delta-opioid agonist metkephamid (0.1-10.0 mg/kg), and the nonopioid dissociative anesthetic ketamine (1.0-100.0 mg/kg) generally produced dose-related decreases in response rates. Following chronic administration of morphine (100.0 mg/kg/6 h), tolerance developed to the effects of morphine on rates of responding. In addition, a comparable degree of cross-tolerance developed to the effects of levorphanol and metkephamid. On the other hand, there was no evidence of cross-tolerance to the effects of ethylketazocine or ketamine. These results are consistent with the evidence suggesting that different opioid agonists exert their behavioral effects through distinct classes of opioid receptors.

Tripelennamine fails to enhance the morphine-like stimulus effects of pentazocine

The effects of tripelennamine alone and in combination with morphine or pentazocine were examined in pigeons trained to discriminate between morphine (5.6 mg/kg, IM) and saline under a fixed ratio 30 schedule of food presentation. Tripelennamine (0.3–10.0 mg/kg) produced only saline-appropriate responding and dose-related decreases in response rates. When administered alone, both morphine (0.3–10.0 mg/kg) and pentazocine (1.0–30.0 mg/kg) produced dose-related increases in morphine-appropriate responding and dose-related decreases in reponse rates. When tripelennamine (0.3, 1.0 mg/kg) was administered in combination with morphine, the morphine dose-effect curve was not altered. Additionally, when tripelennamine (0.3, 1.0, 1.7 mg/kg) was administered in combination with pentazocine, tripelennamine did not alter the extent to which pentazocine produced morphine-appropriate responding. There was some suggestion that tripelennamine attenuated the effects of high doses of pentazocine; however, this effect did not occur in all pigeons. These results suggest that tripelennamine does not enhance the morphine-like discriminative stimulus properties of pentazocine in the pigeon, as it does in the rat.

Tolerance to antinociceptive effects of morphine without tolerance to its effects on schedule-controlled behavior.

The development of tolerance to behavioral effects of morphine was investigated in rats that responded on a two-lever, multiple-trial, multiple differential-reinforcement-of-low-rate fixed-ratio (mult DRL FR) schedule of food presentation. Stable performances were maintained when sessions were conducted just twice per week. The effects of cumulative doses of morphine (1.0-8.0 mg/kg) or chlordiazepoxide (CDP; 4.0-32.0 mg/kg) were evaluated once per week; saline injections were given in the intervening sessions. The effects of saline and morphine on nociception were also evaluated in hot-plate tests conducted on the same subjects 15 min after selected operant sessions. Initially, morphine produced dose-related decreases in response rates and reinforcement rates in the DRL and FR components as well as significant increases in hot-plate response latencies. Following weekly administration of morphine (1.0-8.0 mg/kg) for 10 weeks, there was little or no tolerance to its effects on operant behavior. In contrast, complete tolerance developed to the antinociceptive effects of morphine. These results suggest that tolerance to various behavioral effects of morphine may be dissociated, and that the loss of reinforcement may be insufficient by itself to produce tolerance to effects of morphine on operant behavior. Additionally, whereas CDP initially produced only dose-related decreases in DRL and FR response rates, following weekly morphine the smaller doses of CDP (4.0-16.0 mg/kg) produced increases in response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral effects of adenosine analogs in squirrel monkeys: relation to adenosine A2 receptors

The behavioral effects of seven metabolically stable analogs of adenosine were studied in squirrel monkeys responding under a fixed-interval (FI) schedule of stimulus-shock termination. All drugs produced dose-related decreases in response rate, but differed in potency by up to three orders of magnitude. The 5'-carboxamide and 2-chlorine substituted analogs were more potent than the N6-substituted analogs. The potencies of the adenosine analogs in decreasing schedule-controlled behavior correlate well with their reported affinities for adenosine A2, but not A1, recognition sites as determined by displacement of bound ligands or modulation of adenylate cyclase activity. The results suggest that the behavioral effects of adenosine analogs in squirrel monkeys are linked to their actions at adenosine A2 receptors.

Tolerance to effects of morphine without cross tolerance to effects of clonidine on schedule-controlled behavior of pigeons.

Schedule-controlled responding was maintained under a multiple fixed-interval, fixed-ratio schedule in pigeons. Dose-related decreases in response rates were produced by clonidine (0.001-0.1 mg/kg) and morphine (0.3-5.6 mg/kg). Chronic administration of morphine produced (1) tolerance to effects of morphine, as evidenced by a decrease in potency of morphine and (2) sensitivity to opioid antagonists, as evidenced by an increase in potency of naloxone. Dose-effect curves for clonidine were not appreciably altered by chronic morphine administration.

Effects of MK-212 (6-chloro-2[1-piperazinyl]pyrazine) on schedule-controlled behavior and their reversal by 5-HT antagonists in the pigeon

The effects of MK-212 (6-chloro-2[l-piperazinyl]pyrazine), a centrally-active 5-hydroxytryptamine (5-HT; serotonin) agonist, were studied alone and in combination with the 5-HT antagonists, methysergide (0.01–0.1 mg/kg), metergoline (0.01–1.0 mg/kg) and ketanserin (0.01–3.0 mg/kg). Pigeons were maintained under a procedure where key pecks were reinforced under a multiple fixed-interval (FI) fixed-ratio (FR) schedule of food presentation. In the fixed-interval component, the first response after 3 min had elapsed, produced food, while in the fixed-ratio component, the thirtieth response was reinforced. The drug MK-212 (0.1–3.0 mg/kg) produced dose-related decreases in response rates under both components of the schedule. In smaller doses of MK-212 (0.3 and 1.0 mg/kg), the decrease in the response rate was greater in the fixed-interval component than in the fixed-ratio component. Small doses of methysergide (0.03 mg/kg) and metergoline (0.1 mg/kg), which had little effect when given alone, partially blocked the effects of MK-212 (1.7 and 3.0 mg/kg) in decreasing rate. Larger doses of these compounds, which sometimes increased the response rate when given alone, resulted in a more complete restoration of response rates when administered with MK-212. Ketanserin, a selective 5-HT 2 antagonist, reversed the effects of MK-212 in some cases, but the patterning of responses remained disturbed. These results demonstrate that MK-212 was able to disrupt a complex behavioral task in the pigeon at doses which caused no other noticeable signs, and that these effects were reversed in a systematic way by serotonin antagonists, known to exert a similar antagonism of the effects of MK-212 on other behavioral responses.

Pyrazoloquinoline benzodiazepine receptor ligands: Effects on schedule-controlled behavior in dogs

The effects of diazepam and the pyrazoloquinoline benzodiazepine receptor ligands CGS8216, CGS9896 and CGS9895 on schedule-controlled responding were studied in dogs. Responding was maintained under a multiple fixed-interval (FI) 5-min fixed-ratio (FR) 30 response schedule of food presentation. Diazepam (PO) produced dose-related decreases in response rates under FR component. Under the FI, rates first increased and then decreased with increasing doses of diazepam. Diazepam also produced a dose-related disruption of the temporal pattern of responding under the FI as measured by decreases in quarter-life values. CGS8216 IV produced dose-related decreases in response rates under both components. The highest oral dose of CGS8216 also decreased rates in both components. CGS8216 was approximately 100 times more potent by the IV route as compared to the oral route. CGS9896 IV had no significant effect on responding under either component of the multiple schedule. However, with increasing doses of CGS9896 PO, response rates under components first decreased and then returned to control values. CGS9895 PO was without significant effect on responding. When CGS8216 was administered concomitantly with graded doses of diazepam, the former drug blocked the rate-decreasing effects of diazepam under the FR component, but not the rate-increasing effects of diazepam under the FI. The present results demonstrate that although these three pyrazoloquinolines are benzodiazepine receptor ligands, they do not exhibit diazepam-like effects on schedule-controlled behavior.

Methylxanthine discrimination in the rat: Possible benzodiazepine and adenosine mechanisms

Rats were trained to discriminate either caffeine or theophylline from saline using a two-lever discrimination paradigm. Since methylxanthines have been found to interfere with agonist binding at both adenosine and benzodiazepine (BDZ) receptors, chlordiazepoxide (CDP) and L-PIA (an adenosine analog) were tested for generalization to and blockade of both xanthine cues. Neither L-PIA nor CDP generalized to either xanthine cue, although both produced dose-related decreases in response rate. CDP, but not L-PIA, produced dose-related decreases in drug-lever responses when combined with training doses of caffeine or theophylline. Response rates indicated a complex interaction between the xanthines and both L-PIA and CDP. When combined with the caffeine training dose, pentobarbital also produced a dose-dependent decrease in response rate but not in drug lever choices. Finally, papaverine generalized to the caffeine cue in a dose-dependent fashion. In a second experiment, rats trained to discriminate CDP from saline showed no generalization in L-PIA tests. CDP-appropriate responding was not significantly affected when the CDP training dose was combined with caffeine. These data indicate that: (a) methylxanthine interactions with L-PIA and CDP on response rate likely involve blockade of adenosine mechanisms; (b) the xanthine cue does not appear to depend on interactions with adenosine receptors; and (c) the xanthine cue may involve effects on cyclic AMP activity and/or interaction with the BDZ/GABA receptor complex.

Intravenous cholecystokinin octapeptide in pigs reduces operant responding for food, water, sucrose solution or radiant heat

The effect of intravenous injections of 0 (Saline vehicle), 10, 20 or 40 units of CCK was studied in pigs performing operant responses for food, water, sucrose solution or radiant heat. In hungry pigs working for food, thirsty pigs responding for water, and non-deprived pigs working for sucrose, 20 and 40 units CCK produced significant dose-related decreases in response rates lasting for about 5 min. In pigs responding for 10 sec bursts of infra-red heat at an ambient temperature of 5°C, 40 units CCK significantly reduced the response rate during the 5 min period following injection.

Effects of local anesthetics on fixed-interval responding in rhesus monkeys.

Several local anesthetics of both the ester and amide type were administered IM to rhesus monkeys trained to respond on a fixed-interval 5 min schedule of food delivery. With the exception of procainamide, all local anesthetics produced dose-related decreases in response rates. Effects on pattern of responding varied between local anesthetics. With some (cocaine, dimethocaine and lidocaine), rate-dependent effects were apparent. When control rates were low, these compounds increased rates; when control rates were high, they decreased rates. However, with others (procaine, chloroprocaine, tetracaine and propoxycaine) no rate-dependent effects were noted; i.e., these compounds had little or no effect on the pattern of responding, even at doses that substantially reduced response rates. Consistent with other experiments with these compounds, cocaine was the most potent of the group. In several instances, local anesthetics which had similar stimulus properties in other behavioral paradigms differed in terms of their effects on fixed-interval behavior.

Ethanol, pentobarbital, and chlordiazepoxide effects in squirrel monkeys responding under fixed-ratio food presentation and stimulus-shock termination schedules

Ethanol, pentobarbital, and chlordiazepoxide were administered to squirrel monkeys responding under a multiple schedule comprised of two fixed-ratio 100-response schedules (FR 100). Under one FR schedule, the one-hundredth response produced food. Under the other schedule, the one-hundredth response terminated the prevailing stimuli and accompanying schedule of electric shock presentation (stimulus-shock termination). Comparable high response rates were maintained under the two schedules. Each drug produced dose-related decreases in response rates. With all three drugs the effects on all aspects of performance were quantitatively similar for both stimulus-shock termination and food-maintained responding.