Effects of weekly exposure to anatoxin-a and nicotine on operant performance of rats.

This study examined the effects of acute and weekly administration of anatoxin-a and nicotine on operant performance. Anatoxin-a is a potent nicotinic receptor agonist produced by cyanobacteria, which are found in fresh waters throughout the world. Anatoxin-a is a potential human health hazard and has been responsible for numerous deaths of wildlife, livestock and domestic animals. Remarkably little is known, however, about the effects of anatoxin-a on behavior. Nicotine, the psychomotor stimulant in tobacco, has many well-documented behavioral effects, which often diminish (i.e. tolerance develops) when it is given daily. Male Long Evans rats initially were trained to respond under a multiple variable-ratio 30-response variable-interval 60-s (mult VR-30 VI 60-s) schedule of food reinforcement. They were then divided into 12 groups of 8 that received four weekly subcutaneous injections of anatoxin-a (0.05-0.2 mg/kg), nicotine (0.125-1.8 mg/kg), or vehicle 5-min prior to testing. When initially administered, each compound decreased response rates and reinforcement rates in both components of the multiple schedule. Substantial tolerance developed to the disruptive effects of nicotine with weekly administration. Tolerance also developed to the effects of anatoxin-a, although to a lesser degree; the highest dose severely decreased performance with little evidence of recovery. In conjunction with prior findings, these results suggest the behavioral effects of anatoxin-a and nicotine are similar, but not identical, and that relatively infrequent (episodic) administration can produce tolerance.

Effects of thioridazine on the intellectual performance of mentally retarded drug responders and nonresponders.

Forty mentally retarded adolescents were divided into two divisions on the basis of prestudy assessments that identified subjects as thioridazine hydrochloride responders or nonresponders. Within each division, the participants were assigned randomly to one of four groups. Members of each group received three administrations of the Leiter international performance scale. Four conditions were examined: testing under standard conditions and testing under reinforcement conditions while receiving and not receiving thioridazine. Condition sequences were random in all four groups. Assessments were double-blind and placebo controlled. The results showed that while both drug responders and nonresponders were receiving thioridazine there were no major differences in test scores obtained under standard and reinforcement conditions. While subjects were not receiving thioridazine there were considerable increases in scores obtained under the reinforcement conditions.

Acute and chronic effects of methsuximide and mephenytoin on the delayed-matching-to-sample performance of pigeons.

Acute and chronic effects of methsuximide and mephenytoin were examined in pigeons performing under a delayed-matching-to-sample procedure. Acute administrations of methsuximide (25-175 mg/kg) and mephenytoin (40-160 mg/kg) produced generally dose-dependent decreases in accuracy. At the two highest doses, methsuximide decreased rate of responding to the sample stimulus; mephenytoin did so only at the highest dose. At low doses, both methsuximide and mephenytoin increased response rate over control. After 20 sessions of daily exposure to methsuximide (100 mg/kg) or mephenytoin (80 mg/kg), tolerance developed to the accuracy-decreasing effects of both drugs.

The effects of d-amphetamine on the automaintained key pecking of pigeons.

Three food-deprived pigeons were initially exposed to an automaintenance procedure in which 8-s response key illuminations were followed by food delivery without regard to the subject's behavior. The percentage of occasions on which key illumination was followed by food delivery was then successively reduced from 100 to 50, 25, 10, and 2.5%. Despite the lack of a programmed contingency between key pecking and food delivery or key illumination, key pecking occurred under all automaintenance conditions. Mean responses per 8-s key illumination during non-drug sessions varied from over 15 to less than one, with the 100 and 50% pairing conditions engendering the highest rates and the 2.5% pairing condition the lowest. Under all automaintenance conditions, d-amphetamine in does of 0.5, 1, and 2 mg/kg decreased responding in a dose-dependent fashion. Rate-dependent effects were not evident despite the appreciable differences in mean response rates engendered by the various conditions.

Effects of delaying food availability contingent on ethanol-maintained lever pressing.

The effects of delaying food availability 8 s contingent on every, every second, and every fourth lever press maintained by 4,8, and 16% (v/v) ethanol solutions were examined when food was initially available to rats on a fixed-interval 26-s schedule. The delay contingency decreased ethanol-maintained responding at all ethanol concentrations, with the degree of decrease inversely related to the intermittency of the delay schedule and to the ethanol concentration. Such decreases were not evident in the performance of yoked-control animals which received food coincidentally with experimental animals. Temporal changes in food presentation alone therefore could not account for the decreases produced by the delay contingency.

Drug effects on the performance of pigeons under a negative automaintenance schedule.

Pigeons were exposed to a negative automaintenance schedule in which food was delivered following brief key illumination only if the illuminated key was not contacted; contact of the lighted key prevented food delivery. All subjects emitted some responses under this procedure when drugs were not given. However, the number of responses was less than that which occurred under an automaintenance procedure in which food followed key illumination regardless of the bird's behavior. Under the negative automaintenance procedure, acute administration of atropine (0.01--0.1 mg/kg), d-amphetamine (0.4--1.6 mg/kg), and morphine (3,8--15 mg/kg) reduced in a dose-dependent manner the percentage of key illuminations in which subjects contacted the lighted key. Diazepam (1.0--6.0 mg/kg) increased the percentage of key illuminations during contact responses occurred.

Effects of methsuximide and mephenytoin on the responding of pigeons under a fixed-consecutive-number schedule with and without an external discriminative stimulus.

The effects of the antiepilepsy drugs methsuximide and mephenytoin were examined in pigeons responding under a fixed-consecutive-number (FCN) schedule with and without an added external discriminative stimulus. On this schedule, food was delivered whenever subjects responded between 8 and 12 times on one response key (work key), and then responded once on a second response key (reinforcement key). Under one variant of the FCN schedule (FCN 8-SD), an external discriminative stimulus signalled completion of the response requirement on the work key; no such stimulus change occurred under the other (FCN 8) schedule. The two FCN schedules (with an without stimulus change) alternated at 5-min intervals within each session for all subjects. Methsuximide (25-200 mg/kg) and mephenytoin (40-160 mg/kg) produced generally dose-dependent decreases in percentage of reinforced response runs and rate of responding. The magnitudes of these effects were comparable under both variants of the FCN schedule.

Effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin on the delayed matching-to-sample performance of pigeons.

The effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin were examined in pigeons performing under a delayed matching-to-sample procedure. Clonazepam, valproic acid, ethosuximide, and phenytoin typically reduced the rate of responding to the sample stimulus, whereas phenobarbital usually increased response rates at high doses. Phenobarbital, clonazepam, and valproic acid produced generally dose-dependent decreases in accuracy; ethosuximide and phenytoin failed to do so. These results suggest that there are qualitative as well as quantitative differences in the effects of anticonvulsant drugs under the delayed matching-to-sample procedure.

MDMA and memory: the acute and chronic effects of MDMA in pigeons performing under a delayed-matching-to-sample procedure.

The purpose of the present study was to examine the acute and chronic effects of (+/-)3,4-methylenedioxy-methamphetamine (MDMA) in pigeons responding under a delayed-matching-to-sample procedure with 0-, 3-, and 6-s delays. In the absence of drug, accuracy (percent correct responses) was inversely related to delay length. When administered pre-chronically, MDMA (0.32-5.6 mg/kg) generally decreased accuracy and response rates at doses of 3.2 mg/kg and above. Although humans report a distinct "hangover" when exposure to MDMA ends, performance of pigeons in the present study did not deteriorate when the chronic regimen ended, indicating an absence of behavioral dependence on the drug. Tolerance developed following chronic exposure to 3.2 mg/kg. In general, greater tolerance occurred at the 0-s delay than at longer delays. Although MDMA is reported to have neurotoxic effects, it does not inevitably produce long-lasting or cumulative behavioral impairment.

Discriminative stimulus properties of phenytoin in the pigeon.

Pigeons trained under a two-key drug discrimination procedure eventually learned to discriminate 5 mg/kg phenytoin from saline injections. When 1.25-20 mg/kg doses of phenytoin were substituted for the training dose, the percentage of responses directed to the phenytoin-appropriate key varied directly with dose. Chlorpromazine, d-amphetamine, diazepam, and phenobarbital failed to produce phenytoin-like patterns of responding.

Discriminative stimulus properties of valproic acid in the pigeon.

Pigeons were successfully trained to discriminate 60 mg/kg valproic acid from saline using a two-key drug discrimination procedure. When 5-80 mg/kg doses of valproic acid were administered during generalization tests the percentage of responses directed to the valproic acid-appropriate key varied directly with dose. The effects of administering the training dose of valproic acid at presession injection intervals ranging from 15 to 120 min were described by an inverted U-shaped function; the 30-min interval used during discrimination training engendered the largest percentage of valproic acid-appropriate responses. The discriminative stimulus properties of valproic acid failed to generalize to the anticonvulsant compounds phenobarbital (10, 20 mg/kg), phenytoin (2.5, 5 mg/kg), and ethosuximide (40, 80 mg/kg), indicating that not all anticonvulsant compounds share similar discriminative properties. Clonazepam (0.25, 0.50 mg/kg) and diazepam (1, 2 mg/kg), two benzodiazepines with anticonvulsant properties, produced quite different effects. The stimulus properties of valproic acid generalized to all doses of clonazepam, whereas intermediate generalization was evident with diazepam. Pentylenetetrazol (10, 20 mg/kg), chlorpromazine (5, 10 mg/kg), tripelennamine (2.5, 5.0 mg/kg), d-amphetamine (0.5, 1.0 mg/kg), morphine (1.25, 2.50 mg/kg), and imipramine (2.5, 5.0 mg/kg) induced only saline-like patterns of responding. The concomitant administration of pentylenetetrazol failed to antagonize the discriminative stimulus properties exerted by the training dose of valproic acid.

Effects of clonazepam and ethosuximide on the responding of pigeons under a fixed-consecutive-number schedule with and without an external discriminative stimulus.

The effects of the anticonvulsant drugs clonazepam and ethosuximide were examined in pigeons performing under a fixed-consecutive-number schedule with and without an added external discriminative stimulus. Under these schedules, food was delivered whenever subjects responded between and 8 and 12 times on one response key (work key), and then responded once on a second response key (reinforcement key). For one group, an external discriminative stimulus signalled completion of the response requirement on the work key, while no stimulus change was programmed for the other group. Clonazepam (0.06-0.75 mg/kg) produced dose-dependent decreases in percentage of reinforced runs and rate of responding for both groups. The magnitude of the accuracy-decreasing effect was generally greater in the group without the external discriminative stimulus. For this group, the higher doses of clonazepam produced pronounced increases in switching to the reinforcement key before completing the minimum requirement of eight consecutive responses on the work key. No consistent patterns of errors were evident for the subjects with the added external discriminative stimulus. Although ethosuximide (20-160 mg/kg) produced dose-dependent decreases in rate of responding, it had little effect on the percentage of reinforced runs or the run length distributions. These findings are consistent with previous reports indicating that clonazepam, but not ethosuximide, substantially disrupts performance under operant tasks requiring conditional discriminations. These data also suggest that the addition of an external discrimination stimulus attenuates the disruptive behavioral effects of clonazepam.

Discriminative stimulus properties of ethosuximide in the pigeon.

After initial exposure to 80 mg/kg, pigeons trained on a two-key drug discrimination procedure rapidly learned to discriminate 120 mg/kg ethosuximide from saline. When 40-160 mg/kg doses of ethosuximide were administered during generalization tests, the percentage of responses directed to the ethosuximide-appropriate key varied directly with dose. Time-effect determinations revealed that the discriminable properties of ethosuximide were evident as early as 15 min after, and as late as 2 h after, intramuscular injection. The discriminative stimulus properties of ethosuximide failed to generalize to the anticonvulsant compounds clonazepam (0.5-4 mg/kg), methsuximide (25-200 mg/kg), and phenytoin (5-15 mg/kg). Generalization was apparent with certain doses of primidone (250, 300 mg/kg) and mephenytoin (80, 160, 240 mg/kg). The concomitant administration of pentylenetetrazol (5, 10, 20 mg/kg) partially blocked the discriminable properties of the training dose of ethosuximide.

Discriminative stimulus properties of tripelennamine in the pigeon.

Pigeons trained under a two-key drug discrimination procedure eventually learned to discriminate the antihistaminic tripelennamine (5 mg/kg) from saline. When 0.63-7.5 mg/kg doses of tripelennamine were administered in generalization test sessions, the percentage of responses directed to the tripelennamine-appropriate key varied directly with dose. At certain doses, the discriminative stimulus properties of the antihistaminics, diphenhydramine and pyrilamine, clearly generalized to tripelennamine, whereas intermediate generalization was evident with the antihistaminics, chlorpheniramine and promethazine. Chlorpromazine, cimetidine, d-amphetamine, diazepam, morphine, pentazocine, phenobarbital, and sodium valproate failed to produce tripelennamine-like patterns of responding.

Effects of phenytoin on schedule-controlled performance of rats.

The present study examined the effects of acute administrations of phenytoin on the lever pressing of rats maintained under fixed-ratio, fixed-interval, and interresponse-time-greater-than-T schedules of food delivery. The drug typically produced dose-dependent decreases in response rates under fixed-ratio and fixed-interval schedules, while response rates under the interresponse-time-greater-than-T schedule were affected little by the drug. These findings indicate that phenytoin effects on schedule-controlled responding differ from those of other anticonvulsants.

Chronic effects of ethosuximide, phenytoin, clonazepam, and valproic acid on the delayed-matching-to-sample performance of pigeons.

Acute and chronic effects of ethosuximide (40, 80, and 120 mg/kg), phenytoin (2.5, 5, and 7.5 mg/kg), clonazepam (0.25, 0.5, and 0.75 mg/kg), and valproic acid (40, 80, and 120 mg/kg) were examined in pigeons performing under a delayed-matching-to-sample procedure. Acute administration of clonazepam or valproic acid produced generally dose-dependent decreases in accuracy; over 50 sessions of daily exposure, complete or nearly complete tolerance developed to the accuracy-reducing effects of these drugs. Whether administered acutely or chronically, ethosuximide and phenytoin failed to affect accuracy. When given acutely, all drugs typically reduced rate of responding to the sample stimulus. A degree of tolerance appeared to develop to the rate-decreasing effects of all of the drugs tested.

Fixed-ratio size as a determinant of the development of tolerance to morphine.

The acute and chronic effects of morphine were examined in pigeons exposed to a multiple schedule with fixed-ratio 5, 25, and 125 components. Acute exposure to morphine (0.56-10.0 mg/kg) resulted in rate reductions under each component when the dose was 1 mg/kg or higher. With chronic exposure to 5.6 mg/kg, tolerance to the rate-reducing effects of morphine was evident under each fixed-ratio component. The development of tolerance was determined to some extent by fixed-ratio size, a result similar to earlier findings with cocaine.

Effects of cocaine administration and withdrawal on the performance of pigeons under a fixed-consecutive-number schedule with and without an external discriminative stimulus.

The effects of administering and withdrawing cocaine (0.3, 1, 3, and 10 mg/kg) were evaluated in pigeons responding under a fixed-consecutive-number schedule of food presentation with (FCN-S(D)) and without (FCN) an external discriminative stimulus. Under both schedules, acute administrations of 10 mg/kg reduced accuracy (per cent reinforced runs) and lower doses had no systematic effect. Both 3 and 10 mg/kg doses reduced response rates under the FCN schedule, but only the 10 mg/kg dose did so under the FCN-S(D) schedule. With chronic exposure to increasing doses (0.3, 1, 3, and 10 mg/kg), tolerance developed to the rate- and accuracy-decreasing effects of 10 mg/kg under both schedules. Abrupt withdrawal from chronic cocaine (10.0 mg/kg) did not disrupt performance under either schedule. This indicates that behavioral dependence did not occur in the present study.

Fixed-ratio size as a determinant of tolerance to cocaine: is relative or absolute size important?

Six studies, examining five drugs in three species, have demonstrated that tolerance development is impaired under relatively long fixed-ratio (FR) schedules compared with relatively short FR schedules. One such study demonstrated that substantial tolerance to the rate-reducing effects of cocaine in pigeons developed under the FR 5 and 25 components of a multiple schedule of food delivery, but little or no tolerance developed under the FR 125 component. The present study examined the acute and chronic effects of cocaine in three groups of pigeons. One group was exposed to a simple FR 5 schedule of food delivery, a second to a simple FR 125 schedule of food delivery, and a third to a simple FR 125 schedule that alternated across sessions with a multiple FR 125 FR 250 schedule. When administered acutely, cocaine (1-10mg/kg) produced dose-dependent rate decreases under all schedules. With chronic exposure to 5.56mg/kg cocaine, tolerance clearly developed under the FR 5 schedule. Evidence of tolerance under the FR 125 schedule was equivocal, but strongest when that schedule alternated with an FR 250 component under a multiple schedule arrangement. There was no consistent evidence of tolerance under the FR 250 component. These results suggest that, although the development of tolerance under an FR schedule may be affected by exposure to a longer schedule, tolerance to cocaine does not develop readily under "long" FR schedules, regardless of the context in which they appear.

Schedule-induced defecation: a demonstration in pigeons exposed to fixed-time schedules of food delivery.

Previous studies have found that defecation increases in rats exposed to intermittent schedules of food delivery. In the present study, food-deprived pigeons were exposed to fixed-time 30-, 60-, 120-, and 240-s schedules of food delivery. For the subjects as a group, significantly more defecation (indexed by fecal weight) occurred under the fixed-time 60-s schedule than during massed-food control sessions in which an equivalent amount of food was presented. Thus, the present findings suggest that schedule-induced defecation occurs in pigeons.