Pramipexole and other direct dopamine agonist medications have been implicated in the development of impulsive behavior such as pathological gambling among those taking the drug to control symptoms of Parkinson’s disease or restless leg syndrome. Few laboratory studies examining pramipexole’s effects on gambling-like behavior have been conducted.
The present study used a rodent model approximating some aspects of human gambling to examine within-subject effects of acute pramipexole (0.03, 0.1, 0.18, & 0.3 mg/kg) on rat’s choices to earn food reinforcement by completing variable-ratio (i.e., gambling-like) or fixed-ratio response requirements.
In a condition in which the variable-ratio alternative was rarely selected, all but the lowest dose of pramipexole significantly increased choice of the variable-ratio alternative (an average of 15% above saline).. The same doses did not affect choice significantly in a control condition designed to evaluate the involvement of nonspecific drug effects. Pramipexole increased latencies to initiate trials (+ 9.12 s) and to begin response runs on forced-choice trials (variable-ratio: + 0.21 s; fixed-ratio: + 0.88 s), but did not affect measures of response perseveration (conditional probabilities of “staying”).
The findings are consistent with clinical reports linking pramipexole to the expression of increased gambling in humans. Results are discussed in the context of neurobehavioral evidence suggesting that dopamine agonists increase sensitivity to reward delay and disrupt appropriate feedback from negative outcomes.
pramipexole; dopamine agonist; gambling; impulsive behavior; Parkinson’s disease; rat
Impulsivity is a defining characteristic of adolescence. Compared to adults, for example, adolescents engage in higher rates of drug and alcohol experimentation, risky sexual practices, and criminal activity. Such behavior may reflect reduced sensitivity to long-term consequences for behavior during adolescence. Recently, our lab has attempted to refine mouse procedures to study developmental trends in decision making in the laboratory. In the present experiment, we examined sensitivity to delayed rewards in C57BL/6J (B6) and DBA/2J (D2) mice during adolescence and adulthood using an adaptation of a two-week delay discounting procedure developed by Adriani & Laviola (2003) [Behavioral Neuroscience, 117, 695-703]. During training, mice could choose between a 20- or 100-ul drop of milk delivered after a 1-s delay. During testing, the delay to the large drop of milk was increased from 1 to 100 seconds. As the delay to the larger volume increased, preference shifted to the smaller, more immediate option. In adolescence, both strains showed similar shifts in preference. In contrast, adult B6 mice were less sensitive to increasing delays than were adult D2 mice, who continued to perform much as their adolescent counterparts. A subsequent resistance-to-extinction test ruled out the possibility that the slower change in the adult B6 mice was due to perseverative responding. The present findings suggest that B6 and D2 strains may be differentially suited to uncovering the biological mechanism of short-term and long-term patterns of impulsive behavior.
Impulsivity; Delay Discounting; Development; Resistance to Extinction; C57BL6/6J; DBA/2J
The present experiment was concerned with the role of environment in the production and form of apomorphine-induced pecking of pigeons. Previous literature has suggested that the pecking occurs even when pigeons are placed in complete darkness, but there are no systematic or quantitative reports of such pecking. Six pigeons were tested with doses of 0.1, 0.3, and 1.0 mg/kg apomorphine. Tests were made in conditions of white and infrared light. The apparatus employed novel force transduction measures that provided for both the detection of a peck as well as its peak forcefulness. At the lowest dose tested, apomorphine elicited pecking when the pigeon was placed in white light, but not when the dose was examined under infrared lighting. As the dose increased, however, pecking was observed regardless of lighting condition. No differences were found in forcefulness of pecking as a function of lighting condition or dose. Though response output was seemingly unaffected by the lighting condition at higher doses, videotaped analysis revealed important changes in the formal characteristics of pecking. In white light, apomorphine elicited pecking at stimuli in the chamber (e.g., screw heads or the pigeon’s own toes), whereas in infrared light pecking was directed at the floor directly in front of the pigeon. Such differences may be attributable to shifts in control to other stimulus modalities when vision in limited. Additionally, apomorphine may have direct effects on retinal dopamine function modulating the expression of pecking in the dark.
Apomorphine; Stereotypy; Infrared light; White light; Force; Pigeon; Peck
The selective serotonin reuptake inhibitor fluvoxamine reduces responding for ethanol at lower doses than responding for food when each is available in separate components or separate groups of rats. However, when both are available concurrently and deliveries earned per session are equal, this apparent selectivity inverts and food-maintained behavior is more sensitive than ethanol-maintained behavior to rate-decreasing effects of fluvoxamine. Here, we investigate further the impact concurrent access to both food and ethanol has on the potency of fluvoxamine. Fluvoxamine (5.6-17.8 mg/kg) potency was assessed under conditions where food and ethanol were available concurrently and response rates were equal (average variable intervals (VI) 405-s and 14-s for food and ethanol, respectively), as well as when density of food delivery was increased (average VI 60-s food & VI 14-s ethanol). The potency of fluvoxamine was also determined when only ethanol was available (food extinction and average VI 14-s ethanol) and under a multiple VI (VI 30-s food and ethanol) where either food or ethanol was the only programmed reinforcer available during each component. Fluvoxamine was less potent at decreasing ethanol self-administration when food was available concurrently (ED50 [95% C.L.]: 8.2 [6.5-10.3] & 10.7 [7.9-14.4]) versus when ethanol was available in isolation (ED50: 4.0 [2.7-5.9] & 5.1 [4.3-6.0]). Effects on food were similar under each condition where food was available. The results demonstrate that the potency of fluvoxamine to reduce ethanol-maintained behavior depends on whether ethanol is available in isolation or in the context of concurrently scheduled food reinforcement.
alcoholism; SSRI; concurrent; reinforcement; selective; pharmacotherapy; Fluvoxamine; ethanol; food; reinforcement schedule; rat
Behavioral momentum theory proposes that operant behavior is the product of two separable processes: its rate of occurrence and its resistance to change. Generally speaking, operant situations providing more densely spaced or greater magnitudes of reinforcement should be more resistant to disruption. Attempts to disrupt ongoing behavior by manipulating the availability of food or deprivation level typically have supported the predictions of behavioral momentum. Tests with pharmacological disruptors, however, have yielded mixed results. Most investigations of pharmacological disruption of operant behavior have evaluated momentum across situations that differ in rate of reinforcement. The present experiment was an attempt to systematically replicate prior work, but under conditions of differing reinforcement magnitudes. Pigeons were trained to key peck on a multiple fixed-ratio thirty schedule of food presentation, where different components programmed 2, 4, or 8-s access to grain. Resistance to rate-decreasing effects of drugs was evaluated with several compounds drawn from distinct pharmacological classes: chlordiazepoxide, cocaine, clonidine, haloperidol, morphine, and ethanol were tested. Additionally, disruption by pre-feeding and extinction was examined. Generally, resistance to change by drug administration was not modulated by reinforcement magnitude. Pre-feeding and extinction tests, however, replicated previous work, indicating that our procedure was sensitive to more common disruptors. The results give additional support to the notion that pharmacological disruptors may not behave in the manner predicted by behavioral momentum theory.
behavioral momentum; reinforcement magnitude; fixed ratio; resistance to change; pigeon; key peck
When given to pigeons, the direct-acting dopamine agonist apomorphine elicits pecking. The response has been likened to foraging pecking because it bears remarkable similarity to foraging behavior, and it is enhanced by food deprivation. On the other hand, other data suggest the response is not related to foraging behavior and may even interfere with food ingestion. Although elicited pecking interferes with food capture, it may selectively alter procurement phases of feeding, which can be isolated in operant preparations. To explore the relation between operant and elicited pecking, we provided pigeons the opportunity to earn different reinforcer magnitudes during experimental sessions. During signaled components, each of 4 pigeons could earn 2-, 4-, or 8-s access to grain for a single peck made at the end of a 5-min interval. In general, responding increased as a function of reinforcer magnitude. Apomorphine increased pecking for 2 pigeons and decreased pecking for the other 2. In both cases, apomorphine was more potent under the component providing the smallest reinforcer magnitude. Analysis of the pattern of pecking across the interval indicated that behavior lost its temporal organization as dose increased. Because apomorphine-induced pecking varied inversely with reinforcer magnitude, we conclude that elicited pecks are not functionally related to food procurement. The data are consistent with the literature on behavioral resistance to change and suggest that the effects of apomorphine may be modulated by prevailing stimulus–reinforcer relationships.
apomorphine; foraging; reinforcer magnitude; resistance to change; pigeon; key peck
Response rate can influence the behavioral effects of many drugs. Reinforcement magnitude may also influence drug effects. Further, reinforcement magnitude can influence rate-dependent effects. For example, in an earlier report, we showed that rate-dependent effects of two antidepressants depended on reinforcement magnitude. The ability of reinforcement magnitude to interact with rate-dependency has not been well characterized. It is not known whether our previous results are specific to antidepressants or generalize to other drug classes. Here, we further examine rate-magnitude interactions by studying effects of two stimulants (d-amphetamine [0.32-5.6 mg/kg] and cocaine [0.32-10 mg/kg]) and two sedatives (chlordiazepoxide [1.78-32 mg/kg] and pentobarbital [1.0-17.8 mg/kg]) in pigeons responding under a 3-component multiple fixed-interval (FI) 300-s schedule maintained by 2-, 4-, or 8-s of food access. We also examine the effects of d-amphetamine [0.32-3.2 mg/kg] and pentobarbital [1.8-10 mg/kg] in rats responding under a similar multiple FI300-s schedule maintained by 2- or 10- food pellet (45mg) delivery. In pigeons, cocaine and, to a lesser extent, chlordiazepoxide exerted rate-dependent effects that were diminished by increasing durations of food access. The relationship was less apparent for pentobarbital, and not present for d-amphetamine. In rats, rate-dependent effects of pentobarbital and d-amphetamine were not modulated by reinforcement magnitude. In conclusion, some drugs appear to exert rate-dependent effect which are diminished when reinforcement magnitude is relatively high. Subsequent analysis of the rate-dependency data suggest the effects of reinforcement magnitude may be due to a diminution of drug-induced increases in low-rate behavior that occurs early in the fixed-interval.
chlordiazepoxide; pentobarbital; cocaine; d-amphetamine; rate-dependent; reinforcement magnitude; fixed-interval; pigeon; rat
Lewis rats have been shown to make more impulsive choices than Fischer 344 rats in discrete-trial choice procedures that arrange fixed (i.e., nontitrating) reinforcement parameters. However, nontitrating procedures yield only gross estimates of preference, as choice measures in animal subjects are rarely graded at the level of the individual subject. The present study was designed to examine potential strain differences in delay discounting using an adjusting-amount procedure, in which distributed (rather than exclusive) choice is observed due to dynamic titration of reinforcer magnitude across trials. Using a steady-state version of the adjusting-amount procedure in which delay was manipulated between experimental conditions, steeper delay discounting was observed in Lewis rats compared to Fischer 344 rats; further, delay discounting in both strains was well described by the traditional hyperbolic discounting model. However, upon partial completion of the present study, a study published elsewhere (Wilhelm & Mitchell, 2009) demonstrated no difference in delay discounting between these strains with the use of a more rapid version of the adjusting-amount procedure (i.e., in which delay is manipulated daily). Thus, following completion of the steady-state assessment in the present study, all surviving Lewis and Fischer 344 rats completed an approximation of this rapid-determination procedure in which no strain difference in delay discounting was observed.
Lewis rats; Fischer 344 rats; delay discounting; adjusting amount; impulsive choice; lever press; rat
In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.
fragile X syndrome; dopamine; amphetamine; focused stereotypy; striatum; voltammetry
In this study, we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared with wild-type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared with WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding predrug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.
Fragile X syndrome; dopamine; amphetamine; focused stereotypy; striatum; voltammetry
Clinical reports, primarily with Parkinson’s patients, note an association between the prescribed use of pramipexole (and other direct-acting dopamine agonist medications) and impulse control disorders, particularly pathological gambling. Two experiments examined the effects of acute pramipexole on rats’ impulsive choices where impulsivity was defined as selecting a smaller-sooner over a larger-later food reward. In Experiment 1, pramipexole (0.1 to 0.3 mg/kg) significantly increased impulsive choices in a condition in which few impulsive choices were made during a stable baseline. In a control condition, in which impulsive choices predominated during baseline, pramipexole did not significantly change the same rats’ choices. Experiment 2 explored a wider range of doses (0.01 to 0.3 mg/kg) using a choice procedure in which delays to the larger-later reinforcer delivery increased across trial blocks within each session. At the doses used in Experiment 1, pramipexole shifted choice toward indifference regardless of the operative delay. At lower doses of pramipexole (0.01 & 0.03 mg/kg), a trend toward more impulsive choice was observed at the 0.03 mg/kg dose. The difference in outcomes across experiments may be due to the more complex discriminations required in Experiment 2; i.e., multiple discriminations between changing delays within each session.
Pramipexole; D2/D3 agonist; Impulsivity; Choice; Gambling
The present experiment examined the effects of acute and daily cocaine on spontaneous behavior patterns of pigeons. After determining the acute effects of a range of doses, 9 pigeons were divided into three groups that received one of three doses of cocaine daily, either 1.0, 3.0, or 10.0 mg/kg cocaine. Measures were taken of spontaneous locomotion, pecking, preening, and emesis. Under daily administration, cocaine induced consistent and substantial enhancements of its locomotor effects in all 9 pigeons, consistent with the phenomenon of locomotor sensitization. The maximum locomotor output did not differ according to the size of the daily dose. Locomotion was not elevated following tests of the saline vehicle, suggesting the effect was due to cocaine, not to a change in baseline or reactivity to the injection procedure. Cocaine dose-dependently decreased preening when given acutely, and those effects were not altered by repeated cocaine administration. Pecking occurred at very low rates and was unresponsive to cocaine treatment. Cocaine-induced emesis showed a dose-dependent increase under initial tests with cocaine, and those effects were attenuated following daily exposure. In a final condition, cocaine was replaced with daily saline for 30 days to assess the persistence cocaine-related increases in locomotion. Approximately half of the pigeons continued to show enhanced effects even after 30 days without cocaine, so although persistence was obtained, it showed marked intersubject variability. The data indicate that the effects of repeated cocaine administration on the behavior of pigeons shows parallels with many effects commonly reported with rodents (i.e., increased locomotion following repeated treatment, decrease in preening or grooming, persistence following drug withdrawal).
cocaine; sensitization; locomotion; preening; pecking; emesis; pigeon
Oxidative stress can cause methionine oxidation that has been implicated in various proteins malfunctions, if not adequately reduced by the methionine sulfoxide reductase system. Recent evidence has found oxidized methionine residues in neurodegenerative conditions. Previously, we have described elevated levels of brain pathologies and an abnormal walking pattern in the methionine sulfoxide reductase A knockout (MsrA−/−) mouse. Here we show that MsrA−/− mice have compromised complex task learning capabilities relative to wild-type mice. Likewise, MsrA−/− mice exhibit lower locomotor activity and altered gait that exacerbated with age. Furthermore, MsrA−/− mice were less responsive to amphetamine treatment. Consequently, brain dopamine levels were determined. Surprisingly, relative to wild-type mice, MsrA−/− brains contained significantly higher levels of dopamine up to 12 months of age, while lower level of dopamine was observed at 16 months of age. Moreover, striatal regions of MsrA−/− mice showed an increase of dopamine release parallel to observed dopamine levels. Similarly, the expression pattern of tyrosine hydroxylase activating protein correlated with the age-dependent dopamine levels. Thus, it is suggested that dopamine regulation and signaling pathway are impaired in MsrA−/− mice, which may contribute to their abnormal bio-behavior. These observations may be relevant to age-related neurological diseases associated with oxidative stress.
dopamine; oxidative stress; methionine oxidation; neurodegenerative diseases
Previous research has shown that Lewis rats make more impulsive choices than Fischer 344 rats. Such strain-related differences in choice are important as they may provide an avenue for exploring genetic and neurochemical contributions to impulsive choice. The present systematic replication was designed to determine if these findings could be reproduced using a procedure less susceptible to within- or between-session carry-over effects that may have affected previous findings. Specifically, delays to the larger–later food reinforcer were manipulated between conditions following steady-state assessments of choice, and the order of delays across conditions was mixed. The results confirmed previous findings that Lewis rats made significantly more impulsive choices than Fischer 344 rats. Fischer 344 rats' preference for the larger–later reinforcer, on the other hand, was less extreme than reported in prior research, which may be due to carry-over effects inherent to the commonly used technique of systematically increasing delays within session. Previously reported across-strain motor differences were reproduced as Lewis rats had shorter latencies than Fischer 344 rats, although these latencies were not correlated with impulsive choice. Parallels between reduced dopamine function in Lewis rats and clinical reports of impulse-control disorders following treatment of Parkinson patients with selective D2/D3 dopamine agonists are discussed.
Fischer 344 rats; Lewis rats; choice; impulsivity; delay-discounting; rat; lever press
The reproducibility of experimental outcomes depends on consistent control of independent variables. In food-maintained operant performance, it is of utmost importance that the quantity of food delivered is reliable. To that end, some commercial food pellet dispensers have add-on attachments to sense the delivery of pellets. Not all companies, however, offer such add-ons. Aside from availability, cost and temporary reduction in throughput may be a problem for smaller labs. The present paper outlines our recent development of a simple, inexpensive infrared device to detect and confirm the delivery of pellets. The in-line construction of the detector routes the falling pellet through a barrel so that it passes between an infrared emitter and receiver. The circuitry was designed to be compatible with all commercially available behavioral measurement systems, and so may be retrofit to any existing system. Our tests with the detector so far have shown that it is 100% accurate in detecting pellet delivery. The individual unit cost is approximately 25 dollars. The low cost and versatility of the device offer an easy method to ensure the integrity of food delivery in operant settings.
pellet; detection; infrared; reliability
Daily administration of cocaine often results in the development of tolerance to its effects on responding maintained by fixed-ratio schedules. Such effects have been observed to be greater when the ratio value is small, whereas less or no tolerance has been observed at large ratio values. Similar schedule-parameter-dependent tolerance, however, has not been observed with fixed-interval schedules arranging comparable interreinforcement intervals. This experiment examined the possibility that differences in rate and temporal patterning between the two types of schedule are responsible for the differences in observed patterns of tolerance. Five pigeons were trained to key peck on a three-component multiple (tandem fixed-interval fixed-ratio) schedule. The interval values were 10, 30, and 120 s; the tandem ratio was held constant at five responses. Performance appeared more like that observed under fixed-ratio schedules than fixed-interval schedules. Effects of various doses of cocaine given weekly were then determined for each pigeon. A dose that reduced responding was administered prior to each session for 50 days. A reassessment of effects of the range of doses revealed tolerance. The degree of tolerance was similar across components of the multiple schedule. Next, the saline vehicle was administered prior to each session for 50 days to assess the persistence of tolerance. Tolerance diminished in all subjects. Overall, the results suggested that schedule-parameter-dependent tolerance does not depend on the temporal pattern of responding engendered by fixed-ratio schedules.
Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no change or an increase in the drug's effects, with the latter usually referred to as sensitization. In the present study, repeated postsession administration of a relatively small dose of cocaine (3.0 or 5.6 mg/kg) to pigeons responding under a multiple fixed-ratio 5, fixed-ratio 100 schedule of food presentation generally resulted in tolerance to the rate-decreasing effects of the drug. When the same dose was given before sessions, little additional tolerance was observed, although some subjects showed further tolerance in the small-ratio component. A regimen of repeated postsession injection of larger (10.0-23.0 mg/kg) doses suppressed key pecking during the session; responding resumed following discontinuation of postsession administrations. Effects of postsession administration of cocaine, therefore, depended on the dose, with smaller doses leading to tolerance and larger ones to suppression of behavior during the session. Effects of postsession drug administration of either small or large doses were not related to whether effects of postsession drug were experienced mainly in the operant test chamber or in the pigeon's home cage. The results with large postsession doses are compatible with a view that the drug acted as a Pavlovian unconditional stimulus, with the session-related stimuli acting as a long-duration Pavlovian conditional stimulus. Tolerance following postsession administration of the smaller doses challenges the view that it depended on experiencing the drug's effects while the arranged reinforcement contingencies were in effect.