Mark P. Reilly

Impulsive choice in a rodent model of attention-deficit/hyperactivity disorder

The spontaneously hypertensive rat (SHR) has been studied extensively as a purported rodent model of attention-deficit/hyperactivity disorder (ADHD). Because ADHD in humans is partially defined by marked impulsivity, SHRs, if a valid model of ADHD, ought to behave more impulsively than their normotensive parent strain, Wistar Kyoto (WKY). This prediction was evaluated in two experiments that employed an intertemporal choice procedure in which SHRs and WKYs made repeated choices between a single food pellet delivered immediately and three food pellets delivered after a delay. Four or five delays were investigated (1, 3, 6, 12 and 24s); the experiments differed in the manner in which the delays were experienced. In Experiment 1, the delay values changed after each session and were presented in ascending then descending order. SHRs chose more small/immediate reinforcers than WKYs at the longest delays during the ascending series and at nearly all delays during the descending series. In Experiment 2, the delay values remained in effect for several sessions and were presented in random order. Again, the SHRs chose more small/immediate reinforcers than the WKYs at the longest delays. Thus, in the present study, the SHRs were shown to be more impulsive than the WKYs as defined by preference for smaller, immediate reinforcers over larger, delayed ones in an intertemporal choice procedure.

Single electrode micro-stimulation of rat auditory cortex: an evaluation of behavioral performance.

A combination of electrophysiological mapping, behavioral analysis and cortical micro-stimulation was used to explore the interrelation between the auditory cortex and behavior in the adult rat. Auditory discriminations were evaluated in eight rats trained to discriminate the presence or absence of a 75 dB pure tone stimulus. A probe trial technique was used to obtain intensity generalization gradients that described response probabilities to mid-level tones between 0 and 75 dB. The same rats were then chronically implanted in the auditory cortex with a 16 or 32 channel tungsten microwire electrode array. Implanted animals were then trained to discriminate the presence of single electrode micro-stimulation of magnitude 90 microA (22.5 nC/phase). Intensity generalization gradients were created to obtain the response probabilities to mid-level current magnitudes ranging from 0 to 90 microA on 36 different electrodes in six of the eight rats. The 50% point (the current level resulting in 50% detections) varied from 16.7 to 69.2 microA, with an overall mean of 42.4 (+/-8.1) microA across all single electrodes. Cortical micro-stimulation induced sensory-evoked behavior with similar characteristics as normal auditory stimuli. The results highlight the importance of the auditory cortex in a discrimination task and suggest that micro-stimulation of the auditory cortex might be an effective means for a graded information transfer of auditory information directly to the brain as part of a cortical auditory prosthesis.

Extending mathematical principles of reinforcement into the domain of behavioral pharmacology.

Mathematical principles of reinforcement (MPR) attempts to integrate the empirical laws of reinforcement schedules that have accumulated over the decades. MPR is based on three principles: incentives excite behavior; there are temporal constraints on responding; and coupling of responses to reinforcers strengthens behavior [Behav. Brain Sci. 17 (1994) 105]. In the present paper MPR is extended into the domain of behavioral pharmacology, specifically to model the effects of D-amphetamine on operant behavior. In Experiment 1a, a five-component multiple fixed-ratio schedule was designed to generate behavioral baselines that were subsequently used to assess drug effect. In Experiments 1b and 1c, the quality and quantity of reinforcer were manipulated. The data generated by the three experiments were consistent with MPR. In Experiment 2, MPR was used to model the effects of D-amphetamine on rats responding under the five-component multiple fixed-ratio schedule. According to the model, the rate-decreasing effects of D-amphetamine were due primarily to motor disruption and secondarily to increased impulsivity; at the highest dosages, D-amphetamine also may have decreased the incentive value of food.

Response acquisition with delayed reinforcement in a rodent model of attention-deficit/hyperactivity disorder (ADHD)

The spontaneously hypertensive rat (SHR) has been shown to exhibit behavioral characteristics analogous to those exhibited by humans diagnosed with attention-deficit/hyperactivity disorder (ADHD). The present study was conducted to further evaluate the validity of the SHR model of ADHD by characterizing learning of a novel response under conditions of delayed reinforcement. Seven experimentally naïve SHRs and a control group of seven normotensive Wistar-Kyoto (WKY) rats were exposed to a contingency where one lever press initiated pellet delivery after a 15-s, resetting delay. Rats in both groups acquired lever pressing, and the pattern of acquisition was well described with a three-parameter, sigmoidal equation. Response acquisition was retarded in the SHRs; they took longer to acquire the behavior, exhibited lower response rates and earned fewer reinforcers over the course of the experiment. When reinforcer delivery was made immediate in a subsequent condition, the SHRs exhibited higher response rates than the WKY, suggesting that the lower rates of responding seen in the SHRs were due to the reinforcer delay. The results replicate previous research on response acquisition with delayed reinforcement and provide further validation of the SHR strain as a model of ADHD. Like humans diagnosed with ADHD, the SHRs appear to be hypersensitive to delayed consequences, which in the present context, interfered with learning a novel behavior.

Differential effects of d-amphetamine on impulsive choice in spontaneously hypertensive and Wistar-Kyoto rats.

The spontaneously hypertensive rat (SHR) has been shown to exhibit three of the behavioral characteristics of attention-deficit/hyperactivity disorder: hyperactivity, attention deficit and impulsivity. This study used SHRs and a control strain to assess the effects of the commonly prescribed psychomotor stimulant, d-amphetamine, on impulsivity, defined as choice for a small, immediate over a large, delayed reinforcer. d-Amphetamine (1.0, 3.2 and 5.6 mg/kg) was administered to SHR and Wistar–Kyoto rats (WKY; their progenitor strain) before sessions of a choice task involving small, immediate and larger, delayed food reinforcers. As reported earlier, SHRs were more impulsive than WKYs (they preferred the smaller, immediate reinforcer). d-Amphetamine had no effect on preference for the SHRs, but increased choices for the small, immediate reinforcer for the WKYs at the 1.0 and 3.2 doses. Thus, d-amphetamine did not reduce impulsivity in the already impulsive SHRs, but did increase impulsivity in rats that were not already impulsive.

MODELING OPERANT BEHAVIOR IN THE PARKINSONIAN RAT

Mathematical principles of reinforcement (MPR; Killeen, 1994) is a quantitative model of operant behavior that contains three parameters representing motor capacity (delta), motivation (a), and short term memory (lambda). The present study applied MPR to characterize the effects of bilateral infusions of 6-OHDA into the substantia nigra pars compacta in the rat, a model of Parkinsons disease. Rats were trained to lever press under a 5-component fixed-ratio (5, 15, 30, 60, and 100) schedule of food reinforcement. Rats were tested for 15 days prior to dopamine lesions and again for 15 days post-lesion. To characterize functional loss relative to lesion size, rats were grouped according to the extent and the degree of lateralization of their dopamine loss. Response rates decreased as a function of dopamine depletion, primarily at intermediate ratios. MPR accounted for 98% of variance in pre- and post-lesion response rates. Consistent with reported disruptions in motor behavior induced by dopaminergic lesions, estimates of delta increased when dopamine was severely depleted. There was no support for different estimates of a based on pre- and post-lesion performance of any lesion group, suggesting that dopamine loss has negligible effects on incentive motivation. The present study demonstrates the usefulness of combining operant techniques with a theoretical model to better understand the effects of a neurochemical manipulation.

Early cognitive dysfunction in the HD 51 CAG transgenic rat model of Huntington's disease.

Huntingtons disease (HD) is a neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat that produces choreic movements, which are preceded by cognitive deficits. The HD transgenic rat (tgHD), which contains the human HD mutation with a 51 CAG repeat allele, exhibits motor deficits that begin when these rats are 12 months of age. However, there are no reports of cognitive dysfunction occurring prior to this. To assess whether cognitive dysfunction might precede motor deficits in tgHD rats, one group of 9-month-old male rats with homozygotic mutated genes and one group of wild-type (WT) rats underwent three testing phases in a unique Spatial Operant Reversal Test (SORT) paradigm, as well as assessment of spontaneous motor activity. After testing, morphological and histological examination of the brains were made. Results indicated that tgHD rats acquired the cued-response (Phase 1) portion of the SORT, but made significantly more errors during the reversal (Phase 2) and during the pseudorandomized reversals (Phase 3) portion of the study, when compared to WT rats. Analysis of the data using mathematical principles of reinforcement revealed no memory, motor, or motivational deficits. These results indicate that early cognitive dysfunction, as measured by the SORT, occur prior to motor deficits, gross anatomical changes, or cell loss in the tgHD rat with 51 CAG repeats, and suggest that this protocol could provide a useful screen for therapeutic studies.

FLASH RATE DISCRIMINATION IN RATS: RATE BISECTION AND GENERALIZATION PEAK SHIFT

Two experiments were conducted to determine whether responding by albino rats can be brought under the stimulus control of different flash rates. In the first experiment, a conditional discrimination procedure was employed whereby two different flash rates (fast or slow) signaled the availability of reinforcement on one of two levers (left or right). Stimulus control emerged rapidly and improved with continued training. When intermediate flash rates were presented during probe sessions, the bisection point of the fast and slow flash rates was near their geometric mean, consistent with research employing other stimulus types. In the second experiment, a successive discrimination procedure was employed whereby responding in the presence of one flash rate (S(+) ) was reinforced while responding in the presence of another flash rate (S(-) ) was not reinforced. Again, stimulus control emerged quickly and improved with continued training. Test sessions in which many different flash rates were presented for brief periods in extinction revealed the peak shift phenomenon, in which peak response rates are shifted from the S(+) in a direction away from the S(-) . Flash rate is endorsed as a continuous stimulus dimension that is useful for differentially signaling schedule components.

Immediate Postsession Feeding Reduces Operant Responding in Rats.

Three experiments investigated the effects of immediate and delayed postsession feeding on progressive-ratio and variable-interval schedule performance in rats. During Experiments 1 and 2, immediate postsession feeding decreased the breakpoint, or largest completed ratio, under progressive-ratio schedules. Experiment 3 was conducted to extend the results of the first two experiments to responding maintained by variable-interval schedules with different session lengths (15 and 60 min). Response rates decreased in all 4 subjects when postsession feeding immediately followed a 15-min session and in 3 of 4 subjects when postsession feeding immediately followed a 60-min session. The implications of this research are twofold: (1) The functional context in which within-session reinforcers are embedded extends outside the experimental chamber, and (2) supplemental postsession feedings should be sufficiently delayed from the end of a session to avoid weakening operant behavior in the experimental sessions.

Effects of intensity and type of prepulse stimulus on prepulse inhibition in scopolamine treated rats

Prepulse inhibition (PPI) of the auditory startle response (ASR) is a behavioral test that has been used to measure auditory thresholds, to assess sensory-motor integration functions, and its use has been recommended in the United States Environmental Protection Agency Developmental Neurotoxicity Guideline (OPPTS 870.6300). The purpose of the present study was to determine to what extent the intensity and/or type of prepulse stimuli modulate PPI in scopolamine-treated rats. The PPI of the ASR peak amplitude was measured when the intensity of a 10-kHz prepulse tone was varied (69-, 80-, and 90 dB[A]; Experiment 1) and when both the intensity and type of auditory prepulse (a 10-kHz tone vs. a white noise burst) were varied (Experiment 2). Scopolamine treatment attenuated PPI in both experiments and interacted significantly with the prepulse stimulus intensity in Experiment 1. In Experiment 2, the percent of PPI was linearly related to prepulse stimulus intensity for trials using a tone, but was biphasic on trials using a white-noise prepulse stimulus. Prepulse stimuli of certain intensities elicited a response, and this response was greater when the prepulse stimulus was a white noise burst versus a tone of the same intensity. Further, the response to the prepulse altered the amount of inhibition and, therefore, confounded the overall measure of PPI at the higher prepulse stimulus intensity levels. Overall, these results indicate that careful consideration of the intensity and type of prepulse stimuli be taken in the context of their potential to induce a prepulse-elicited response, as well as providing the appropriate measures of such a response, when designing and interpreting PPI experiments.