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In this chapter, we describe a systematic approach for measuring three separate behavioral processes in laboratory animals that may result in failure to inhibit maladaptive behavior: (1) insensitivity to delayed consequences, (2) poor response inhibition, and (3) lapses of attention. We have developed procedures to measure these behavioral processes in both rats and mice. These measures use the same testing apparatus to measure each process in the two species, and these procedures are similar to parallel procedures used to measure these processes in humans. We describe the results from studies that support the validity of these test procedures in two different strains of mice (C57BL/6NTac, and 129/SvEvTac), as consistent differences in behavior indicate that C57 mice are more impulsive than 129s mice. This systematic characterization of differences in impulsivity between C57 and 129s mice illustrates both the wealth of data that can be obtained using these procedures and the potential usefulness of these procedures for characterizing impulsive behavior in rodents and humans.

Rats were treated with a high-dose methamphetamine (METH) regimen (50 mg/kg 3 times at 8-h intervals). Three weeks after treatment, they were trained on a reaction-time task. METH-treated rats failed to improve over a 3-month test period, while controls demonstrated a gradual increase in reaction-time speed over the same test period. METH treatment resulted in a significant dopamine depletions in the caudate/putamen and nucleus accumbens/olfactory tubercle; significant serotonin depletions in caudate/putamen, nucleus accumbens/olfactory tubercle, somatosensory cortex, amygdala and hippocampus. In contrast to the decreases observed in other brain regions, serotonin levels were significantly greater than controls in the hypothalamus. It is suggested that the behavioral impairment in the METH-treated animals is due to (a) serotonin and/or dopamine depletions or (b) abnormal or hyper-innervation of serotonin to the hypothalamus.

The beta adrenergic (beta) agonist salbutamol increased reinforcement rates and decreased response rates on a differential-reinforcement-of-low-rate (DRL) 72-S schedule. These changes in DRL 72-S schedule performance are also produced by most clinically used antidepressants. The effects of salbutamol on a DRL 72-S schedule were dose-dependently antagonized by the beta antagonist metoprolol, but not changed by the 5HT antagonist methysergide. Additionally, neither salbutamol nor the antagonism of salbutamol by metoprolol caused disruption of DRL 72-S schedule performance. These results indicate that stimulation of beta receptors, and not of 5HT receptors, mediates salbutamol antidepressant-like effects on a DRL 72-S schedule.

Rats with hippocampal dialysis probes were treated with DL-fenfluramine (FEN), fluoxetine, or FEN with fluoxetine pre-treatment. FEN (12.5 mg/kg) increased extracellular serotonin (5-HT) from 0.4 +/- 0.04 to 25.2 +/- 4.16 pg/10 microliters. Fluoxetine (10.0 mg/kg) increased extracellular 5-HT levels from 0.4 +/- 0.05 to 2.4 +/- 0.33 pg/10 microliters. FEN-induced increases in extracellular 5-HT were attenuated by 66% with fluoxetine pre-treatment. This result supports the view that the 5-HT releasing properties of FEN are mediated by the 5-HT uptake transporter.

Rats were administered 8 injections of 12.5 mg/kg fenfluramine over a 4-day period. Extracellular hippocampal serotonin levels were monitored in vivo during the 4-day treatment period. Predrug baseline serotonin levels were 0.6 +/- 0.17 pg/5 microliters; 60 min after the first fenfluramine injection extracellular serotonin levels were increased to 28.06 +/- 5.2 pg/5 microliters. Fenfluramine-induced increases in serotonin were substantially reduced on the 2nd through 4th days of the regimen. Baseline serotonin levels were increased on days 2 through 4 of the treatment regimen. In a separate group of animals post-mortem tissue concentrations of serotonin were measured 2 weeks after 1,2,4, or 8 injections of 12.5 mg/kg fenfluramine. There were decreases in serotonin tissue concentrations which were related to the number of fenfluramine injections administered. The in vivo dialysis and post-mortem tissue assay results are consistent with the view that fenfluramine is neurotoxic.

We describe an interresponse-time analysis of performance on a differential-reinforcement-of-low-rate 72-s schedule. This analysis compares the obtained interresponse-time distribution of individual rats to a corresponding random interresponse-time distribution. The random interresponse-time distribution is a negative exponential probability function; it predicts the relative distribution of interresponse times if the rat emitted the same number of responses randomly (i.e., with a constant probability) with respect to time. The analysis provides quantitative measures of peak location and dispersion of the interresponse times toward random performance. In Experiment 1, an unexpected outcome of this analysis was that the rats would have obtained more reinforcers had they responded at the same rate but randomly. Based on the interresponse-time analysis in Experiment 1, it was shown that rats trained on the differential-reinforcement-of-low-rate 72-s schedule could increase the number of reinforcers obtained in two ways: first, by a coherent shift of the interresponse-time distribution toward longer durations and, second, by dispersal of the interresponse times toward a random interresponse-time distribution. Experiment 2 applied the analysis described in Experiment 1 to the effects of desipramine and gepirone. Both drugs decreased response rate and increased reinforcement rate, but their effects on the distribution of interresponse times were different. The increase in reinforcement rate observed with desipramine was accompanied by a coherent shift of the reinforcement rate observed with gepirone was accompanied by dispersal of the interresponse-time distribution toward the random negative exponential prediction.

Although previous studies have shown that the Balloon Analogue Risk Task (BART; [Lejuez, C.W., Read, J.P., Kahler, C.W., Richards, J.B., Ramsey, S.E., Stuart, G.L., et al. (2002). Evaluation of a Behavioral Measure of Risk Taking: The Balloon Analogue Risk Test (BART). J Exp Psychol, Appl, 8, 75-84.; Lejuez, C., Aklin, W., Jones, H., Richards, J., Strong, D., Kahler, C.W., et al. (2003a). The Balloon Analogue Risk Task (BART) Differentiates Smokers and Nonsmokers. Exp Clin Psychopharmacol, 11, 26-33.; Lejuez, C., Aklin, W., Zvolensky, M., & Pedulla, C. (2003b). Evaluation of the Balloon Analogue Risk Task (BART) as a Predictor of Adolescent Real-world Risk-taking Behaviors. J Adolesc, 26, 475-479.]) can be used to index real-world risk-taking behavior, questions remain regarding how performance on the task may vary as a function of reward/loss value and how this relationship may differ as a function of relevant personality traits. The present study examined BART score at 1, 5, and 25 cents per pump and how this relationship differed at low and high levels of impulsivity and sensation seeking. Results indicated that riskiness on the BART decreased as reward/loss magnitude increased. Further, this decrease was most prominent in those low in Impulsivity/Sensation Seeking, whereas those high in Impulsivity/Sensation Seeking were largely insensitive to variation in reward/loss magnitude. Findings are discussed in terms of sensitivity to reward and loss, and how these processes can be studied further using the BART including extensions to cognitive modeling and the measurement of neurobehavioral functioning.

Rats trained to turn in circles have been used by a number of investigators to study brain dopamine metabolism. We report the results of a behavioral analysis of conditioned rotation and describe the apparatus used in our laboratory to train rats and monitor their performance. A novel discrimination procedure was used which required each rat to turn left in one training chamber with one set of stimulus conditions and right in a different chamber. Water-deprived animals were trained to circle for a water reward. Initial acquisition of this task required 11 days of training. At the end of acquisition, a discrimination test indicated that turning in the left and right directions was under stimulus control of the chamber environment. We found that trained turning had a highly stereotyped temporal organization with a rapid movement component during which the rat executed the turn, and a longer pause time component during which the rat consumed the water reinforcer.

Rats were trained to rotate for a water reward using a procedure which required each rat to turn in both the left and right directions. The rats were then lesioned with unilateral injections of 6-hydroxydopamine in the nigrostriatal bundle to produce unilateral dopamine depletion. Rats which had greater than 95% depletion had significant deficits in turning both ipsilateral and contralateral to the depleted side. Circling contralateral to the lesion was more impaired than circling ipsilateral to the lesion. All animals showed deficits in both the initiation of movement and in speed of turning. In addition, the rats displayed a chronic turning bias in the ipsilateral direction 16 weeks postlesion. These results indicate that unilateral dopamine depletion causes a variety of impairments in trained circling behavior. Although contralateral circling is most impaired, there is a significant decrease in ipsilateral performance. We conclude that normal conditioned circling behavior requires bilateral dopamine innervation.

In vivo dialysis was used to measure extracellular fluid concentrations of dopamine and dihydroxyphenylacetic acid (DOPAC) in rats which were trained to run on a circular disk treadmill for water reinforcement. Turning resulted in bilateral increases in DOPAC in lateral striatum as well as nucleus accumbens/medial striatum. Dopamine release showed small but not significant increases at both sides. Changes in DOPAC release were not lateralized. Free drinking without circling also resulted in significant increases in DOPAC in these two brain areas. During free drinking, dopamine release was significantly increased in lateral striatum but not in nucleus accumbens/medial striatum. These experiments indicate that dopamine metabolism is increased in rat striatum and nucleus accumbens in animals running on circular treadmills as well as by free drinking.

The purpose of this study was to examine the effects of sleep deprivation on impulsive behavior. Patients with impulse control disorders often report sleep problems, and sleep deprivation even in healthy individuals impairs cognition, decision-making, and perhaps impulse control. To characterize the effects of sleep loss on specific forms of impulsive behavior, we tested the effects of overnight, monitored sleep deprivation on measures of impulsivity and cognition in healthy volunteers. Ten men and ten women completed two 24 h sessions in random order, in which they were either allowed to sleep normally or remained awake all night. At 8:30 am and 6:15 pm on the day after sleep or no sleep, participants were tested on the Balloon Analogue Risk Task (BART), the Experiential Discounting Task, the Adjusting Amount Delay and Probability Discounting Task, and the Stop Task. Participants also completed mood questionnaires and the Automated Neuropsychological Assessment Matrix (ANAM) throughout the course of the day. Sleep deprivation did not affect most of the measures of impulsive behavior. However, on the BART, sleep deprivation decreased risk taking in women, but not men. Sleep deprivation produced expected increases in subjective fatigue, and impaired performance on measures of attention and cognitive efficiency on the ANAM. The results indicate that sleep deprivation does not specifically increase impulsive behaviors but may differentially affect risk taking in men and women.

There are reports that diazepam can increase, decrease, or have no effect on measures of impulsive behavior, which may be related, in part, to differences among the tasks used to measure impulsivity. This study examined the effects of a relatively high dose of diazepam (20 mg) on 5 measures of impulsive behavior in healthy adult men and women. Volunteers (N = 18) participated in a 2-session double-blind randomized design in which they received 20 mg diazepam or placebo. One hour after ingesting the capsule, participants completed mood questionnaires and several impulsivity tasks to measure subtypes of impulsive behavior, including behavioral inhibition, delay and probability discounting, and risk taking. Diazepam impaired behavioral inhibition but had no effect on measures of discounting or risk taking. These results are discussed in the context of other recent findings suggesting that different behavioral indices of impulsivity are dissociable and governed by separate underlying mechanisms.

Both humans and non-humans discount the value of rewards that are delayed or uncertain, and individuals that discount delayed rewards at a relatively high rate are considered impulsive. To investigate the neural mechanisms that mediate delay discounting, the present study examined the effects of excitotoxic lesions of the nucleus accumbens (NAC) on discounting of reward value by delay and probability. Rats were trained on delay ( n = 24) or probability discounting ( n = 24) tasks. Following training, excitotoxic lesions of the NAC were made by intracranial injections of 0.5 μl 0.15 M quinolinic acid ( n = 12) or vehicle ( n = 12) aimed at the NAC (AP +1.6, ML ±1.5, DV −7.1). NAC lesions did not alter performance in animals tested with a constant delay (4 s) or probability (0.4) of reinforcement. However, when tested with between session changes in the delay (0, 1, 2, 4, and 8 s) of reinforcement, the lesioned rats had flatter discount curves than the sham group, indicating that they were less sensitive to frequent changes in the delay to reward. In contrast, the NAC lesions did not affect discounting of probabilistic rewards. NAC lesions impaired the ability to adapt to frequent between session changes in the delay to reward but did not increase or decrease discounting when the delay was held constant across sessions. NAC lesions may disrupt the ability of the animals to predict the timing of delayed rewards when the delay to reward is changed frequently.

This study examined relations between adult smokers and non-smokers and the devaluation of monetary rewards as a function of delay (delay discounting, DD) or probability (probability discounting, PD). The extent to which individuals discount value, either as a function of a reward being delayed or probabilistic, has been taken to reflect individual differences in impulsivity. Those who discount most are considered most impulsive. Previous research has shown that adult smokers discount the value of delayed rewards more than adult non-smokers. However, in the one published study that examined probability discounting in adult smokers and non-smokers, the smokers did not discount the value of probabilistic rewards more than the non-smoker controls. From this past research, it was hypothesized that measures of delay discounting would differentiate between smokers and non-smokers but that probability discounting would not. Participants were 54 (25 female) adult smokers (n = 25) and non-smokers (n = 29). The smokers all reported smoking at least 20 cigarettes per day, and the non-smokers reported having never smoked. The results indicated that the smokers discounted significantly more than the non-smokers by both delay and probability. Unlike past findings, these results suggest that both delay and probability discounting are related to adult cigarette smoking; however, it also was determined that DD was a significantly stronger predictor of smoking than PD.

The effects of altering sucrose solution concentration on discounting of delayed rewards in rats were examined. Five different delays were used (0, 1, 2, 4, and 8 s) and three different sucrose solution concentrations (3, 10, and 30%). It was hypothesized that high value sucrose solution concentrations would be discounted less than low value sucrose solution concentrations. The results indicated that the rats discounted the 30% sucrose solution concentration at a higher rate than the 3 or 10% sucrose solution concentration, a finding that apparently contradicted the hypothesis that higher value sucrose solution concentrations would be discounted less than lower value sucrose solution concentrations. However, a follow up experiment indicated that the 3 and 10% sucrose solution concentrations were preferred over the 30% concentration. Thus the results of Experiment 1 can be interpreted as supporting the hypothesis that high valued sucrose solution concentrations are discounted less than lower valued sucrose solution concentrations.

This study investigated the acute effects of delta(9)-tetrahydrocannabinol (THC) on four behavioral measures of impulsivity in recreational marijuana users. Although impulsive behavior has been studied using several different measures of impulsivity, few studies have utilized more than one of these measures on a single cohort. In this study, 37 healthy men and women participated in three sessions, in which they received capsules containing placebo, 7.5, or 15 mg THC in randomized order under double-blind conditions. Subjects were tested on the following four tasks: the Stop task, which measures the ability to inhibit a prepotent motor response; a Go/no-go task; a Delay discounting task, which measures the value of delayed or uncertain reinforcers; and a time estimation task, which measures alterations in time perception through a time reproduction procedure. Subjects also completed mood questionnaires and general measures of performance. THC produced its expected effects on subjective measures including increases in ARCI euphoria and marijuana scales. THC increased impulsive responding on the Stop task but did not affect performance on either the Go/no-go or Delay or Probability discounting tasks. On the time reproduction task, THC increased estimates of the duration of short intervals while not affecting estimates of longer intervals. There were no significant correlations between the four tasks either before or after drug administration. These results suggest that THC may increase certain forms of impulsive behavior while not affecting other impulsive behaviors. The dissociations between the four measures of impulsivity suggest that impulsivity is an assemblage of distinct components rather than a unitary process.

Agreement between computer and questionnaire measures of delay discounting in smokers was compared. Correlations between measures for small, medium, or large rewards were significant. Log k values decreased as the reward delay increased, with values lower for the computer task than the questionnaire, with significant differences for small rewards. The 2 measures were related to smoking rate but not to age, gender, or obesity. The Bland-Altman test of agreement indicated large within-subject differences in k values between the 2 measures. The size of the difference between the log k values and magnitude of the log k values were positively related. Results suggest k values from the 2 measures are related but may not be used interchangeably.

In trying to better understand why individuals begin and continue to smoke despite the obvious health consequences, researchers have become interested in identifying relevant personality variables, such as risk taking. In this study, the authors compared the ability of 2 behavioral measures of risk taking, the Bechara Gambling Task (BGT) and the Balloon Analogue Risk Task (BART), to differentiate smokers and nonsmokers. Self-report measures of impulsivity and sensation seeking were taken for comparison with the 2 behavioral risk-taking tasks. Results indicate that behavior on the BART, and not the BGT, was related to smoking status. Further, when considered in a logistic regression analysis, only the Sensation Seeking total score and the BART score contributed uniquely to the differentiation of smokers and nonsmokers.

This study investigated the acute behavioral effects of d-amphetamine on several behavioral indices of impulsivity. Impulsivity has been defined, variously, as difficulty in inhibiting inappropriate behaviors, inability to wait, insensitivity to delayed consequences or an alteration in the perception of time; standardized procedures have been developed to measure these behavioral dimensions. However, it is not known how drugs affect these measures, and few studies have examined more than one measure in a single study. In this study, 36 healthy men and women participated in three sessions, in which they received placebo, 10 mg, or 20 mg d-amphetamine in randomized order. On each session they performed the following five tasks: the Stop Task, which measures behavioral inhibition, a delay discounting task, which measures the relative value of immediate vs. delayed rewards, a delay of gratification task, a Go/No-Go task, and a time estimation task. Subjects also completed mood questionnaires. Amphetamine produced its expected subjective, mood-altering effects, including increases in POMS Friendliness and Elation scales, and ARCI Euphoria and Stimulant scales. On the measures of impulsivity, amphetamine decreased impulsive responding on three of the tasks: on the Stop Task it decreased Stop reaction times without affecting Go reaction time, on the Go/No-Go task, it decreased the number of false alarms, and on the delay discounting measure, amphetamine (20 mg) decreased k values indicating less discounting of delayed reward. Other measures of impulsive behavior were unaffected. These results suggest that acute doses of amphetamine decrease several forms of impulsive behavior. These findings extend and confirm previous findings in humans and laboratory animals.

This study investigated the effects of acute serotonin depletion on two measures of impulsive behavior in healthy men with a family history of alcoholism. Serotonin has been implicated in several forms of impulsive behavior, as well as in the etiology of Type II alcoholism. The present study was designed to determine if an acute disturbance of serotonin function would increase impulsive responding on two behavioral indices of impulsivity, and whether this effect would be greater in individuals with a genetic predisposition to alcoholism. Forty healthy men, half of whom had an alcoholic father, participated in a two-session study. Subjects ingested a tryptophan-depleting diet on one session and a balanced diet on the other session, and completed tasks measuring behavioral inhibition and delay discounting. Tryptophan depletion impaired performance on the behavioral inhibition task in the males with a positive family history, relative to the males without alcoholic relatives, whereas it improved behavioral inhibition in the family history negative group. Tryptophan depletion had negligible effects on mood, and it did not alter performance on the delay discounting task. The results provide partial support for the hypothesis that impulsive behavior is related to low serotonin function, and further suggests that the role of serotonin depends on genetic factors related to alcoholism. The results complement the results of a parallel study investigating the effects of serotonin depletion on a similar behavioral inhibition procedure in rats. Parallel studies in rats and humans are important to validate the large body of neurobiological research with non-human species to humans.

Experiment I investigated the effects of reinforcer magnitude on differential-reinforcement-of-low-rate (DRL) schedule performance in three phases. In Phase 1, two groups of rats (n = 6 and 5) responded under a DRI. 72-s schedule with reinforcer magnitudes of either 30 or 300 microl of water. After acquisition, the water amounts were reversed for each rat. In Phase 2, the effects of the same reinforcer magnitudes on DRL 18-s schedule performance were examined across conditions. In Phase 3, each rat responded unider a DR1. 18-s schedule in which the water amotnts alternated between 30 and 300 microl daily. Throughout each phase of Experiment 1, the larger reinforcer magnitude resulted in higher response rates and lower reinforcement rates. The peak of the interresponse-time distributions was at a lower value tinder the larger reinforcer magnitude. In Experiment 2, 3 pigeons responded under a DRL 20-s schedule in which reinforcer magnitude (1-s or 6-s access to grain) varied iron session to session. Higher response rates and lower reinforcement rates occurred tinder the longer hopper duration. These results demonstrate that larger reinforcer magnitudes engender less efficient DRL schedule performance in both rats and pigeons, and when reinforcer magnitude was held constant between sessions or was varied daily. The present results are consistent with previous research demonstrating a decrease in efficiency as a function of increased reinforcer magnituide tinder procedures that require a period of time without a specified response. These findings also support the claim that DRI. schedule performance is not governed solely by a timing process.

The present study (N = 86) sought to evaluate a laboratory-based behavioral measure of risk taking (the Balloon Analogue Risk Task; BART) and to test associations between this measure and self-report measures of risk-related constructs as well as self-reported real-world risk behaviors. The BART evidenced sound experimental properties, and riskiness on the BART was correlated with scores on measures of sensation seeking, impulsivity, and deficiencies in behavioral constraint. Also, riskiness on the BART was correlated with the self-reported occurrence of addictive, health, and safety risk behaviors, with the task accounting for variance in these behaviors beyond that accounted for by demographics and self-report measures of risk-related constructs. These results indicate that the BART may be a useful tool in the assessment of risk taking.

Little is known about the acute effects of psychoactive drugs on impulsivity and decision making in humans. This study examined the effects of d-amphetamine (AMP; 10 and 20 mg; N = 20) and ethanol (EtOH; 0.2, 0.4, and 0.8 g/kg; N = 17) on the stop task, a putative measure of behavioral inhibition and impulsivity in healthy human volunteers. The stop task provides a measure of the reaction time (RT) needed to inhibit a response (Stop RT [SRT]), relative to the time taken to execute a simple response (Go RT [GRT]). Healthy volunteers performed the stop task before and after receiving one of the drugs. AMP decreased SRT-that is, improved inhibition-only in participants with slow baseline SRTs. EtOH increased SRTs-that is, impaired inhibition-at doses that did not affect GRTs. These results suggest that AMP and EtOH have specific and distinctive effects on the ability to inhibit responses. Impairment in the ability to inhibit responses is thought to reflect a certain form of impulsivity.

This study was designed to develop a version of the stop task, a putative measure of behavioral inhibition, for use in rats and to assess the effects of d-amphetamine (AMP) and alcohol (ALC). The stop task provides a quantitative index of the ability to inhibit a response that has been initiated. Rats (N = 11) were tested after intraperitoneal injections of AMP (0.125, 0.25, 0.5, 1.0 mg/kg) and ALC (250, 500, 750 mg/kg). AMP improved the ability to inhibit responses only in rats with relatively poor inhibitory performance at baseline. ALC impaired inhibition at doses that did not affect simple reaction time. The results support the sensitivity, reliability, and validity of the procedure as a measure of behavioral inhibition in rats and are highly concordant with a parallel study conducted with humans.

Rationale: Impulsive individuals exhibit an exaggerated preference for immediate rewards over delayed but larger rewards, perhaps because they value the delayed rewards less. Dopamine (DA) has been postulated to mediate the incentive value of rewards, thus it may also mediate the exaggerated preference for immediate rewards in impulsive individuals. In this paper, we investigate the effects of DA agonists and antagonists on the value of delayed versus immediate rewards. Objectives: The study had three main objectives: (1) to determine the effects of D1 and D2 type DA antagonists on the value of delayed rewards, (2) to determine the effect of the indirect DA agonist d-amphetamine on the value of delayed rewards, (3) to determine the sensitivity of the adjusting amount (AdjAmt) procedure to acute one-day changes in delay to reward, amount of reward, deprivation level and starting amount. Methods: In the AdjAmt procedure, rats choose between an adjusting amount of water given immediately (adjusting alternative) and a constant 150 µl water delayed by 4 s (standard alternative). The immediate amount of water is adjusted across trials until the rat chooses both alternatives with equal frequency (indifference point). The final adjusted amount is an indicator of the subjective value of the standard alternative. Results: The D1/D2 antagonist flupenthixol (25, 50, and 100 μg/kg) and the D2 antagonist raclopride (40, 80, and 120 μg/kg), decreased the indifference points, whereas the D1 antagonist SCH 23390 (5, 10, and 20 μg/kg) did not affect the indifference point. All three DA antagonists slowed responding. The indirect DA agonist amphetamine (0.5, and 1.0 mg/kg) had effects opposite to those of the DA antagonists, it decreased choice latency, increased the number of trials completed and increased the indifference point. Decreasing the water deprivation level (6, 24, and 48 h) had no effect on the indifference points but slowed responding. Increasing the delay to reward (2, 4, and 8 s) and decreasing the amount of water available for choosing the standard alternative (300, 150, 75 µl) decreased the indifference point. Conclusions: The results indicate that amphetamine increased the value of delayed rewards (decreased impulsivity) and that D2 but not D1 receptor antagonists decreased the value of delayed rewards (increased impulsivity). The procedure was sensitive to acute 1-day changes in delay and magnitude of reward.

An adjusting-amount procedure was used to measure discounting of reinforcer value by delay. Eight rats chose between a varying amount of immediate water and a fixed amount of water given after a delay. The amount of immediate water was systematically adjusted as a function of the rats' previous choices. This procedure was used to determine the indifference point at which each rat chose the immediate amount and the delayed amount with equal frequency. The amount of immediate water at this indifference point was used to estimate the value of the delayed amount of water. In Experiment 1, the effects of daily changes in the delay to the fixed reinforcer (100 microliters of water delivered after 0, 2, 4, 8, or 16 s) were tested. Under these conditions, the rats reached indifference points within the first 30 trials of each 60-trial session. In Experiment 2, the effects of water deprivation level on discounting of value by delay were assessed. Altering water deprivation level affected the speed of responding but did not affect delay discounting. In Experiment 3, the effects of varying the magnitude of the delayed water (100, 150, and 200 microliters) were tested. There was some tendency for the discounting function to be steeper for larger than for smaller reinforcers, although this difference did not reach statistical significance. In all three experiments, the obtained discount functions were well described by a hyperbolic function. These experiments demonstrate that the adjusting-amount procedure provides a useful tool for measuring the discounting of reinforcer value by delay.

Amphetamine and related compounds have previously been shown to differentially release dopamine (DA) and serotonin (5HT) in vivo and in vitro. The purpose of this report is directly to compare five amphetamine analogs on differential reinforcement of low rate 36-s (DRL 36-s) schedule performance, and to determine whether the reported increases in dopamine and/or serotonin release induced by these drugs can be related to observed behavioral differences. Amphetamine (AMPH) and methamphetamine (METH) induced large increases in response rate, methylene-dioxymethamphetamine (MDMA) and para-chloroamphetamine (PCA) caused small increases in response rate, while fenfluramine (FEN) had no effect on response rate. AMPH, METH, PCA and MDMA caused a dose-dependent decrease in reinforcement rate, and FEN had no effect on reinforcement rate. AMPH, METH, and PCA but not FEN, shifted the peak of the inter-response time (IRT) distribution toward shorter intervals, MDMA decreased peak location only at the highest dose. All five drugs caused a dose-dependent decrease in peak area, indicating a loss of schedule control on the DRL 36-s schedule. Consistent with in vitro and in vivo release studies, the differential results of these five drugs on DRL 36-s schedule performance suggest a predominant dopamine role for AMPH and METH, a predominant serotonin role for FEN, and different degrees of combined dopaminergic and serotonergic roles for MDMA and PCA in the mediation of the task.

Peak deviation analysis is a quantitative technique for characterizing interresponse-time distributions that result from training on differential-reinforcement-of-low-rate schedules of reinforcement. It compares each rat's obtained interresponse-time distribution to the corresponding negative exponential distribution that would have occurred if the rat had emitted the same number of responses randomly in time, at the same rate. The comparison of the obtained distributions with corresponding negative exponential distributions provides the basis for computing three standardized metrics (burst ratio, peak location, and peak area) that quantitatively characterize the profile of the obtained interresponse-time distributions. In Experiment 1 peak deviation analysis quantitatively described the difference between the interresponse-time distributions of rats trained on variable-interval 300-s and differential-reinforcement-of-low-rate 72-s schedules of reinforcement. In Experiment 2 peak deviation analysis differentiated between the effects of the psychomotor stimulant d-amphetamine, the anxiolytic compound chlordiazepoxide, and the antidepressant desipramine. The results suggest that peak deviation analysis of interresponse-time distributions may provide a useful behavioral assay system for characterizing the effects of drugs.

Caffeine and PD 116,600 were found to decrease the reinforcement rate and increase the response rate in rats performing under a differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule of reinforcement. In contrast, antidepressant drugs previously have been found to increase the reinforcement and decrease the response rate. Caffeine has been found to test similar to antidepressant drugs on at least one other behavioral screen, but caffeine does not possess clinical antidepressant properties. These results provide further support for the DRL 72-s schedule as a behavioral screen for antidepressant drugs.

Rats were trained to turn for water reinforcement and then were given unilateral 6- hydroxydopamine lesions. After lesion, rats showed deficits in trained turning both contraand ipsilateral to the side of the lesion, with contralateral turning more severely impaired. The lesioned rats were then transplanted with fetal mesencephalic dopamine tissue into striatum. A control group of lesioned rats were sham transplanted. Four weeks after transplant, 1.5 mg/kg D-amphetamine challenge injections were used to test the functioning of the transplants. In the control rats, D-amphetamine induced ipsilateral turning; in transplanted rats, D-amphetamine slowed the rate of ipsilateral turning or reversed the direction of amphetamine-induced rotation. Only rats which reversed their, amphetamine-induced turn direction after transplant were used for the rest of the experiment. Trained turning was assessed at 4, 8, 12 and 16 weeks post transplant. Transplants did not improve learned performance at any time post transplant. When D-amphetamine was administered in conjunction with the trained turning sessions, a low dose (0.12 mg/kg) enhanced contralateral trained turn rates, without affecting ipsilateral turn rates. Higher doses of amphetamine reduced ipsilateral turn rate in the transplanted animals. The results of this study suggest that transplants alone do not reinstate performance of conditioned rotation.

The non-competitiveN-methyl- d -aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain. dl -Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.

Advances in technology and decreasing costs are enabling microcomputers to displace more traditional devices in the scientific laboratory. The availability of various approaches to software-system development for the use of microcomputers in the on-line control of experiments has contributed to the trend. This report describes a software system developed to control conditioned behavior during schedules of reinforcement while simultaneously accumulating behavioral data and physiological (analog) data using a hardware system base on the Radio Shack TRS-80 Model I microcomputer. The software utilizes a high-level interpretive language (Microsoft BASIC), assembly language and compiled BASIC to attain an acceptable execution speed and ease of programming.

Transplantation of fetal dopamine neurons has been performed in rats for 10 years (Bjorklund and Stenevi, 1979; Perlow et al., 1979) and these experiments have established several basic principles likely to be of value for transplantation efforts in other species including man. First is an appropriate experimental model. The unilaterally lesioned rat which circles in response to amphetamine or apomorphine as described by Anden et al. (1966) and Ungerstedt (1969) has been useful for studying transplant effects. Ventral mesencephalon from fetal embryonic day 13 to 15 is transplanted to dopamine denervated striatum. After 3 to 6 weeks of growth, the transplants produce changes in circling behavior (Bjorklund and Stenevi, 1979; Perlow et al., 1979; Dunnett et al., 1984). With amphetamine treatment, animals which formerly circled ipsilateral to the side of the dopamine denervation lesion may reverse their circling direction to circle contralateral to the initial lesion. Successful transplants are demonstrated by showing survival of dopamine cells along the transplant track as well as by replacement of dopamine content on the side of transplant from values of near total depletion to about 10% of intrinsic dopamine concentration (Schmidt et al., 1984).

Nearly 10 years have elapsed since the first reports in rats that transplantation of fetal dopamine neurons have an influence on motor behavior in animals with a unilateral lesion of the nigrostriatal tract (Bjorklund and Stenevi, 1979; Perlow et al., 1979). These experiments were important in establishing several basic principles for brain transplantation. First it is a good experimental model. The unilaterally lesioned rat which circles in response to amphetamine or apomorphine as described by Anden et al. (1966) and Ungerstedt (1969) has been useful for studying transplant effects. Second was the discovery that only fetal tissue of a narrow developmental range was useful for transplant. Only the dopamine cells from ventral mesencephalon of fetal rat embryonic day 13 to 15 could successfully reinnervate dopamine denervated striatum. In this animal model, the transplants produced changes in circling behavior within three to six weeks of transplant (Bjorklund and Stenevi, 1979; Perlow et al., 1979; Dunnett et al, 1984). With amphetamine treatment, animals which formerly circled ipsilateral to the side of the dopamine denervation lesion may show a reversal in their circling direction to circle contralateral to the initial lesion. Successful transplants have dopamine cells which survive along the transplant track. In addition, dopamine concentration increases from near total depletion to about 10% of the normal intrinsic dopamine concentration (Schmidt et al., 1984).