Differential Reinforcement Of Low-rate Responding Research Articles

Acute but not long-lasting antidepressant-like effect of psilocybin in differential reinforcement of low-rate 72 schedule in rats.

In clinical studies, psychedelics including psilocybin and D-lysergic acid diethylamide (LSD) demonstrate rapid and persistent antidepressant effects. Since the effective treatment with psychedelics is usually provided with psychotherapy, it is debatable whether their prolonged efficacy can be observed in infrahuman species. Preclinical reports on psychedelics' effects most often address their acute actions, and different tests and models provide inconsistent results. The goal of this study was to examine whether the treatment with psilocybin and/or LSD would demonstrate immediate and/or sustained antidepressant-like effects in the differential reinforcement of low-rate responding (DRL) schedule in rats. In contrast to the antidepressant screening tools, the DRL 72s test is known to detect antidepressants with high predictive validity as it differentiates clinically effective antidepressants from other psychoactive drugs in non-stressed animals. Adult male Sprague Dawley rats were injected over three consecutive days with psilocybin (1 mg/kg), LSD (0.08 mg/kg), or saline and then tested in DRL 72s for the following 4 weeks. Treatment with psilocybin but not LSD demonstrated an immediate antidepressant-like effect, manifested as an increased number of reinforced presses and response efficiency. By contrast, neither of the drugs showed a long-term (up to 4 weeks following administration) antidepressant-like effect. Using DRL 72s schedule of reinforcement, we demonstrated the acute antidepressant-like effect of psilocybin but not of LSD, and failed to detect their persistent antidepressant-like efficacy. The present study suggests that the detection of long-lasting antidepressant-like activity in rats could be challenging and may require entirely novel behavioral methods.

Interval timing relative to response inhibition in the differential reinforcement of low-rate responding in normally developing young adults.

With recent proposal suggesting the multifaceted nature of impulsivity, researchers have been intrigued by the question of whether the impulsive behaviour measured in the traditionally psychological paradigms is unitary. One such paradigm, the differential reinforcement of low-rate responding (DRL), has been used to assess response inhibition, but its underlying mechanism has still been debated. In present research, we examined and differentiated the effects of both response inhibition and interval timing on a multisession DRL-10s (DRL-10s) in a large sample of normally developing young adults, as well as with three other measures including the stop-signal reaction task (SSRT), time production task-10s (TPT-10s), and the Barrett impulsivity scale-11 (BIS-11). The results showed that behavioural changes existed in DRL. As the task sessions progressed, there was an increase in both reinforcement probability and peak time, but a decrease in burst responses. Most importantly, both principal component analysis and generalized multilevel modeling yielded consistent results that as the task progressed, there was an increasing involvement of the TPT in the late sessions of DRL. However, none of the effect of SSRT was found. In sum, the differential degrees of involvement of the timing process, relative to response inhibition, were observed in DRL.

Examination of the effects of SCH23390 and raclopride infused in the dorsal striatum on amphetamine-induced timing impulsivity measured on a differential reinforcement of low-rate responding (DRL) task in rats

Although the striatal dopamine (DA) is reportedly involved in impulsive action, little is known about the DA subtype receptors of dorsal striatum (dSTR) in the impulsive control involved in differential reinforcement of low-rate-responding (DRL) behavior. We examined the receptor-specific dopaminergic modulation of d-amphetamine (AMP)-altered DRL 10 s (DRL-10 s) performance by locally infusing SCH23390 (SCH) and raclopride (RAC), DA D1 and D2 receptor antagonists, respectively, into the rat’s dSTR. Systemic injection of AMP significantly affected DRL-10 s behavior by increasing total, non-reinforced, and bust responses, as well as by decreasing reinforced responses, which correspondingly caused a leftward shift of the inter-response-time distribution curve as confirmed by a profound decrease in peak time (i.e., <10 s). Neither SCH nor RAC into dSTR pharmacologically reversed the timing impulsivity produced by AMP as measured by non-reinforced responses and peak time. However, the increase in total responses and the decrease in reinforced responses by AMP were reversed by intra-dSTR SCH or RAC. These results suggest that the D1 and D2 receptors of the dSTR may be involved in behavioral components apart from the timing impulsivity produced by AMP on a DRL task, which components are distinctly different from those in other terminal areas of midbrain DA systems.

Early childhood adversity and serum lipid profiles in major depression: Correlations with cognitive functions

Although the striatal dopamine (DA) is reportedly involved in impulsive action, little is known about the DA subtype receptors of dorsal striatum (dSTR) in the impulsive control involved in differential reinforcement of low-rate-responding (DRL) behavior. We examined the receptor-specific dopaminergic modulation of d-amphetamine (AMP)-altered DRL 10 s (DRL-10 s) performance by locally infusing SCH23390 (SCH) and raclopride (RAC), DA D1 and D2 receptor antagonists, respectively, into the rat’s dSTR. Systemic injection of AMP significantly affected DRL-10 s behavior by increasing total, non-reinforced, and bust responses, as well as by decreasing reinforced responses, which correspondingly caused a leftward shift of the inter-response-time distribution curve as confirmed by a profound decrease in peak time (i.e., <10 s). Neither SCH nor RAC into dSTR pharmacologically reversed the timing impulsivity produced by AMP as measured by non-reinforced responses and peak time. However, the increase in total responses and the decrease in reinforced responses by AMP were reversed by intra-dSTR SCH or RAC. These results suggest that the D1 and D2 receptors of the dSTR may be involved in behavioral components apart from the timing impulsivity produced by AMP on a DRL task, which components are distinctly different from those in other terminal areas of midbrain DA systems.

Regional differences in dopamine receptor blockade affect timing impulsivity that is altered by d-amphetamine on differential reinforcement of low-rate responding (DRL) behavior in rats

The ability to control when to start an action and when to stop is crucial in human and animal behavior. A failure to suppress premature behavior or to carry out an action in a timely manner is commonly seen in several neuropsychological disorders. Despite the phenomenon, the exact neural mechanisms underlying this timing impulsivity remain to be elucidated. Systemic injection of d-amphetamine (AMP) has been shown to disrupt rat’s performance in the differential reinforcement of low-rate (DRL) task that requires both optimal timing and proper impulsive control as measured by peak time and non-reinforced responses, respectively. By directly infusing selective D1 or D2 receptor antagonists (SCH23390 and raclopride, respectively) into three brain areas, we aimed to uncover which brain regions and which dopamine receptor subtypes are involved in counteracting the rat’s deficit of DRL performance induced by the systemic injection of AMP. We found that D1, but not D2 receptors in the dorsal hippocampus (dHIP) and nucleus accumbens (NAC) played an important role in impulsive control as well as in timing. In the medial prefrontal cortex (mPFC), both D1 and D2 receptors played an equal role in impulsive control, but only mPFC D1 was critical in the control of timing. Together, our data revealed a regional-dependent and dopamine receptor subtype specific effect across each region tested in the mesocorticolimbic circuits on the deleterious effect of AMP in the DRL task. The current findings further advance our understanding of the neurobehavioral mechanisms involved in timing impulsivity.

Differential effects of dopamine receptor subtype-specific agonists with respect to operant behavior maintained on a differential reinforcement of low-rate responding (DRL) schedule

Previous studies have shown that d-amphetamine, a dopamine (DA) indirect agonist, alters operant responding with respect to the behavior maintained on a differential reinforcement of low-rate (DRL) schedule of reinforcement. These behavioral changes have been presumed to result from drug-induced hyperdopaminergia that leads to activation of DA receptors. This study investigated the acute dose effects of DA receptor subtype-selective agonists on the performance of DRL 10-sec behavior by rats. SKF38393 (a D1 receptor agonist) and quinpirole (a D2/D3 receptor agonist) were able to dose-dependently disrupt DRL 10-sec behavior by decreasing the total responses, the non-reinforced responses, and the peak rate of response. Bromocriptine (a D2/D3 receptor agonist) produced a significantly different pattern of behavioral changes when examined during two distinct time phases (15min and 3hr after the drug injection). DRL responding was only altered at higher doses of bromocriptine in the second phase as indicated by decreasing reinforced responses and peak rate, together with an increase of burst responses. In contrast to the D1 and D2/D3 receptor agonists, PD168077 (a D4 receptor agonist) did not affect DRL 10-sec behavior. None of these tested drugs affected DRL 10-sec behavior in a manner similar to that of d-amphetamine. These findings show that there are differential effects on the performance of DRL 10-sec behavior when drugs are able to preferentially activate D1, D2/D3 and D4 receptors, supporting the assertion that there is functional heterogeneity of the DA receptor subtypes.

An examination of the effects of subthalamic nucleus inhibition or μ-opioid receptor stimulation on food-directed motivation in the non-deprived rat

The subthalamic nucleus (STN) serves important functions in regulating movement, cognition, and motivation and is connected with cortical and basal ganglia circuits that process reward and reinforcement. In order to further examine the role of the STN on motivation toward food in non-deprived rats, these experiments studied the effects of pharmacological inhibition or μ-opioid receptor stimulation of the STN on the 2-h intake of a sweetened fat diet, the amount of work exerted to earn sucrose on a progressive ratio 2 (PR-2) schedule of reinforcement, and performance on a differential reinforcement of low-rate responding (DRL) schedule for sucrose reward. Separate behavioral groups (N=6–9) were tested following bilateral inhibition of the STN with the GABAA receptor agonist muscimol (at 0–5ng/0.5μl/side) or following μ-opioid receptor stimulation with the agonist D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO; at 0, 0.025 or 0.25μg/0.5μl/side). Although STN inhibition increased ambulatory behavior during 2-h feeding sessions, it did not significantly alter intake of the sweetened fat diet. STN inhibition also did not affect the breakpoint for sucrose pellets during a 1-h PR-2 reinforcement schedule or impact the number of reinforcers earned on a 1-h DRL-20s reinforcement schedule in non-deprived rats. In contrast, STN μ-opioid receptor stimulation significantly increased feeding on the palatable diet and reduced the reinforcers earned on a DRL-20 schedule, although DAMGO microinfusions had no effect on PR-2 performance. These data suggest that STN inhibition does not enhance incentive motivation for food in the absence of food restriction and that STN μ-opioid receptors play an important and unique role in motivational processes.

Response disinhibition evoked by the administration of nicotine and nicotine-associated contextual cues

Nicotine causes dose-dependent alterations in accuracy on the differential-reinforcement of low-rate responding (DRL) 29.5-s schedule in rats. The current investigation evaluated whether nicotine-associated contextual cues can produce nicotine-like perturbations in DRL-schedule performance in the absence of nicotine. Nicotine and saline administrations occurred just prior to DRL 29.5-s schedule responding for sucrose solution, and two different experimental contexts (differentiated by visual, olfactory, and tactile cues) were utilized. All subjects ( N = 16) experienced two consecutive sessions of DRL-schedule responding per day. The experimental group ( n = 8) was exposed to saline immediately prior to the first session and 0.3 mg/kg nicotine before the second session, and the context was changed between sessions. This sequence of saline and then nicotine administration, paired with two reliable contexts, persisted for 12 consecutive days and successive nicotine administrations corresponded with increasingly poorer performance on the DRL 29.5-s schedule. No nicotine was administered for days 13-20 during context testing, and the nicotine-associated context produced response disinhibition on the DRL schedule. Two control groups were included in the design; subjects in one control group ( n = 4) received saline in each context to verify that the contexts themselves were not exerting control over operant responding. To assess how explicit and non-explicit pairings of nicotine and contextual cues influenced DRL behavior, subjects in a second control group ( n = 4) were given nicotine prior to the second session, but the contexts were not altered between sessions. The results from this experiment suggest that environmental stimuli associated with nicotine exposure can come to elicit nicotine-induced performance decrements on a DRL 29.5-s schedule.

Spontaneously hypertensive rats do not predict symptoms of attention-deficit hyperactivity disorder

The validity of the Spontaneously Hypertensive rat (SHR) as a model for Attention Deficit Hyperactivity Disorder (ADHD) is explored by comparing the SHR with Wistar-Kyoto (WKY) and Wistar rats in a number of different tests. In the open field, SHR are hyperactive compared to both Wistar and WKY, but only at specific ages. At those ages, methylphenidate (1 mg/kg) did not attenuate hyperactivity. Subsequently, a dose response study of methylphenidate (0.1–10 mg/kg) was conducted in the Differential Reinforcement of Low-rate responding (DRL)-72s and five-choice serial reaction time tests (5-CSRTT). Compared to WKY but not Wistar rats, SHR performed worse on the DRL-72s. Performance was not improved by methylphenidate (0.1–1.0 mg/kg). In the 5-CSRTT, attentional performance was similar for all rat strains, but Wistar rats made more impulsive responses than both the SHR and the WKY. Methylphenidate only attenuated impulsivity in Wistar rats. Because SHR do not consistently display symptoms of ADHD across the different tests, and methylphenidate effects were observed in both WKY and Wistar rats, but not in SHR, we conclude that SHR is not a representative animal model for ADHD.

Effects of DRL and DRL combined with response cost on perseverative verbal behavior of an adult with mental retardation and obsessive compulsive disorder

AbstractAlthough there has been increased interest in the identification and diagnosis of obsessive compulsive disorder (OCD) in people who have developmental disabilities, clinical research has been reported infrequently. The present single‐case study evaluated the effects from systematic behavioral intervention with a 26‐year‐old man who had moderate mental retardation, OCD, and exhibited perseverative verbalizations. Verbalizations were reduced when the man gained access to preferred activities contingent upon a low response frequency (DRL: differential reinforcement of low‐rate responding). The behavior was reduced further when a DRL contingency was implemented in the form of a response cost procedure. The implications of these findings for the treatment of OCD in people with developmental disabilities are discussed. Copyright © 2001 John Wiley &amp; Sons, Ltd.

Effects of combined or separate 5,7-dihydroxytryptamine lesions of the dorsal and median raphe nuclei on responding maintained by a DRL 20s schedule of food reinforcement

Previous studies have shown that long-term 5-hydroxytryptamine (5-HT) depletion induced by combined dorsal and median raphe injections of 5,7-dihydroxytryptamine (5,7-DHT) leads to impairments in the acquisition and performance of behaviour maintained under a differential-reinforcement-of-low-rate (DRL) schedule of reinforcement. The present studies examined the relative importance of dorsal versus median raphe 5-HT projections in mediating these effects by investigating the impact of separate versus combined infusions of 5,7-DHT into these sites on DRL responding. Adult male rats received injections of 3 μg 5,7-DHT into both dorsal raphe and median raphe, dorsal raphe only, or median raphe only. Sham-operated controls received vehicle injections. Animals were then trained to respond on a DRL 20s schedule for 36 days. Combined dorsal raphe and median raphe 5,7-DHT infusions depleted striatal and hippocampal 5-HT by >90%, increased responding, decreased the number of reinforcers earned, lowered the mean inter-response time (IRT), and shifted the frequency distribution of IRTs to the left. Median raphe 5,7-DHT infusions induced similar behaviouraleffects and reduced hippocampal 5-HT by 64%. Dorsal raphe 5,7-DHT lesions, that depleted striatal 5-HT by 56%, and hippocampal 5-HT by 30%, had no effect on behaviour. In a final experiment it was shown that providing an external cue light to signal food availability, and that removed the need to rely on internal timing processes, resulted in rapid acquisition of responding, and prevented the behavioural deficits in 5,7-DHT-lesioned rats. Following removal of this cue, responding deteriorated, and the 5,7-DHT treated animals performed worse than controls. These results suggest that destruction of 5-HT neurons arising from the median raphe is sufficient to disrupt behaviour maintained by a DRL 20s schedule, and that the behavioural changes observed may involve a deficit in timing.

Thermal stress modulates temporal patterns of responding on a multiple DRL-FR schedule

To investigate temporal changes in behavior induced by moderate cold temperatures, rats performing on a multiple differential-reinforcement-of-low-rate (DRL) fixed-ratio (FR) schedule were exposed to ambient temperatures of 2, 8, 16, and 24°C. DRL response rates markedly increased with decreasing cold temperatures, while FR response rates remained unchanged. In addition, as ambient temperatures decreased, the interresponse time (IRT) distribution of DRL responses shifted toward shorter times and short IRT bursts increased. Compared with cold effects, exposure to 38°C heat induced decreases in both DRL and FR response rates which were associated with increases in long IRTs. Decreases in reinforcement frequency were associated only with the DRL schedule in cold, and with both DRL and FR schedules during heat exposures. The distinct effects of cold and heat on both DRL and FR responding suggest that the increases in DRL response rates and shifts in IRT distribution are unique to cold, and are not due to general effects of nonspecific thermal change in the ambient environment.

Residual effects of chronic cannabis treatment on behavior in mature rats.

Mature rats (starting weight at least 270 g) were treated daily with cannabis extract (daily THC dose 20 mg/kg) for 3 months. After a 1- to 4-month drug-free period, residual effects on a variety of behaviors were studied. No residual effects were found in learning of an eight-arm radial maze task, nor on a differential reinforcement of low-rate responding (DRL-20) task, nor on open field activity. On the other hand, two-way shuttle box avoidance learning was facilitated by previous cannabis treatment, since cannabis-treated rats exhibited shorter mean latencies to avoid footshock than vehicle controls. The findings indicate greater vulnerability of immature organisms (previous studies) than mature organisms (the present study) to long-term effects of chronic cannabis administration.

Behavioral effects of prolonged administration of delta 9-tetrahydrocannabinol in the rat.

Rats treated chronically with delta 9-tetrahydrocannabinol (THC, daily oral dose 20 mg/kg) were examined for residual effects on a variety of behaviors following a 1-4-month drug-free period. Learning a 12-arm radial maze and a differential reinforcement of low-rate responding (DRL-20) task was significantly retarded in THC-treated animals, although performance reached control levels by the end of testing. Learning two-way shuttle box avoidance was slightly facilitated in the drug-treated subjects. In open field tests THC-treated rats displayed an initial hypoactivity, followed by hyperactivity, but these changes were not significant. Most of the effects of THC resemble, but are weaker than those of chronic treatment with cannabis extract in a dose containing the same amount of THC. The findings are discussed in terms of the role of other constituents of cannabis that may add to, or potentiate the effects of THC itself.

Damage to hippocampus and hippocampal connections: effects on DRL and spontaneous alternation.

Male albino rats were tested both pre- and postoperatively either on a schedule of differential reinforcement of low-rate responding (DRL 20 sec; Experiment 1) or for spontaneous alternation (Experiment 2). Selective lesions were produced in the hippocampus and its fiber connections. Performance of both behaviors was consistently disrupted by total fornix, medial fornix, and septum lesions, while neither behavior was significantly disrupted by postcommissural fornix or entorhinal cortex lesions. Anterior hippocampus lesions consistently disrupted only DRL performance, while neither posterior hippocampus nor lateral fornix lesions resulted in consistently impaired performance of either behavior. These data are discussed as representing a possible functional differentiation between anterior and posterior portions of the hippocampal system.

Controlling human fixed-interval performance with fixed-ratio responding or differential reinforcement of low-rate responding in mixed schedules

Low response rates and postreinforcement pauses occurred under an FI schedule when a DRL schedule and the FI schedule operated in alternation. High constant FI responding (no pauses) occurred when FR and FI schedules alternated. These results were similar to previous ones which were obtained when FR or DRL responding occurred prior to exposure to an FI schedule.

Reductions in DRL Responding following Removal of the Response-Reinforcer Dependency

Rats' bar-press responses were conditioned on differential-reinforcement-of-low-rate (DRL) schedules. The number of responses emitted was reduced to near 0 within 12 sessions after removal of the response-reinforcer dependency by changing to variable time schedules which approximated the pattern and frequency of reinforcer delivery during the previous DRL. These response reductions were similar to, but more rapid than, those observed when the response-reinforcer dependency is removed following extended conditioning on other schedules of response-dependent reinforcer presentation.

Conditioned suppression or facilitation as a function of the behavioral baseline.

Rats were exposed to a multiple schedule of reinforcement. During one component, a bar-press was followed by reinforcement only if it occurred between 15 and 20 sec after the previous response. This differential-reinforcement-of-low-rate (DRL) schedule produced a typical slow rate of responding. During the other component, reinforcement followed the first response to be emitted during limited periods of time which occurred at fixed intervals. These fixed-interval schedules with a limited hold produced higher response rates, described as ;interval' or ;ratio-like' behavior. Responding during the DRL component increased in frequency during a tone which ended with an unavoidable shock of low intensity, but decreased during the tone when the shock intensity was raised. The ;interval' and ;ratio-like' responding decreased in frequency during the tone at all shock intensities. Initial acceleration of the DRL responding appeared to be due to adventitious punishment of collateral behavior which was observed between the bar-presses. The more severe conditioned suppression during the fixed-interval components might be the result of the lower probability of reinforcement after any single response.