Dopamine receptor antagonists reverse amphetamine-induced behavioral alteration on a differential reinforcement for low-rate (DRL) operant task in the rat

Previous studies have shown that amphetamine significantly alters operant responding on the behavior maintained on a schedule of differential reinforcement of low-rate (DRL). As such, behavioral deficiency of DRL responding has been observed by the drug-induced increase of non-reinforced responses and a leftward shift of inter-response time (IRT) curve on DRL responding in the rat. However, the neurochemical basis for amphetamine-induced DRL behavioral alternations remain to be elucidated. The present study was then designed to examine whether the effects of amphetamine were dependent on dopamine-subtyped receptors, this was carried out by the co-administration of the selective D1 and D2 receptor antagonists, SCH23390 and raclopride respectively. Rats were first trained to perform on DRL 10-sec task and then divided into four groups, which received separate types of double injections before the behavioral session. The four groups were the saline control group, the amphetamine alone group, the dopamine antagonist alone group, and the combination of [corrected] amphetamine and dopamine antagonist group. The saline control group performed DRL responding in an efficient manner with a major index for the peak time of the IRT curve, which was fairly localized within the 10-sec bin throughout the test phase. The subjects injected with amphetamine (1 mg/kg) significantly shortened IRT that led to a leftward shift of IRT curve, which was further revealed by a decreased peak time without significant effectiveness on the peak rate and burst response. Even though the group given SCH23390 or raclopride alone showed profound disruption on DRL behavior by flattening the IRT curve, the co-administration of amphetamine with SCH23390 or raclopride reversed the aforementioned amphetamine-induced behavioral deficiency on DRL task. Together, these results suggest that the dopamine D1 and D2 receptors are involved and important to the temporal regulation of DRL response under psychostimulant drug treatment. Furthermore, this highlights the involvement of the brain dopamine systems in the temporal regulation of DRL behavior performance.     

Acute effects of d-amphetamine on the differential reinforcement of low-rate (DRL) schedule behavior in the rat: comparison with selective dopamine receptor antagonists

Amphetamine and it analogs have been shown to affect operant behavior maintained on the differential reinforcement of a low-rate (DRL) schedule. The aim of the present study was to investigate what specific component of the DRL response is affected by d-amphetamine. The acute effects of d-amphetamine on a DRL task were compared with those of the selective dopamine D1 and D2 receptor antagonists, SCH23390 and raclopride, respectively. Pentylenetetrazole and ketamine were also used as two reference drugs for comparison with d-amphetamine as a psychostimulant. Rats were trained to press a lever for water reinforcement on a DRL 10-s schedule. Acute treatment of d-amphetamine (0, 0.5, and 1.0 mg/kg) significantly increased the response rate and decreased the reinforcement in a dose-related fashion. It also caused a horizontal leftward shift in the inter-response time (IRT) distribution at the doses tested. Such a shifting effect was confirmed by a significant decrease in the peak time, while the mean peak rate and burse response remained unaffected. In contrast, both SCH23390 (0, 0.05, and 0.10 mg/kg) and raclopride (0, 0.2, and 0.4 mg/kg) significantly decreased the total, non-reinforced, and burst responses. The de-burst IRT distributions were flattened out as shown by the dose-related decreases in the mean peak rate for both dopamine antagonists, but no dramatic shift in peak time was detected. Interestingly, neither pentylenetetrazole (0, 5, and 10 mg/kg) nor ketamine (0, 1, and 10 mg/kg) disrupted the DRL behavioral performance. It is then conceivable that d-amphetamine at the doses tested affects the temporal regulation of DRL behavior. The effectiveness of d-amphetamine is derived from its drug action as a psychostimulant. Taken together, these data suggest that different behavioral components of DRL task are differentially sensitive to pharmacological manipulation.     

Resistance to variable-time schedules produced by spaced-response reinforcement schedules

Two experiments are reported in which rats were exposed to either a tandem fixed-ratio 1 differential-reinforcement-of-low-rate 10 sec schedule (tand FR1 DRL 10) (Experiment 1) or to a DRL 10 sec schedule (Experiment 2) prior to being exposed to a variable-time (VT) schedule. Response decrement was not universally found during the VT phase, one rat emmitting an increase in response rate relative to baseline (Experiment 1), while another showed neither an increase nor decrease during VT relative to baseline (Experiment2). The VT schedule induced less efficient responding in both experiments. Interresponse time (IRT) distributions (Experiment 2) indicated that the VT changed the pattern of responding. These results, when combined with others from our laboratory, indicate that although unsignalled variable delay of reinforcement may be a sufficient condition for producing resistance to response-independent reinforcement, it is not a necessary condition. It was concluded that a response competition model of the kind proposed by Henton and Iversen (1978) might have explanatory merit in this kind of experimental situation.     

Repeated post trial administration of vasopressin impairs subsequent Differential Reinforcement of Low rates (DRL) performance

Twenty-six male rats, maintained on a 23-h food deprivation regime, were trained on a DRL learning schedule. During pretraining (CRF) rats were placed in two groups according to speed in obtaining the criterion (good and poor learners). The performance of good and poor learners, injected with lysine vasopressin (LVP) immediately after each training session, was compared with that of control good and poor learners injected with saline. During the first DRL 20 stage, injected rats had fewer reinforcements than control rats. Fifty-five days later, during reacquisition of DRL 20, LVP rats again had fewer reinforcements, especially those which were formerly good learners in the CRF stage. Nonetheless, treated rats were able to shift their rate of responding from high to low frequency. A reduction of the minimal interresponse time to 16 s showed that LVP rats were able to adapt to this condition and that, in a further DRL 20 stage, the difference between the two groups was no longer significant.The results are discussed in terms of a modification of the behavioral expression of a learned response, without a specific action on memory processes.     

Intensity threshold for 60-Hz magnetically induced behavioral changes in rats

Experiments were conducted to further investigate the effect of 60-Hz cyclotron-resonance exposures on rats performing on a multiple FR-DRL schedule. The previously reported temporary loss of DRL baseline response, when measured as a function of A.C. magnetic intensity, was found to have a threshold. Utilizing the component of A.C. magnetic intensity parallel to the D.C. field, we report this threshold as (0.27 +/- 0.10) x 10(-4) Trms.     

Effects of antianxiety and antipsychotic drugs on DRL responding for brain stimulation

Satiated rats could be trained to give stable rates of responding for rewarding stimulation of the lateral hypothalamus delivered on differential reinforcement of low rate (DRL) schedule requiring 2 to 8 sec interresponse intervals for reinforcement (DRL-2 to 8). The performance on a DRL-8 schedule was tested 30 min after the oral administration of benzodiazepines. Diazepam (5 and 10 mg/kg) and meprobamate (200 mg/kg) caused significant increases in response rates during the first 5 min of a session, but not thereafter. Bromazepam (1 and 5 mg/kg) also caused a significant increase in the rates during the first and second 5 min. On the other hand, chlorpromazine (20 mg/kg) caused no effect in the first 5 min but decrease in second and third 5 min. These results indicate that DRL schedules with a brain stimulation reward provided a useful tool for evaluation of antianxiety drugs. The advantage of the brain stimulation reward over food reward is that the possible effects of the drugs on hunger motivation need not be considered.     

The acquisition in dogs of temporal regulation by differentiated reinforcement of the response duration using an exteroceptive component and the pharmacological modulation of this reflex (diazepam, clozapine)]

Transformation of expectation phenomenon into the phenomenon of temporal regulation is usually achieved by the suppression of preliminary factors or by means of their physical modification. Our studies show that such transformation can be obtained in dogs using Kupalov paradigm with the presentation of additional stimuli. These stimuli strictly identical, from the physical point of view, to the signals which interrupt expectation are randomly introduced into the temporal limit. Absence of the reinforcement in response to the additional stimulus impels the animal to include temporal regulation in its behaviour, and an additional negative discriminative stimulus promotes an expression of active character of inhibition. These circumstances make our pattern closer to DRRD (differential reinforcement of response duration). In order to evaluate the merits of this procedure the influence was studied of anxiolytic (diazepam) and neuroleptic (closepine) on the stabilized reaction of experimental animals. The increase of responses duration by closepine and their shortening by diazepam as well as the influence of these pharmacological substances on the frequency of responses in dependence of dose, confirm the results of the previous studies of DRRD and DRL (differential reinforcement of low rate of responses) and prove differential sensitivity of our procedure to pharmacological substances.     

Effect of contingent auditory stimuli on concurrent schedule performance: an alternative punisher to electric shock

This study explored whether load auditory stimuli could be used as functional punishing stimuli in place of electric shock. Three experiments examined the effect of a loud auditory stimulus on rats’ responding maintained by a concurrent reinforcement schedule. In Experiment 1, overall response rate decreased when a concurrent 1.5 s tone presentation schedule was superimposed on the concurrent variable interval (VI) 180-s, VI 180-s reinforcement schedule. On the contrary, response rate increased when a click presentation schedule was added. In Experiment 2, the extent of the response suppression with a 1.5 s tone presentation varied as a function of the frequency of the reinforcement schedule maintaining responses; the leaner the schedule employed, the greater the response suppression. In Experiment 3, response suppression was observed to be inversely related to the duration of the tone; response facilitation was observed when a 3.0-s tone was used. In Experiments 1 and 2, a preference shift towards the alternative with richer reinforcement was observed when the tone schedule was added. In contrast, the preference shifted towards the leaner alternative when the click or longer duration stimulus was used. These results imply that both the type and duration of a loud auditory stimulus, as well as the reinforcement schedule maintaining responses, have a critical role in determining the effect of the stimuli on responding. They also suggest that a loud auditory stimulus can be used as a positive punisher in a choice situation for rats, when the duration of the tone is brief, and the reinforcement schedule maintaining responses is lean.     

Fixed interval and fixed time treadle pressing in the pigeon: A comparison with FI and FT keypecking

Experiment I used non-naive pigeons having previously performed on both keypecking and treadlepressing Fixed Interval schedules. In condition IT, treadlepressing was reinforced on successive Fixed Interval 60 seconds, Fixed Time 60 seconds and Fixed Interval 60 seconds schedules. Subsequently (condition IK), the same subjects pecked a key on an identical schedule sequence (FI60, FT60, FI60). In Experiment II, separate groups of naïve subjects were assigned either to treadlepressing (condition IIT) or keypecking (condition IIK) and to the same schedule sequence (FI60, FT60, FI60). Treadle pressing and keypecking decreased greatly in Fixed Time schedules. Curvature indices, pauses and running rates were less sensitive than response rates to the switching from one schedule to the other. Experiments I and II yielded similar results, experimental history accounting only for minor differences. The results were discussed in relation to interspecies differences in the temporal regulation of behavior and operant versus respondent control of the response and schedule-induced behaviour.     

Le point sur les niveaux de référence diagnostiques en médecine nucléaire en 2011

Seven years after the publication of the first diagnostic reference levels (DRL) order, the analysis of the data allows the French Institute for radiation protection and nuclear safety (IRSN) to assess and evaluate the increase of the nuclear medicine departments involvement and of the level administered activities to the patients during the most common examinations performed in France. IRSN analyses show a good agreement between the distribution of transmitted examinations and the frequency of examinations performed in France, taking into account 95% of the number of examinations and 95% of the dose delivered to patients by nuclear medicine. These analyses highlight the necessary consistency between DRL regulation, the French society of nuclear medicine (SFMN) recommendations and national practice. The IRSN recommendations established from data analyses have leaded the authorities to publish a new DRL order in January 2012. This first update of the regulation takes into account actual clinical practice in nuclear medicine and introduces fundamental points as pediatric DRL. In the future, periodical updates will be implemented in order to take into account procedures and devices evolutions.     

Transformation of a waiting schedule into a temporal regulation schedule (DRRD) by addition of external stimuli in the dog

Waiting schedules do not impose temporal regulation but condition the animal to give the operant response during a given time. At the end of the required delay, a positive discriminative stimulus is presented. The suspension of the response while the discriminative stimulus is being given suspension of the response while the discriminative stimulus is being given is accompanied by reinforcement. The transformation of a waiting schedule into a temporal regulation schedule is generally achieved by suppressing the external facilitating factors or by physically modifying them. Our study reveals that a similar transformation can be achieved in the dog by the addition of a further stimulus. This stimulus, which is physically exactly the same as the excitatory stimulus and which punctuates the waiting period, is randomly introduced into the temporal delay. The absence of reinforcement in response to the added stimulus should force the animal to regulate its behavior in time and the additional negative discriminative stimulus favours the expression of the active nature of the inhibation. The results show that subjects can differentiate their response durations according to stimuli that only differ according to temporal location. Thus this pattern resembles a DRRD schedule. The peak of responses at the time of the inhibition stimulus reveals considerable behavioral conflict : either the response must be maintained or the inhibition suppressed. The positive or negative resolution of this conflict reveals noteworthy aspects of the behavioural inhibition process.     

Pentobarbital-like effects of N-methyl-D-aspartate antagonists in mice

The effects of the competitive N-methyl-D-aspartate (NMDA) antagonist, 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), and of the noncompetitive NMDA antagonist, dizocilpine (MK-801), were determined in mice trained to discriminate pentobarbital (20 mg/kg i.p.) from saline under a standard two-lever fixed-ratio 20 schedule of sweetened milk reinforcement. CPP substituted for pentobarbital; however, pentobarbital-lever responding was usually associated with decreases in response rates. Dizocilpine produced a maximum average of only 62% pentobarbital-lever responding, accompanied by a 50% decrease in response rates. These results suggest that pentobarbital-like discriminative stimulus effects are more likely to be produced by competitive than by noncompetitive NMDA antagonists. This extends previous observation in rats and provides further evidence for differences in the behavioral effects of competitive and noncompetitive NMDA antagonists and for an overlap in the behavioral pharmacology of NMDA antagonists and classical CNS depressants.     

Low-intensity magnetic fields alter operant behavior in rats

The present study demonstrates that operant behavior is affected by a combination of a 60-Hz magnetic field and a magnetostatic field 2.6 X 10(-5) T (about half the geomagnetic field). Rats exposed to this combination for 30 min consistently exhibited changes in the rate and pattern of responding during the differential reinforcement of low rate (DRL) component of a multiple fixed ratio (FR) DRL reinforcement schedule. By contrast, there were no measurable changes following exposure to the static field alone or to the oscillating field alone, even with a 10-fold increase in intensity (5 X 10(-5) to 5 X 10(-4) Trms). A cyclotron resonance mechanism has been suggested as a possible explanation for the observation that weak static magnetic fields modify the response of in vitro brain tissue to low-frequency magnetic fields. The choice of static field intensity Bo and frequency nu in the present study follows from the cyclotron resonance condition nu = (1/2 pi)(q/m)Bo, for singly charged lithium, an element in extensive use in the clinical treatment of affective disorders in humans. The present research is consistent with a cellular cyclotron resonance mechanism and tends to imply a functional dependence of behavior on the geomagnetic field.     

A comparison of responses and stimuli as time markers

A rat's behavior, as well as a stimulus, may be a time marker. But do they lead to similar performance? Eight rats were trained on a 20-s DRL procedure in which head-entry responses were time markers, i.e., each head-entry response indicated that food would not be delivered for 20 s. Concurrently, eight rats were trained on a control procedure in which light stimuli, yoked to the responses of a rat in the DRL procedure, were time markers, i.e., each light stimulus indicated that food would not be delivered for 20 s. A comparison of performance between the two groups showed a lower response rate in the DRL procedure than in the yoked control procedure. However, similar response patterns between the two groups were observed, suggesting that rats anticipated the food similarly with a stimulus or a response as the time marker.     

Choice and timing in concurrent chains: effects of initial-link duration

Theories of timing have been applied to choice between delayed rewards by assuming that delays are represented in memory and that subjects sample from memory when choosing between alternatives. To search for covariation in single-trial measures of performance that might confirm this assumption, we used a procedure that allowed for convergent measurement of choice and timing behavior. Four pigeons responded in a concurrent chains/peak procedure in which the terminal links were fixed-interval (FI) 8s and FI 16s, across conditions the duration of the initial-link schedule was either short or long, and one quarter of the terminal links lasted for 48 s and ended without reinforcer delivery. Preference for the FI 8-s alternative was stronger with shorter initial links, replicating the 'initial-link effect'. Responding on no-food trials was unaffected by initial-link duration, and aggregated across trials, was typical of the peak procedure: response distributions were approximately Gaussian, with modes near the FI schedule durations, and variance was greater for the FI 16-s terminal link. Analysis of local measures of initial-link performance (e.g., pause to begin responding, time spent responding, number and duration of visits to each alternative, etc.) found that the initial-link effect was associated with an increase in the number and duration of visits per cycle to the nonpreferred alternative. Regression analyses showed that local initial-link measures contributed relatively little additional variance in predicting performance on individual no-food trials beyond that accounted for by FI schedule. Our results provide no clear evidence that initial- and terminal-link responding in concurrent chains are mediated by a common representation of terminal-link delays.     

Vigilance levels during and after bright light exposure in the first half of the night

Fourteen healthy subjects (8 women, 6 men, aged 22-35 yr) were recruited. Each subject was exposed, in a counterbalanced order, to bright white light (BWL: 3000 lux) and to dim red light (DRL: <15 lux) at a 1-week interval. Light treatments were administered from 00:30 to 04:30 h during sleep deprivation. Salivary melatonin and urinary cortisol concentrations were measured as was core body temperature. Vigilance levels were evaluated by subjective estimates, maintenance of wakefulness tests (MWT), waking EEG recordings, and three performance tests. Under BWL melatonin secretion was suppressed and core body temperature was significantly higher than under DRL. The BWL and DRL conditions produced no difference in cortisol secretion. Significant effects of BWL treatment were found for the MWT and theta-alpha and beta-1 frequency bands of the waking EEG. There was no significant effect of BWL on subjective alertness and performance. Vigilance measures were similar under the two conditions for the tests performed 1.5 h after the end of light treatments. Overall, the findings suggest that bright light (BL) exposure in the first half of the night decreases EEG-defined sleep propensity but has only modest effects on other aspects of vigilance.     

Comparative effects of pulsed and continuous-wave 2.8-GHz microwaves on temporally defined behavior

The effects of pulsed-(PW) and continuous-wave (CW) 2.8-GHz microwaves were compared on the performance of rodents maintained by a temporally defined schedule of positive reinforcement. The schedule involved food-pellet reinforcement of behavior according to a differential-reinforcement-of-low-rate (DRL) contingency. The rats were independently exposed to PW and to CW fields at power densities ranging from 1 to 15 mW/cm². Alterations of normal performance were more pronounced after a 30-minute exposure to the PW field than to the CW field. The rate of emission of appropriately timed responses declined after exposure to PW at 10 and 15 mW/cm², whereas exposure at the same power levels to the CW field did not consistently affect the rate of responding. Change in performance associated with microwave exposure was not necessarily related to a general decline in responding: in some instances, increases in overall rates of responding were observed.     

DRL1 regulates adaxial leaf patterning and shoot apical meristem activity in<Emphasis Type="Italic">Arabidopsis</Emphasis>

Leaf shape is controlled early on by initiation at the shoot apical meristem (SAM), as well as by changes in the rates and planes of cell division and the polarity-dependent differentiation of leaf cells. To elucidate the regulation of this differentiation by signal(s) from the SAM, we screened for mutations in genes that might be involved in these early processes. A novel recessive mutant, 356-2 [identified as a new allele of thedeformed root and leaf1 (drl1) mutant], was isolated from a collection ofDs transposon insertion lines. The356- 2/drl1- 101 mutant produces narrow, filamentous leaves and defective mer-istems. Its palisade cells have a spongy cell-like structure and are fewer in number, indicating that the leaves are abaxialized. Interestingly, some of those filament-like leaves have no vascular tissues inside their blades.DRL1 encodes a protein similar to the yeast elongator-associated protein (EAP) KTI12. The amino acid sequence of DRL1 is universally conserved in prokaryotes and eukaryotes. These facts suggest that DRL1 might positively regulate leaf polarity and SAM activity by controlling cell proliferation and differentiation.     

Anatomical substrates for the discriminative stimulus effects of methamphetamine in rats

Methamphetamine is a psychostimulant drug acting on central monoaminergic neurons to produce both acute psychomotor stimulation and long-lasting behavioral effects including addiction and psychosis. Drug discrimination procedures have been particularly useful in characterizing subjective effects of addictive drugs. In the present study, to identify potential anatomical substrates for the discriminative stimulus effects of methamphetamine, we investigated the drug discrimination-associated Fos expression in Sprague-Dawley rats trained to discriminate methamphetamine from saline under a two-lever fixed ratio 20 (FR-20) schedule of food reinforcement. The rats that fulfilled the criteria for learning the discrimination were anesthetized and perfused 2 h after the drug discrimination test, and Fos immunoreactivity was examined in 15 brain regions. Fos expression in the brains of rats that discriminate methamphetamine from saline was significantly increased in the nucleus accumbens (NAc) and the ventral tegmental area (VTA), but not in other areas including the cerebral cortex, caudate putamen, substantia nigra, hippocampus, amygdala and habenulla, as compared with the expression in control rats that were maintained under the FR-20 schedule. The present findings suggest a role for the VTA and NAc as possible neuronal substrates in the discriminative stimulus effects of methamphetamine.