Atropine effects on delayed discrimination performance of rats

The effects of atropine sulfate (ATS) and atropine methyl nitrate (ATM) on the conditional discrimination behavior of rats were investigated in eight-hour experimental sessions. Responding of rats was reinforced on either a lighted or a darkened lever depending on whether lights over both levers had been on during the preceding sample portion of the trial. Zero-delay and four-second-delay trials were randomly interspersed. Quality of performance was analyzed using the A' sensitivity measure of signal detection theory. Both drugs reduced both sensitivity and the percentage of trials on which responding occurred (percent response) below saline treatment levels. The two drugs did not reliably differ from each other in their effects on sensitivity during the zero-delay condition, but reliable differences between the two drugs emerged during the four-second-delay condition at doses above 0.8 mg/kg. Percent response recovered more rapidly for animals treated with ATS than responding occurred (percent response) below saline treatment levels. The two drugs did not reliably differ from each other in their effects on sensitivity during the zero-delay condition, but reliable differences between the two drugs emerged during the four-second-delay condition at doses above 0.8 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serotonergic drug effects on a delayed conditional discrimination task in the rat; involvement of the 5-HT1A receptor in working memory

We investigated the effects of serotonergic drugs on working memory (WM) in a delayed conditional discrimination task. The 5-HT(1A) receptor full agonist flesinoxan (0.3-3.0 mg/kg) dose- and delay-dependently impaired performance, indicating a specific effect on WM. The 5-HT(1A) receptor partial agonist ipsapirone, the 5-HT( 1B/1D/2C) agonist TFMPP, the 5-HT(1A) antagonist NAN190 and the serotonin re-uptake inhibitor fluvoxamine dose-dependently impaired performance, in a delay-independent manner, indicating no specific effect on WM. The 5-HT( 2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron did not affect performance. It is suggested that the role of central serotonin receptors in WM may be restricted to 5-HT(1A) receptors.     

Benzodiazepine receptor ligands have no specific action on working memory in a delayed conditional discrimination task in rats

We investigated effects of benzodiazepine (BDZ) receptor ligands on working memory in a delayed conditional discrimination (DCD) task. The BDZ receptor full agonist midazolam (0.1-1.0mg/kg) dose-dependently impaired performance independent of delay, indicating no specific effect on working memory. The non-sedative BDZ receptor partial agonist bretazenil (0.06-0.6mg/kg), the inverse agonist beta-CCM (0.05-0.45mg/kg), the partial inverse agonist FG 7142 (0.5-5.0mg/kg), the antagonist flumazenil (1-10mg/kg), and the antagonist ZK 93 426 (1-10mg/kg) did not significantly affect performance. It is concluded that BDZ ligands do not affect working memory in a positively-motivated DCD task. Midazolam also impaired performance in the no-delay condition, suggesting loss of stimulus control, possibly through an attentional impairment.     

Effects of cholinergic drugs on delayed discrimination disruption by AF64A in rats

In a 2-lever operant chamber situation for food reinforcement, the effects of nicotine, arecoline and physostigmine on delayed discrimination responses in rats treated with ethylcholine mustard aziridinium ion (AF64A) were investigated. AF64A at 6 nmol, i.c.v., decreased the percentage of correct choices (% CR) at the delay time of 4 sec, and this effect depended on the delay time. On the other hand, AF64A at the same dose shortened the latency (LAT: the period from the end of the delay time to the initiation of lever-pressing responses) at the delay time of 16 sec, but this effect didn't depend on the delay time. Nicotine at 0.25 mg/kg, s.c., improved the decrease of % CR; and at 0.13-0.5 mg/kg, s.c., it shortened LAT at the delay time of 4 sec in rats treated with AF64A. Arecoline at 4 mg/kg, s.c., and physostigmine at 0.06-0.5 mg/kg, s.c., extended LAT, but both drugs showed no effects on % CR at the delay time of 4 sec in rats treated with AF64A. These results suggest that the present procedure might be useful for the evaluation of drug effects on memory in rats, and nicotine improved the delayed discrimination disruption induced by AF64A.     

Effects of loperamide-oxide on fentanyl drug discrimination in rats

The effects of loperamide and loperamide-oxide were studied in rats trained to discriminate 0.04 mg/kg, fentanyl from saline. After oral pretreatment with the doses of 0.63, 2.50, 10.0, and 40.0 mg/kg, neither loperamide nor loperamide-oxide produced any generalization with fentanyl. Both compounds depressed the response rate at 10 and 40 mg/kg. These results indicate that loperamide and loperamide-oxide produce no fentanyl generalization in rats up to doses at least 250 times their antidiarrheal dose and that both drugs are expected to be devoid of an opiate-like addiction liability in man.     

Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats

Phencyclidine (PCP) produces psychotomimetic effects in humans that resemble schizophrenia symptoms. In an effort to screen compounds for antipsychotic activity, preclinical researchers have investigated whether these compounds block PCP-induced behaviors in animals. In the present study, the atypical antipsychotic clozapine was tested in combination with an active dose of PCP in two-lever drug discrimination and mixed signalled-unsignalled differential-reinforcement-of-low-rates (DRL) procedures. PCP produced distinctive effects in each task: it substituted for the training dose in PCP discrimination and it increased the number of responses with short (<3 s) interresponse times as well as increasing overall response rates in the DRL schedule. Acute dosing with clozapine failed to alter the behavioral effects of PCP in either procedure even when tested up to doses that produced pharmacological effects alone. These results suggest that acute dosing with clozapine would not affect behaviors most closely associated with PCP intoxication. Further, they bring into question the utility of using PCP combination procedures in animals to screen for antipsychotic potential. Since chronic dosing is required for therapeutic efficacy of antipsychotics, future studies should focus on investigation of chronic dosing effects of these drugs in combination with PCP.     

Impact of training history on discrimination of a drug mixture by rats

The impact of training sequence on discrimination of a mixture of two drugs was investigated with five groups of rats (n = 10). In phase I, two groups were trained according to conventional two-lever, operant drug discrimination protocols with food reinforcement; one of these groups was trained with nicotine (0.4mg/kg) and the other group was trained with midazolam (0.15mg/kg). The three remaining groups served as controls and were subjected to 'sham' training in which administrations of saline, nicotine or midazolam were unrelated to contingencies of reinforcement. After completion of phase I (40 sessions), all five groups were trained to discriminate a mixture of nicotine (0.4mg/kg) plus midazolam (0.15mg/kg) from saline (phase II). Any differences between the groups in their performance during phase II could, therefore, be attributed to their different histories in phase I. During phase II, all groups discriminated the mixture from saline with similar accuracy (89-94% drug-appropriate responding after mixture as compared with 2-7% after saline). In the three groups of rats subjected to 'sham' training in phase I, there was partial generalization to both nicotine (45-53%) and midazolam (39-40%), each of which therefore contributed about equally to stimulus control by the mixture. In rats that were initially trained to discriminate nicotine, midazolam had acquired little stimulus control over behaviour (9%) and discrimination of the mixture was attributable largely to the nicotine (87%). Conversely, in rats that were initially trained to discriminate midazolam, nicotine contributed 3% and midazolam 76% to stimulus control by the mixture. These powerful, persistent effects of training sequence were interpreted as examples of associative blocking demonstrated with the interoceptive stimuli produced by psychoactive drugs.     

Effects of cholinergic and non-cholinergic drugs on visual discrimination and delayed visual discrimination performance in rats

The effects of several centrally active drugs were investigated using two visual discrimination tasks: a two-lever food-rewarded conditional brightness discrimination, and a similar conditional brightness discrimination where a delay was introduced between the disappearance of the stimulus and the opportunity to respond on the levers for food. The substances tested (amphetamine, scopolamine, methylscopolamine, physostigmine, diazepam and-carboline benzodiazepine receptor antagonist, ZK 93426), all produced differing profiles of action on the performance parameters recorded. In the simple conditional visual discrimination, amphetamine increased omissions without significant effects on accuracy or response latency. Physostigmine enhanced response latencies and failures to respond without significant effects on accuracy. ZK 93426 had no consistent effects on accuracy although at higher doses, some increase in response latency was seen in the delayed responding version of the visual discrimination task. Diazepam had negative effects on all parameters in both discrimination procedures. Scopolamine disrupted responding, but not accuracy in the simple discrimination, whereas accuracy was reduced in a dose, but not delay dependent manner in the delayed discrimination. A similar effect to that observed with scopolamine was observed following methylscopolamine in the delayed discrimination procedure. In the simple visual discrimination small increases in accuracy were recorded, accompanied by increased response latencies.     

Agmatine inhibits morphine-induced drug discrimination in rats

Our previous studies have shown that agmatine inhibited morphine-induced conditioned place preference and locomotor sensitization in rats. In the present study, we further investigated the effects of agmatine on the discriminative stimulating effects produced by morphine in rats. Agmatine, at the dose range of 10-80 mg/kg (i.g.), neither induced drug discrimination, nor substituted for morphine stimulus in rats that were previously treated with morphine, suggesting that agmatine itself has no psychomotor-stimulating potential. However, pretreatment with agmatine (40, 80 mg/kg, i.g.) significantly inhibited the acquisition, but not expression, of morphine-induced drug discrimination as assessed by the correct nose-poke response. Further, chronic administration of agmatine (40, 80 mg/kg/dayx12 days, i.g., 25 min prior to morphine) also significantly accelerated the extinction of the discrimination induced by morphine. These data suggest that agmatine inhibits the acquisition and accelerates the extinction of morphine-induced discrimination, supporting possible use of agmatine in the treatment of opioid dependence.     

Assessment of tolerance to barbital by means of drug discrimination procedures

This study was designed to determine the relative development of tolerance to the discriminative-stimulus and hypnotic properties of barbital. By selectively reinforcing lever presses only in the presence of one of the drug states, rats were trained in a Skinner Box to discriminate the effect of sodium barbital (80 mg/kg) injection from that of saline injection. After the rats were well trained, the administration of daily hypnotic doses of barbital (240 mg/kg) for 8 days produced marked tolerance to the hypnotic effect of the barbiturate in all animals. The ability of the 80 mg/kg dose to serve as a discriminative stimulus was not impaired in animals which had been trained with the drug as the condition during which bar presses had been reinforced (S ^D condition). Animals for which bar presses had gone unrewarded under barbital (S condition) displayed a tendency to develop tolerance to the stimulus properties of barbital. These findings are interpreted in the light of dose-effect studies, and it is suggested that the acquired polarity of the drug condition determined by its assignment as S ^D or S may influence the discriminability of the drug in future exposures.Supported in part by the Research Institute on Alcoholism of the New York State Department of Mental Hygiene and Grant No. 15406 from the National Institute of Mental Health.     

Effect of multiple discrimination reversals on acquisition of a drug discrimination task in rats

There are many similarities between exteroceptive stimuli and interoceptive stimuli. Nevertheless, it has been suggested that behavior maintained by drug stimuli might be more difficult to reverse than behavior controlled by exteroceptive stimuli. Once a discrimination is established with an exteroceptive stimulus, it can be reversed by switching the reinforcement contingencies, and repeated reversals result in progressively faster relearning of the discrimination. To determine whether faster relearning of successive discrimination reversals also occurs when the discrimination is controlled by an internal drug stimulus, we trained rats to discriminate 3.2mg/kg phencyclidine-(PCP) from saline, in a two-lever food-reinforced operant task. After this discrimination was acquired, the reinforcement contingencies were reversed. A number of such discrimination reversals were performed to determine whether fewer trials would be needed to reach criterion performance with each reversal. Each time the reinforcement contingencies were switched, fewer training sessions were required for the subjects to reach criterion. These results are similar to those observed when a discrimination has been established with exteroceptive stimuli. The present study provides further evidence of the similarity between interoceptive drug stimuli and exteroceptive sensory stimuli.     

Biphasic effects of ethanol tested with drug discrimination in HAD and LAD rats.

Seventh-generation selectively bred high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats were trained to make differential responses for ethanol (0.75 g/kg, IP) and saline vehicle, following postadministration intervals (PI) of 2 min (HAD-2 and LAD-2 animals) and 30 min (HAD-30 and LAD-30 animals). ED50 values of 0.395 and 0.352 g/kg, respectively, for HAD-2 and LAD-2 animals and 0.269 and 0.314 g/kg, respectively, for HAD-30 and LAD-30 animals reflect the absence of any phenotypic difference for the discriminative stimulus effects of ethanol. HAD-2 animals were more responsive than LAD-2 animals to the stimulating effects of ethanol as measured by total response rates during training sessions. The differential ethanol response generalized to pentobarbital in all four groups but not to morphine, an alternative CNS depressant. The specific antagonist of 5-hydroxytryptamine3 receptors, 3-tropanyl-3,5-dichlorobenzoate (MDL 72222), up to doses of 14.0 mg/kg failed to antagonize the discriminative effects of ethanol. Ethanol sleep times did not differ between groups.     

Modelling working and reference memory in rats: effects of scopolamine on delayed matching-to-position(1,2)

A model of working and reference memory in rats is described, based on a discrete-trial operant procedure with concurrent components of spatial matching (for working memory) and nonspatial discrimination (for reference memory). On each trial in the matching component, rats received food for pressing one of two retractable levers after a delay if that lever had been presented in the prior sample phase of the trial. On each trial in the discrimination component, food was delivered if the rat pressed a lever illuminated by a cue light after the delay interval. The model was tested with scopolamine (0.10 to 0.56 mg/kg, ip), which reduced matching accuracy in a dose-related manner. Linear slope and intercept estimates of retention gradients showed that intercepts declined and slopes remained unchanged with increasing scopolamine dose. In contrast, scopolamine had no significant effect on nonspatial discrimination accuracy, indicating a relative insensitivity of reference memory to cholinergic blockade. Because the matching component involved spatial cues and the discrimination component did not, a second group of rats was trained to discriminate between the spatial locations of two levers, to compare the effects of scopolamine on spatial and nonspatial discriminations. Scopolamine at the same doses caused a small, consistent decrease in spatial discrimination accuracy, suggesting that spatial discrimination was more sensitive to disruption by scopolamine than was nonspatial discrimination. The combined delayed matching-to-position/nonspatial discrimination procedure appears to provide a useful technique for characterizing mnemonic effects of drugs and toxicants in rats.     

Facilitating effects of SR 57746A on short-term memory in an operant delayed alternation task in aged rats

The effects of SR 57746A during acquisition and on stabilized performance of a delayed alternation task in a Skinner Box (Model E 10.10, Coulbourn Instruments, Lehigh Valley, PA) were investigated in aged rats (22–26 months old). Test sessions consisted of repeated trials during which animals were first presented with a single lever (left or right) followed several seconds later by two levers. A press on the lever opposite to that presented previously (delayed alternation) was rewarded. The number of correct responses and the reaction times to the one- and two-lever presentations were recorded. SR 57746A (0.3 and 3 mg/kg p.o.) was first evaluated during the acquisition of the delayed alternation, given before each of 10 daily acquisition sessions to different groups of aged animals. The imposed delay was 5 sec. Afterward, training continued without drug until asymptotic performance was reached. Rats were then given repeated drug test sessions during which different intervals (5, 10, and 20 sec) were presented in a random order. During this phase, both young and aged animals received all the different treatments (SR 57746A at 0.3, 1, and 3 mg/kg and vehicle p.o.). Aged animals showed clear deficits during both acquisition and stabilized performance phases. SR 57746A, particularly at the highest dose tested (3 mg/kg p.o.), clearly increased response accuracy of aged animals both during acquisition of the delayed alternation and during stabilized performance. In the latter phase, the facilitation of response accuracy was observed only in conditions (10 sec retention delay) where aged animals showed a deficit compared with young animals. SR 57746A did not affect response accuracy during stabilized performance in young animals at any delay. The drug-induced increase in response accuracy in aged animals occurred at a dose of SR 57746A (3 mg/kg p.o.) that lengthened reaction times, particularly simple reaction times, during both acquisition and stabilized performance and also lengthened reaction times in young animals during the stabilized performance phase. These results suggest that SR 57746A specifically attenuates age-related short-term memory impairment in rats. © 1995 Wiley-Liss, Inc.     

Detecting drug effects on short-term memory function using a combined delayed matching and non-matching to position task

Operant delayed non-matching-to-position (DNMTP) and delayed matching-to-position (DMTP) have become standard techniques to investigate drug effects on short-term memory function in rats. However, these two tasks are normally conducted in isolation. Using two standard drugs, the 5HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the muscarinic antagonist scopolamine, this study looked at a two-choice operant task that essentially involved a mixed DNMTP/DMTP paradigm. Thus, DNMTP trials were interspersed with DMTP trials in a random sequence for the duration of a session. 8-OH-DPAT (0.03 mg/kg) slightly but significantly improved response accuracy in a delay-dependent fashion during DMTP but not DNMTP trials. The highest dose of 8-OH-DPAT (0.1 mg/kg) impaired accuracy during DNMTP trials independent of delay and had no significant effect during DMTP trials. Scopolamine (0.1 mg/kg) produced delay-dependent deficits in accuracy during DMTP trials but delay-independent impairments during DNMTP trials. Because both 8-OH-DPAT and scopolamine produced delay-dependent effects with DMTP trials types and either had no effect (8-OH-DPAT) or produced delay-independent impairments (scopolamine) during DNMTP trials types, it is suggested that DMTP trials had a greater dependence on short-term working memory function than DNMTP trials that probably relied more on positional (mediating) strategies for solving the task. Therefore, we believe that this mixed DNMTP/DMTP task offers greater potential for more reliable and discerning interpretation of data regarding short-term memory function in rodents than either of the paradigms performed in isolation.     

Effects of drug discrimination history on anti-punishment properties of chlordiazepoxide in rats

Several studies have indicated that acquiring discriminative stimulus control for a certain anxiolytic drug influences its subsequent anti-conflict properties. To further elaborate on the question whether drug discrimination procedures affect behaviour in a conflict paradigm, a classical two-lever drug discrimination procedure was combined with an operant conflict procedure within the same animals. To this extent, rats were trained to discriminate the anxiolytic chlordiazepoxide (CDP, 30 mg/kg, po) from saline (SAL), and subsequently punished responding periods were introduced within the same session. In addition to the rats that were trained to discriminate CDP from vehicle, a group of rats was trained on a random relationship between CDP and the rewarded lever. CDP and alprazolam completely substituted for CDP, whereas mianserin did not. Responding during punished components in a session was increased by CDP and alprazolam, but not by mianserin in rats that were trained to discriminate CDP from vehicle and in randomly trained rats. The data indicate that rats can be reliably trained and tested in drug discrimination and conflict procedures within a single session and that CDP's discriminative stimulus does not alter its anti-conflict effects.     

Differential effects of iloperidone,clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm

Rationale Because cognitive function, particularly working memory (WM), is severely impaired in schizophrenia, evaluation of neuroleptic medication should include investigation of possible effects on cognition. Iloperidone is a promising, novel atypical neuroleptic drug (NL), for which no cognitive data is presently available.Objective To investigate whether the novel atypical NL iloperidone would affect performance of rats on a WM test, using a delayed non-matching-to-position (DNMTP) paradigm, and compare its effects with those of the atypical NL clozapine and the typical NL haloperidol.Methods Male Lister Hooded rats trained to criterion in an operant DNMTP task (0–64 s delay intervals) were administered vehicle, iloperidone (0.03, 0.1 mg/kg, i.p.), clozapine (0.1, 0.3 mg/kg, s.c.), haloperidol (0.003, 0.01, 0.03 mg/kg, s.c.), or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured.Results It was found that: (1) iloperidone significantly improved choice accuracy delay-dependently while impairing task performance; (2) the atypical NL clozapine had no effect on choice accuracy and parameters related to motor function, but significantly increased the number of uncompleted trials; (3) haloperidol did not affect choice accuracy except at the longest delay with the highest dose, but in contrast to clozapine it significantly impaired task performance.Conclusion In accordance with their different pharmacological profiles, the three NLs iloperidone, clozapine, and haloperidol have different effects in this preclinical cognitive task. These results might provide important information for the development of NLs with beneficial effects on cognition.     

Reversal of overshadowing in a drug mixture discrimination in rats

Previous studies have suggested that in some circumstances, learning processes such as overshadowing may determine the effects that one drug has upon the response to another. The experiments described here examined overshadowing in rats trained to discriminate mixtures of nicotine plus midazolam in two-lever operant procedures with food reinforcement. After training for 60 sessions, midazolam (0.32 mg/kg SC) overshadowed nicotine (0.32 mg/kg SC) so that the discriminative stimulus effect of nicotine seen in control rats trained with nicotine alone was abolished (n=8–10). In the next phase of the study, the discriminative response to midazolam in one group of mixture-trained rats was devalued by means of an extinction procedure which weakened the relationship between administration of midazolam and the response that was reinforced. Dose-response determinations then showed that the devaluation procedure had indeed attenuated the response to midazolam, whereas the previously overshadowed response to nicotine was restored. Post-session injections of drugs were used to equate the pharmacological histories of the groups and the effects seen were therefore attributable to training with the drugs and not simply to repeated exposure to them. Additionally, in the control rats trained with nicotine only (with midazolam given post-session), midazolam markedly reduced response rates, whereas in the three groups of rats trained with the mixture, midazolam had little response rate-depressant effect; this observation suggests that behaviourally contingent tolerance had developed to the response rate-reducing effect of midazolam. Application of devaluation procedures in studies of the discriminative stimulus effects of single drugs with multiple effects may provide a means for manipulating the characteristics of the discriminations obtained and for identifying individual elements of the drug-produced stimulus complex.     

Amphetamine-haloperidol discrimination: effects of chronic drug treatment

Rats responding for food reinforcement were trained in a 2-lever drug discrimination task. Groups of rats were trained to discriminate one of four doses of amphetamine (0.0, 0.1, 0.3, or 0.5 mg/kg) from haloperidol (0.02 mg/kg). Both the rate of acquisition and level of discrimination at asymptote were a function of amphetamine training dose. Following acquisition of this discrimination, choice behavior was assessed in the absence of drug during two test sessions. Twenty-four hours following the second drug-free test session, chronic drug treatment commenced. Half of the animals received 10 mg/kg amphetamine for 10 consecutive days while the other half received 1 mg/kg haloperidol during the same period. Choice behavior was assessed during three 2.5-minute unreinforced drug-free test sessions 24, 48, and 72 hours following the chronic drug regimen. Following chronic haloperidol, animals responded as though a small dose of amphetamine had been administered, while following chronic amphetamine, they responded as though a small dose of haloperidol had been administered. Collectively, these results suggest that animals trained to discriminate amphetamine from haloperidol respond on the basis of a continuum of dopaminergic function. Further, this continuum can be used to elucidate the net effect of pharmacologically-induced alterations in dopaminergic function, as well as the effect of nonpharmacological manipulations that may result in dopaminergic changes.     

Differentiating the discriminative stimulus effects of gamma-hydroxybutyrate and ethanol in a three-choice drug discrimination procedure in rats

Anecdotal reports indicate that GHB produces subjective effects similar to those of ethanol. However, recent investigations comparing the discriminative stimulus effects of GHB to those of ethanol suggest that the subjective effects of these substances may differ considerably. To explore further potential differences between GHB and ethanol, 16 male Sprague–Dawley rats were trained in a three-lever drug discrimination procedure to discriminate ethanol (1.0 g/kg, experiment 1; 1.5 g/kg, experiment 2) and GHB (300 mg/kg) from vehicle. Dose–response functions determined with both training compounds revealed a clear dissociation between the discriminative stimulus effects of these drugs. As expected, the GHB precursors gamma-butyrolactone and 1,4-butanediol produced full substitution for GHB. In addition, the GABA_B receptor agonist baclofen substituted for GHB, whereas the benzodiazepine flunitrazepam and the NMDA receptor antagonist ketamine engendered greater responding on the ethanol-lever. GHB's discriminative stimulus effects were blocked by the GABA_B receptor antagonist CGP-35348 but only partially blocked by the putative GHB receptor antagonist NCS 382. These findings are consistent with previous reports of GHB's discriminative stimulus effects in two-choice drug discrimination procedures and provide additional evidence that these effects are distinct from those of ethanol.