Generalization of behavioral history across responses in the reversal of the effects of cocaine and d-amphetamine on the punished behavior of squirrel monkeys

Previous research has demonstrated that the effects of d-amphetamine on punished lever pressing of squirrel monkeys are modified by an avoidance history in which lever pressing postpones shock. In the present experiment generalization of behavioral history across responses was assessed by determining the effects of d-amphetamine and cocaine on punished lever pressing of squirrel monkeys before and after exposure to an avoidance procedure in which a chain-pulling response postponed shock. The punishment schedule consisted of a fixed-interval 5-min schedule of food delivery in which every 30 lever presses produced a 5-mA electric shock. During avoidance sessions each chain pull postponed shock delivery for 25s; in the absence of chain pulling, shocks occurred every 5s. Only a single response manipulandum was present in each phase. Punished lever pressing was initially unaltered or decreased by d-amphetamine and cocaine. Following the chain-pull avoidance history, however, d-amphetamine produced dose-dependent increases in the punished lever pressing of all three monkeys at several doses that formerly did not alter or reduce responding; a similar pattern of results was obtained when cocaine was administered to two of the subjects. The effects of d-amphetamine and cocaine on punished lever pressing were subsequently determined within the context of a multiple schedule of lever-press punishment and chain-pull avoidance, with both manipulanda present simultaneously. The effects of the drugs on punished lever pressing within the multiple schedule were similar to their initial, pre-avoidance effects for the two monkeys whose responding was increased by both drugs in the preceding, post-avoidance phase. Chain pulling during the punishment component was dose-dependently increased, suggesting that chain pulling during punishment reduced the opportunity to exhibit increases in punishing lever pressing. The remaining monkey's punished lever pressing was increased by both drugs within the context of the multiple schedule. This experiment demonstrates that avoidance-dependent upward shifts in the dose-response curves of d-amphetamine and cocaine can occur when the punishment and avoidance responses differ, and that original effects can be partially restored when both responses are available simultaneously. The results suggest that generalization across responses of the effects of a critical behavioral history may be a general property of behavioral history phenomena within behavioral pharmacology. These findings underscore the generality and importance of behavioral history as a modulatory influence on the effects of abused drugs.     

Effects of scopolamine,physostigmine and chlordiazepoxide on punished and extinguished water consumption in rats

It has been postulated that behavioral inhibition due to punishment or extinction may be mediated by brain acetylcholine, and drugs which have disinhibitory action are thought to interact with this system. This notion was tested by comparing the effects of scopolamine, physostigmine and chlordiazepoxide on punished and extinguished water consumption. Scopolamine hydrobromide (0.3, 0.5 mg/kg, i.p.), a centrally and peripherally acting antimuscarinic agent and physostigmine sulfate, (0.3 mg/kg, i.p.), a centrally and peripherally acting acetylcholinesterase inhibitor, lowered both non-punished and punishment suppressed water intake and lick rate, whereas their quaternary analogs which primarily act in the periphery, had no significant effect at comparable dose levels. Scopolamine and physostigmine suppressed punished water consumption at lower dose levels than nonpunished intake. In contrast, chlordiazepoxide (5.0, 10.0, 20.0 mg/kg, i.p.) enhanced punished as well as non-punished water intake. In a further experiment comparing punishment and extinction suppression, scopolamine and physostigmine did not affect punished or extinguished water intake; chlordiazepoxide (5.0, 10.0, 20.0 mg/kg) reliably increased punished, but not extinguished licking on the water nozzle. These results suggest (1) that scopolamine and chlordiazepoxide do not act via a common mechanism, and (2) that punishment and extinction suppression are not a pharmacological entity.     

Reconciling differences in drug effects on behavior punished or maintained by response-produced shock

Comparable patterns of behavior maintained by different events are affected similarly by certain drugs and differently by others. The present paper argues that patterns of behavior maintained by response-produced shock (“shock-maintained behavior”), although similar in appearance to lever pressing maintained by more conventional positive reinforcers, are generated through differential punishment of long interresponse times; hence, drug effects on this behavior should more closely resemble drug effects on pressing suppressed by punishment. Because the operants suppressed in these procedures are diametrically opposed (long interresponse times vs. pressing), the baseline patterns of behavior will differ (suppressing long interresponse times produces high rates of pressing, punishing pressing produces low rates). Furthermore, any drug-induced changes in the frequency of the punished operant will result in what appear to be dissimilar drug effects if the rate of only one operant class serves as the dependent variable. That is, drugs that increase the rate of pressing that has been suppressed by punishment should increase long interresponse times similarly suppressed. This results in an overall increase in pressing rate under typical punishment procedures, but a decrease in overall pressing rates (an increase in the rate of punished long interresponse times) under shock-maintenance procedures. Hence, similar drug effects on these inversely related operants should generate opposite changes in pressing rate under the two sets of procedures. A review of the literature revealed this to hold true in 12 of 15 cases. Drug effects on comparable patterns of pressing maintained by shock or food presentation split more evenly. The literature indicates that, of 21 such, comparisons between pressing maintained under fixed-interval schedules of food or shock, ten yielded comparable drug effects under both, and 11 yielded dissimilar effects. These results suggest that what appear to be dissimilar drug effects on pressing maintained or suppressed by shock may in fact be similar effects on the inversely related operants differentiated under these procedure.     

Effects of scopolamine, amphetamine and benzodiazepines on conditioned suppression

Conditioned suppression of operant behavior was produced by preshock stimuli (i.e., stimuli that precede the noncontigent presentation of electric shock), or prereward stimuli (i.e., stimuli that precede the noncontingent presentation of food) in rats and squirrel monkeys responding on a variable interval schedule of food reinforcement. Benzodiazepine derivatives and amphetamine differentially affect conditioned reactions which are elicited by preshock and prereward stimuli. Conditioned suppression to prereward stimuli were unaffected by chlordiazepoxide, diazepam, scopolamine hydrobromide and scopolamine methyl nitrate but clearly reduced by amphetamine. On the other hand, chlordiazepoxide attenuated the conditioned suppression to preshock stimuli whereas amphetamine, scopolamine hydrobromide and scopolamine methyl nitrate had no significant effects in this paradigm. The results suggest that the effects of drugs on conditioned suppression cannot be interpreted, a priori, in terms of selective effects on mechanisms related to emotional behavior or inhibition.     

Effects of intrastriatal injections of scopolamine on appetitive behavior

Direct application of the anticholinergic drug scopolamine to the corpus striatum of food-deprived rats reliably inhibited the intake of solid food as well as food-rewarded lever pressing. Water intake and operant responding for water rewards in water-deprived rats were not affected, suggesting that the drug treatment did not interfere with swallowing or with the animals' ability to lever press. The intake of a liquid diet by food-deprived rats was also not affected by intrastriatal scopolamine, suggesting that the observed suppression of food intake and food-rewarded instrumental behavior may not be related to a loss of food motivation per se.     

Effects of chlordiazepoxide on heart rate and behavioural suppression in pigs subjected to operant conditioning procedures

Two groups of four pigs were subjected to a punishment discrimination (conflict) or to a non-reinforcement procedure. Conflict behaviour was evidenced by the suppression of operant responding and the occurrence of a marked decrease in heart rate during the presentation of the conditioned stimulus. Pigs in the non-reinforcement procedure showed no consistent changes in heart rate although an important decrease occurred in response rate. Chlordiazepoxide was administered in order to establish whether it would attenuate the response suppression in either procedure. The drug produced a weak attenuation of conflict in terms of the operant and heart rate responses at the maximum dose used (20 mg/kg) and a small disinhibiting effect on the non-reinforced responding at 10 mg/kg. Such effects were less clear-cut than usually reported in other species.     

Effect of minor tranquilizers, tryptamine antagonists and amphetamine on behavior punished by brain stimulation

Earlier observations have shown that septal lesions released operant responding punished by foot-shock, but did not change behavior punished by electrical stimulation of the dorsal periaqueductal gray (DPAG) substance of the rat brain. In contrast, chlordiazepoxide facilitated both kinds of punished responding. In order to further study the mechanism of brain stimulation punishment, dose-response curves of two minor tranquilizers, chlordiazepoxide and pentobarbital, of two tryptamine antagonists, methysergide and cyproheptadine as well as of amphetamine on lever-pressing behavior of rats maintained by water reinforcement and punished by DPAG stimulation were determined. A multiple schedule with a variable-interval 2 min (VI 2) non-punished component and a continuous reinforcement (CRF) component in which every response was both rewarded and punished was used. Chlordiazepoxide and pentobarbital caused dose-dependent increases in punished responding. Unpunished VI response rates were also moderately increased by the minor tranquilizers. In contrast, neither methysergide nor cyproheptadine increased punished or unpunished responding at doses that have been previously shown to markedly release behavior punished by foot-shock, in the rat. Conversely, amphetamine, a drug that usually does not release responding punished by peripheral noxious stimulation, caused dose-dependent increases in responding suppressed by DPAG punishment without affecting VI response rate. These and previous results with septal lesions suggest that neither the septo-hippocampal system nor its serotonergic input from the mesencephalon mediate response suppression by DPAG electrical stimulation, in contrast to their active role in peripheral punishment. This difference may also explain the marked facilitatory effect of amphetamine on responding punished by brain stimulation shown by the present results.     

Insulin effects on positively-reinforced lever pressing by rats

Regular insulin in doses greater than 0.1 units/kg produced dose-dependent maximum decreased in plasma glucose levels of food deprived rats 60 minutes after injections. FR 1 food reinforced lever pressing showed a dose-dependent, food deprivation-dependent and pretreatment time-dependent decrement in operant responding. Insulin suppression of responding was reduced when subjects were partially food satiated. FR 1 water reinfroced behavior also showed a dose-dependent and pretreatment time-dependent decrement in lever pressing. VI 1 min food reinforced level pressing similarly showed a dose-dependent and pretreatment time-dependent decrement in responding. Thus, effects of insulin on operant responding were largely independet of type of reinforcer and schedule of reinforcement. Further, the failure to observe a consistent increase in responding with insulin did not support the view that insulin induces a state comparable to increased food deprivation levels. These findings suggest that the spectrums of effects of insulin and food deprivation differ.     

Effects of diazepam on responding suppressed by response-dependent and independent electric-shock delivery

While the effects of benzodiazepines on punished responding (response-dependent shock) are straightforward and unambiguous, their effects on behavior suppressed by response-independent shock are conflicting and inconsistent. Some investigators reported that benzodiazepines either have no effect on, or suppress further, responding during response-independent shock, while others reported that benzodiazepines enhance response rates during independent shock delivery in the same manner as during dependent shock. The present study compared the effects of diazepam on rates of lever pressing maintained by a variable-interval 35-sec schedule of food delivery in rats exposed alternately to fixed-interval 180 sec (response-dependent) and fixed-time 180 sec (response-independent) schedules of shock delivery. Diazepam increased punished responding in a dose-dependent manner for each animal. "Rate-dependency," degree of suppression and presence of external stimuli influenced rate-enhancement by the drug. Effects of diazepam on responding suppressed by response-independent shock were inconsistent, with two animals revealing rate enhancement comparable to punished responding, and two others revealing further increases in response suppression. Reasons for the differential effects of diazepam on response-rates suppressed by the two forms of shock delivery remain obscure, although the basic phenomenon seems to be real and not merely an artifact of "rate-dependency."     

Effects of cholinergic drugs on aversive operant behavior induced by dorsal central gray stimulation in rats

Involvement of a central cholinergic mechanism in the central aversive operant behavior induced by dorsal central gray (DCG) stimulation was investigated in rats. Each animal was chronically implanted with bipolar electrodes at the DCG and was trained to press a lever to decrease the DCG-stimulation current. Physostigmine (0.1 and 0.2 mg/kg, i.p.) and arecholine (0.5-2.0 mg/kg, i.p.) produced an increase of DCG-stimulation threshold at 0.5-2 hr and 1-4 hr, respectively, after the administration. On the other hand, scopolamine (0.1-0.5 mg/kg, i.p.) and atropine (5 and 10 mg/kg, i.p.) caused a marked decrease of the threshold at 0.5-2 hr after. In addition, an increasing effect of physostigmine on the threshold was decreased by scopolamine. Physostigmine potentiated the increasing effect of chlorimipramine on the stimulation threshold, while scopolamine suppressed it. These results suggest that the operant behavior induced by DCG-stimulation may be related to not only the central serotonergic mechanism but also to the cholinergic mechanism.     

Disinhibitory effects of intrahippocampal of intrahypothalamic injections of anticholinergic compounds in the rat.

The effects of intrahippocampal or intrahypothalamic injections of anticholinergic compounds on operant responding were observed in a multiple schedule paradigm consisting of reinforced, punished, and nonreinforced components and on a punished ingestive passive avoidance task. The pattern of results suggests that cholinergic components of the hippocampus and hypothalamus mediate responding suppressed by nonreinforcement but not by punishment. The data are discussed with reference to Carlton's proposed central cholinergic inhibitory mechanisms.     

Anxiolytic-like action of beta-blockers: effects of stimulus salience.

Eighteen rats were trained on a multiple schedule: lever pressing was rewarded on a Variable Interval (VI 20 s) in both components but, in addition, punished on a similar schedule in one. Shock intensity was individually adjusted to produce high or low degrees of response suppression during punishment periods in two different groups of animals. For some rats in each group, punishment periods were signalled by a flashing light; for others, by a steady light. d,l-Propranolol (2.5-7.5 mg/kg), l-propranolol (3.75, 7.5 mg/kg) and atenolol (20 mg/kg) released responding in animals in which suppression was low. These effects were restricted to the group for which the punishment signal was flashing light. The results are consistent with the view that activation of peripheral beta-adrenoceptors is involved in the suppression of responding by signals of punishment, but only in some conditions. Adding chlordiazepoxide (3.75 mg/kg) to d,l-propranolol (7.5 mg/kg) increased punished responding in the high-suppression group, but reduced it in the low-suppression group.     

"Conflict" situation based on intracranial self-stimulation behavior and the effect of benzodiazepines

Based on lateral hypothalamic self-stimulation behavior of the rat in a Skinner box, a "conflict" situation was established by combining foot shock punishment with brain stimulation. Diazepam (10-20 mg/kg, PO) caused a marked increase in the lever pressing response in the punished period without affecting the unpunished response. Bromazepam (10--20 mg/kg PO) also caused an increase in the lever pressing response in the punished period and a decrease of the punished response. These results indicate that a "conflict" situation based on self-stimulation behavior is useful for the evaluation of antianxiety action.     

Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure

An important aspect of motivated behavior is that organisms will perform complex instrumental behaviors to gain access to stimuli such as food. In the present study, food-deprived rats were tested in an operant chamber in which the animals had a choice between pressing a lever to obtain a more-preferred food (Bioserve pellets), or free feeding on a less-preferred food (lab chow). Typically, rats pressed the lever to obtain the preferred food pellets, and ate little of the less-preferred food even though it was freely available. Pre-fed rats showed suppression of both lever pressing and feeding. Systemic administration of 0.1 mg/kg haloperidol (HP) led to a dramatic shift in the behavior of these rats, such that the number of lever presses was substantially reduced, but the amount of less-preferred food consumed showed a significant increase. This result occurred if the rats pressed a lever on either a CRF or FR5 schedule. Injection of 3.5-7.0 micrograms HP directly into the nucleus accumbens, or intra-accumbens injections of 6-hydroxy-dopamine, also decreased lever pressing for food and increased feeding on laboratory chow. Thus, interference with brain dopamine suppressed a highly active instrumental response for food, although the behavior of the animal was still directed towards food acquisition and consumption.     

Different behavioral effects of haloperidol,clozapine and thioridazine in a concurrent lever pressing and feeding procedure

Rats were tested using a lever pressing/feeding procedure in which a preferred food (Bioserve pellets) was available by pressing a lever on a fixed ratio 5 schedule, but a less preferred food (lab chow) was also available concurrently in the operant chamber. The effects of repeated (14 day) injections of haloperidol, clozapine and thioridazine were compared. Haloperidol (0.05–0.15 mg/kg) significantly reduced lever pressing and increased chow intake throughout the drug treatment period. Injections of clozapine (2.0–6.0 mg/kg) suppressed lever pressing but failed to produce substantial increases in chow intake. In the haloperidol experiment there was a significant inverse correlation between lever pressing and chow intake, but in the clozapine experiment there was not. Regression analysis indicated that rats treated with the high dose of clozapine showed some tolerance to the suppression of lever pressing. Tests of sedation also were conducted before and after the instrumental behavior sessions. Haloperidol produced little or no sedative effect in the dose range tested. Clozapine produced substantial sedation during the first 10 days of administration, but this effect, like the suppression of lever pressing, showed signs of tolerance. Thioridazine (3.0–9.0 mg/kg) produced some effects that resembled haloperidol, and other effects, including sedation, that resembled clozapine. These studies indicate that haloperidol suppresses lever pressing for food at low doses that do not produce severe motivational or sedative effects that disrupt food intake. In contrast, it appears as though the suppression of lever pressing produced by clozapine stems from a sedative effect that also serves to set limits on chow intake. These results indicate that haloperidol and clozapine suppress lever pressing through different mechanisms.     

Distinct effects of diazepam and NK1 receptor antagonists in two conflict procedures in rats

Convergent data suggest that SP, through the activation of neurokinin1 receptors (NK1-R), may be involved in anxiety. In particular, NK1-R antagonists have been reported to exert anxiolytic-like effects in a variety of animal procedures in which anxiety-related behaviour is induced by novelty. The present study investigated the effects of acute blockade of NK1-R in conflict paradigms, another category of anxiety-related procedures, in which positively reinforced responses are suppressed by contingent punishment. For this purpose, three selective antagonists with nanomolar affinity for rat NK1-R, GR205171, RP67580 and [2-cyclopropoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2-phenylpiperidin-3-yl)amine (Compound L), were tested in the safety signal withdrawal operant paradigm. In this procedure, suppression of lever pressing for food was induced by the withdrawal of a conditioned signal for safety, with no presentation of a conditioned signal for punishment, and no punishment. Compound L was also tested in the punished drinking test, which consists of the contingent delivery of electric footshocks upon water drinking. As expected, the reference compound, diazepam (2 mg/kg s.c.), induced an anxiolytic-like effect, as indicated by significant increases of the number of responses emitted during conflict period in the operant procedure, and footshocks received in the drinking test. In contrast, GR205171 (10 mg/kg s.c.), RP67580 (0.25-8 mg/kg s.c.) and Compound L (10 and 30 mg/kg s.c.) failed to release lever pressing during the operant conflict period. In addition, punished drinking was not affected by Compound L (3-30 mg/kg s.c.). These data show that NK1-R blockade has no anxiolytic-like effects in conflict paradigms, thereby suggesting that the anxiolytic properties of NK1-R antagonists are less broad than those reported for benzodiazepines.     

Rate-dependency hypothesis and the rate-decreasing effects of d-amphetamine on schedule-induced drinking

The high levels of drinking induced by intermittent food-reinforcement schedules are dose-dependently reduced by acute doses of d-amphetamine. The present study evaluated whether the effects of d-amphetamine on this schedule-induced drinking reflect the reduction of high rates of responding. Twenty-four rats were divided into six groups (n = 4) according to the interval and time durations of a multiple fixed-time (FT) fixed-interval (FI) schedule (15s, 30s, 60s, 120s, 240s and 480s). FT components were signalled by a tone and by lever withdrawal. Doses of 0.25 to 4.0mg/kg of d-amphetamine were administered i.p. 10min before test sessions. d-amphetamine produced similar dose-dependent reductions in rate of licking induced by FT and FI schedules. Rate-decreasing effects on operant lever pressing were also found after administrations of d-amphetamine. The dose-dependent decrements produced by d-amphetamine were a function of the inter-food interval length in both schedule-induced and operant behaviours. These rate-decreasing effects were rate-dependent, but d-amphetamine interacted differentially with control rates of adjunctive and operant behaviours, causing a greater suppression of the lower rates of adjunctive licking and the higher rates of operant lever pressing.     

A reappraisal of scopolamine effects on inhibition

A series of related experiments was conducted to examine the effects of scopolamine on discrimination performance in the presence of a stimulus signalling non-reinforcement. In Experiment 1, rats trained to respond on 1 of two levers in the presence of a 1000-Hz tone and on the other lever in the presence of a 3000-Hz tone were not reinforced when white noise was added to 1 of the tones. Pairing white noise with the other tone during an extinction session demonstrated that the white noise had become a conditioned inhibitory stimulus. In Experiment 2, scopolamine decreased responding and discrimination accuracy on the excitatory (reinforced) trials, and increased responding on the inhibitory (non-reinforced) trials. The magnitude of the drug's effect was similar on excitatory and inhibitory trials. Using combinations of visual and auditory discriminative stimuli, Experiment 3 confirmed the results of experiment 2. These experiments show that scopolamine disrupts animals' ability to discriminate, and that scopolamine-induced increases in non-rewarded responses cannot be attributed solely to a disinhibitory effect of the drug as Carlton (1969) and others have claimed.     

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.     

Effects of muscimol, amphetamine, and DAMGO injected into the nucleus accumbens shell on food-reinforced lever pressing by undeprived rats

Previous studies have shown that large increases in food intake in nondeprived animals can be induced by injections of both the GABA_A agonist muscimol and the μ-opioid agonist DAMGO into the nucleus accumbens shell (AcbSh), while injections of the catecholamine agonist amphetamine have little effect. In the current study we examined whether injections of these drugs are able to increase food-reinforced lever pressing in nondeprived rats. Twelve subjects were trained to lever press on a continuous reinforcement schedule while food deprived and were then tested after being placed back on ad libitum feeding. Under these conditions, responding was markedly increased by injections of either muscimol or DAMGO, although the onset of the effects of the latter drug was delayed by 30-40 min. In contrast, amphetamine injections failed to increase reinforced lever pressing, although they did enhance responding on a non-reinforced lever, presumably reflecting alterations in behavioral activation. These results demonstrate that stimulation of GABA_A and μ-opioid receptors within the AcbSh is able to promote not only food intake, but also food-directed operant behavior. In contrast, stimulation of AcbSh dopamine receptors may enhance behavioral arousal, but does not appear to specifically potentiate behaviors directed toward food procurement.