Amphetamine increases schedule-induced drinking reduced by negative punishment procedures

Rationale. d-Amphetamine has been reported to increase schedule-induced drinking punished by lick-dependent signalled delays in food delivery. This might reflect a drug-behaviour interaction dependent on the type of punisher, because no such effect has been found when drinking was reduced by lick-contingent electric shocks. However, the anti-punishment effect of amphetamine could be mediated by other behavioural processes, such as a loss of discriminative control or an increase in the value of delayed reinforcers. Objectives. To test the effects of d-amphetamine on the acquisition and maintenance of schedule-induced drinking reduced by unsignalled delays in food delivery. Methods. Rats received 10-s unsignalled delays initiated by each lick after polydipsia was induced by a fixed-time 30-s food reinforcement schedule or from the outset of the experiment. Yoked-control rats received these same delays but independently of their own behaviour. d-Amphetamine (0.1–3.0 mg/kg) was then tested IP. Results. d-Amphetamine dose-dependently increased and then decreased punished schedule-induced drinking. The drug led to dose-dependent reductions when the delays were not contingent or when they were applied from the outset of training. Conclusions. These results support the contention that d-amphetamine has an increasing effect on schedule-induced drinking that has been previously reduced by a negative punishment procedure. This effect cannot be attributed to other potentially involved processes, and therefore support the idea that drug effects on punished behaviour depend on punishment being delays in food or shock deliveries. Electronic Publication     

Pharmacological analysis of the effects of benzodiazepines on punished schedule-induced polydipsia in rats

Food-deprived Wistar rats were exposed to a fixed-time 60-s food delivery schedule until they developed schedule-induced polydipsia. Every fifth lick was then followed by an electric shock during two, signalled, 5-min periods, which ran concurrently with the food delivery schedule. Shock intensities were adjusted to reduce licking to 60-70% of the unpunished licking rates. The benzodiazepine full agonists, diazepam (0.3-3.0 mg/kg), chlordiazepoxide (0.3-10.0 mg/kg), oxazepam (0.3-3.0 mg/kg) and the benzodiazepine partial agonist, RU-32698 (3.0-17.0 mg/kg), led to increases in punished responding at intermediate doses and decreases at the highest doses tested. All benzodiazepine agonists brought about dose-dependent decreases in unpunished schedule-induced polydipsia, with doses required to reduce drinking proving higher than doses required to increase punished schedule-induced polydipsia. The antipunishment effect of 0.3 mg/kg of diazepam was dose-dependently antagonized by flumazenil and the benzodiazepine inverse agonist, RU-34000. Flumazenil effects, however, could reflect actions of flumazenil as a partial inverse agonist at GABAA receptors. RU-32698 at 10.0 mg/kg further facilitated the rate-increasing effect of 0.3 mg/kg of diazepam, but at 17.0 mg/kg partially blocked such antipunishment effect. Overall, the present results extend the similarities of the effects of benzodiazepine compounds on adjunctive and operant patterns of behaviour by showing similar interactions within the benzodiazepine receptor complex.     

Effects of d-amphetamine, diazepam and buspirone on schedule-induced polydipsia suppressed by response-dependent and response-independent shock

Food deprived Wistar rats were exposed to a fixed time 60 s food schedule until they developed schedule-induced polydipsia. Rats were matched in pairs according to their licking rate, being designated experimental or yoked control at random. Every fifth lick by experimental rats was then followed by an electric shock (0.05, 0.1, or 0.2 mA) while the food schedule continued in operation. Yoked-control rats received the same shocks as experimental rats, but independently of their own licking. Drugs were then tested on the suppressed rates of licking. Diazepam (0.5-2.0 mg/kg) increased punished schedule-induced polydipsia, a result not observed in yoked controls. No increases in the licks per minute of experimental or control animals were found after d-amphetamine (0.25-4.0 mg/kg) or buspirone (0.5-8.0 mg/kg). In comparison with previous results it is concluded that the antipunishment effects of drugs on schedule-induced behaviour depend on the type of punishment contingency.     

Antipunishment effects of diazepam on two levels of suppression of schedule-induced drinking in rats

Food-deprived Wistar rats were exposed to a fixed-time (FT) 60-s food delivery schedule until they developed schedule-induced drinking. Rats were matched in pairs according to their licking rates and were designated master or yoked at random. Every fifth lick by master rats was followed by an electric shock during two signalled 5-min periods, which ran concurrently with the food delivery schedule. For the master rats, shock intensities were adjusted to reduce licking to 5-30% (low suppression) or 50-75% (high suppression) of the unpunished licking rates. Yoked rats received the same shocks as master rats, but independently of their own licking. The drinking by yoked animals was not decreased by the presentation of these lick-independent shocks. Diazepam (0.3-10.0 mg/kg) was studied for its effects on punished and nonpunished schedule-induced drinking. Intermediate doses of the drug increased the punished behavior of master rats, but only when schedule-induced drinking was highly suppressed. Diazepam dose dependently decreased licking rates in all other conditions. The antipunishment effects of benzodiazepines may depend on the level of suppression of schedule-induced drinking, and this is in keeping with the results of other experimental preparations where behavior was under aversive control.     

Effects of d-amphetamine and of diazepam on non-punished and punished schedule-induced drinking in rats

Drinking induced in food-deprived rats by a Fixed-Time 1min schedule of food presentation was measured by the amount of water consumed per session and the number of licks per inter-food interval. Subsequently each lick initiated a 10-sec signalled delay in the delivery of food, which led to a decrease in drinking (punishment). With three rats the effects of d-amphetamine (0.25, 0.5, 1.0, 2.0mg/kg) were assessed on non-punished and then on punished drinking. With another three rats, the effects of diazepam (0.5, 1.0, 2.0, 4.0mg/kg) were assessed. The smaller doses of d-amphetamine had no consistent effect on overall measures of non-punished schedule-induced drinking, but the largest dose decreased them. With the signalled delay d-amphetamine increased punished schedule-induced drinking. Non-punished drinking was increased by small doses of diazepam and decreased by the largest dose, but no dose of diazepam affected punished drinking.     

Level of response suppression and amphetamine effects on negatively punished adjunctive licking

The purpose of the present study was to investigate whether the level of response suppression is a major determinant of the effect of D-amphetamine on negatively punished adjunctive drinking. Rats were initially exposed to a multiple fixed-time (FT) 30-s FT 30-s food delivery schedule. They were then divided into two groups and subjected to one of two different multiple schedules, FT 30-s FT 45-s or FT 30-s FT 90-s. The FT 45-s and FT 90-s components were signalled by a tone. Comparably high levels of adjunctive licking were observed in both FT 30-s components, intermediate licking levels in the FT 45-s component, and little licking in the FT 90-s component. Licking during the FT 30-s components was subsequently punished by lick-contingent signalled delays (by a blackout) in food delivery. The duration of such delays was adjusted to reduce licking to levels obtained in the FT 45-s or FT 90-s components, respectively for each of the two groups. Punished licking was increased by 0.3 and 1.0 mg/kg of D-amphetamine, an effect that was greater in the FT 30-s FT 90-s group. No increase in licking was observed in the FT 45-s component, but the 1.0 mg/kg dose also increased responding in the FT 90-s component. In general, no statistically significant differences were found between the effects of D-amphetamine on punished and unpunished schedule-induced licking. As licking decreased during the FT 90-s component when the punishment contingency was introduced in the alternate component, the punishment procedure and FT 30-s component were entirely removed. On this occasion, D-amphetamine failed to increase licking induced by the FT 90-s schedule. These results indicate that the level of response suppression might be a good indicator of the degree to which D-amphetamine shows antipunishment effects on adjunctive licking reduced by negative punishment procedures.     

Effects of melatonin and agomelatine in anxiety-related procedures in rats: interaction with diazepam.

The anxiolytic potential of melatonin and agomelatine, a potent MT(1/2) receptor agonist, and their combined effects with diazepam, were investigated in rats using the punished drinking test, the safety signal withdrawal operant paradigm, the elevated-plus-maze and hypophagia-induced novelty. In the punished drinking test, evening injections of melatonin (80 mg/kg, IP, but not 20 and 40 mg/kg) and agomelatine (40 mg/kg, IP) increased the number of foot shocks received. However, neither melatonin (40-80 mg/kg) nor agomelatine (20-40 mg/kg) released response suppression during the period associated with the safety signal withdrawal and affected rats' behaviour in the elevated-plus-maze. Furthermore, agomelatine (40 mg/kg) did not enhance food consumption in unfamiliar environment. However, the co-administration of melatonin (80 mg/kg) or agomelatine (20-40 mg/kg) with diazepam, at a dose (0.25 mg/kg) inactive on its own, induced an anxiolytic-like effect in the punished drinking test and the elevated plus-maze. These results indicate that, although mostly devoid of anxiolytic-like action per se, melatonin and agomelatine can potentiate the anxiolytic effects of diazepam.     

Interaction of d-amphetamine with pentobarbital and chlordiazepoxide: Effects on punished and unpunished behavior of pigeons

Key pecking of two pigeons was maintained under a multiple schedule of food presentation. In the presence of one keylight stimulus responding produced food according to a fixed-interval 5-min schedule. Additionally, during this component, each 50th response produced electric shock. When a different keylight stimulus was present, key pecking resulted in food delivery under a variable-interval 3-min schedule. Responding was suppressed by schock presentation (punishment) but was still positively accelerated throughout each fixed-interval cycle; steady response rates occurred during the alternate component when only the variable-interval schedule was in effect. Overall rates of punished responding were largely unchanged with d-amphetamine (0.1–3.0 mg/kg); unpunished responding was generally either increased slightly or was decreased. Pentobarbital and chlordiazepoxide (1.0–17.0 mg/kg) administered alone increased both punished and unpunished responding at most doses. Combinations of d-amphetamine with either pentobarbital or chlordiazepoxide produced increases in punished responding that exceed those obtained with either of these drugs alone. The combined effects of d-amphetamine and either pentobarbital or chlordiazepoxide on unpunished responding depended on the individual dose combinations. Combinations of d-amphetamine with pentobarbital or chlordiazepoxide produced effects on both punished and unpunished responding that differed substantially from those obtained when any of these drugs were administered separately.     

Selective suppression of schedule-induced ethanol drinking by antialcoholic drugs in rats

Effects of disulfiram and calcium cyanamide, antialcoholic drugs, on schedule-induced ethanol drinking as well as on schedule-controlled response (lever-pressing) under a fixed interval 1 min schedule of food reinforcement were investigated in Wistar strain rats. When ethanol solution was available, the schedule-induced ethanol drinking decreased depending on the ethanol concentration (2-8%). However, the dose of ethanol intake during the 1 hr experimental session was at maximum (2.8 g/kg) when 4% ethanol solution was available. Thereafter, 4% ethanol solution was used in the experiment for studying the effects of disulfiram and calcium cyanamide on the schedule-induced ethanol drinking. Disulfiram (100-200 mg/kg, p.o.), pretreated at 1 hr before the start of the experiment, tended to suppress schedule-induced water drinking. However, the same treatment of calcium cyanamide (5-10 mg/kg, p.o.) did not produce a marked change in it. In contrast, disulfiram (100 and 200 mg/kg) and calcium cyanamide (5 and 10 mg/kg) markedly suppressed schedule-induced ethanol drinking without eliciting a marked change in schedule-controlled response. The present results suggest that both disulfiram and calcium cyanamide selectively suppress ethanol drinking in rats.     

Effects of chlordiazepoxide on schedule-induced water and alcohol consumption in the squirrel monkey

Lever pressing of five squirrel monkeys was maintained by a 3-min fixed-interval schedule of food presentation. 3 monkeys had water concurrently available and, for a second pair of monkeys, initially water, then increasing concentrations of alcohol (1–3% v/v) were present. Substantial amounts of post-pellet drinking occurred with all five monkeys. The amount of water ingested was approximately 100 ml per session, that of 3% alcohol nearly 63 ml. For the monkeys drinking alcohol, increasing concentrations of alcohol decreased both the rate of lever pressing and the volume of fluid consumed. Chlordiazepoxide (1.0–17.0 mg/kg) produced increases in lever pressing and in the schedule-induced consumption of both 3% alcohol and water.     

Nicotine and schedule-induced drinking in rats

In the first experiment 4 rats developed schedule-induced water drinking during daily 1 hr sessions of a fixed-time 1 min schedule of food pellet delivery. Injections of a range of doses (0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg) of nicotine hydrogen tartrate were found to produce a dose related attenuation of water intake. The higher doses also reduced the numbers of entries into the food tray in three rats, while the lowest dose consistently facilitated this behavior in the same animals. In a second experiment schedule-induced water drinking developed in 4 other rats under a similar schedule. Substitution of nicotine solution (0.05 and 0.1 mg/ml) for the water reduced volumes of fluid consumed. However, schedule-induced drinking continued at a rate sufficient for the animals to ing-st average doses of the nicotine salt of up to 8.5 mg/kg. It is concluded that schedule-induced drinking can be used successfully as a method of inducing self-administration of nicotine by rats.     

Patterns of drinking in the rat following the administration of opiate antagonists

Durations of drinking were recorded for water-deprivated rats as they drank to satiety, following SC injections of naloxone (0.1–10.0 mg/kg), naltrexone (0.1–10.0 mg/kg) or saline vehicle. The results provided evidence for the effects of opiate antagonists on the temporal pattern of drinking exhibited by water-deprived animals. A separate, time-sampling procedure was used to supplement the drinking duration data, and showed that the opiate antagonists may suppress water consumption during a period 2.5–7.5 min after the start of the initial drinking bout. A second experiment confirmed that the pattern of drinking displayed during schedule-induced polydipsia in the rat is resistant to any suppressant effect of a moderate dose of an opiate antagonist. The similiarity between opiate receptor blockade and water preloading in their effect on drinking in response to water deprivation, and lack of effect on schedule-induced polydipsia is discussed. Opiate antagonists may affect drinking principally by imposing a thirst satiety signal.     

Olanzapine,an atypical antipsychotic,increases rates of punished responding in pigeons

The effects of olanzapine [LY 170053; 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2, 3b][1,5]benzodiazepine), a potential atypical antipsychotic, were determined in pigeons whose keypeck responding was punished. These effects were compared to the anxiolytic agents chlordiazepoxide and pentobarbital, and to other antipsychotic agents. Keypeck behavior was maintained under a multiple FR30 FR30 schedule, signalled by white and red stimulus lights, respectively. Each component of the schedule alternated every 3 min with a 30-s timeout. During the white keylight component, responding was maintained by food presentation. During the red keylight component, responding was maintained by food and simultaneously suppressed by electric shock presentation, with response rates being only about 5% of those during the white stimulus light. Olanzapine (0.01–1.0 mg/kg) increased punished responding at doses below those which had an effect on unpunished responding. Clozapine (0.01–1.0 mg/kg), ritanserin (0.1–3.0 mg/kg), and, to a lesser extent, risperidone (0.1–1.0 mg/kg) were also effective at increasing punished responding. Generally, the maximum effect seen with olanzapine was equal to that seen with ritanserin, and it exceeded that seen with clozapine. However, these effects were generally less than those seen with chlordiazepoxide and pentobarbital. Haloperidol (0.01–0.1 mg/kg) was completely without effect on punished responding, while it caused decreases in unpunished behavior. These results provide further evidence that olanzapine has a profile in behavioral tests unlike the typical antipsychotic haloperidol. Moreover, this profile is similar to clozapine, a clinically effective antipsychotic with an atypical profile.     

The differential effects of naloxone hydrochloride on the acquisition and maintenance of schedule-induced polydipsia

Rats injected with the opiate antagonist, naloxone hydrochloride (10 mg/kg), 15 min prior to sessions in which they were given free food on a fixed time 75-sec schedule, displayed retarded acquisition of schedule-induced polydipsia relative to vehicle-injected subjects. Rats injected with naloxone after schedule-induced polydipsia had been acquired were unaffected, i.e., they continued to drink at control levels. Given that schedule-induced polydipsia has been considered non-opioid in nature, because of previous reports of its insensitivity to naloxone, the present report of differential effects of naloxone on the acquisition and maintenance of schedule-induced polydipsia suggests that some modification of this conclusion is necessary. Possible alternative mechanisms for these differential effects are discussed.     

Effects of naloxone, β-endorphin and ACTH on acquisition of schedule-induced polydipsia

A series of three experiments examined the possible involvement of endogenous opioid peptides in the development of schedule-induced polydipsia in rats. Repeated pretraining treatment with 2 mg/kg naloxone impaired acquisition of schedule-induced polydipsia, whereas the same treatment injected after training increased drinking. This later effect was time dependent, since a 30-min delay in the injection of naloxone resulted in a disappearance of its effect. Post-training injections of 10 g/kg -endorphin or ACTH delayed the development of drinking. These findings are consistent with the hypothesis that endogenous opioid peptides modulate the development of schedule-induced polydipsia.     

Schedule-induced drinking and thirst: a pharmacological analysis.

Similar levels of water consumption were induced in two groups of rats by means either of prior fluid deprivation or a schedule of food pellet delivery. Injections of d-amphetamine (0.25, 0.5, 1.0 and 2.0 mg/kg) had similar attenuating effects of drinking induced by both procedures. Chlordiazepoxide (2.5, 5.0, 10 and 20 mg/kg), however, exerted differential actions on schedule-induced and deprivation-induced drinking. Drinking induced by deprivation was facilitated by all doses of this drug while the higher doses decreased levels of schedule-induced drinking. This result emphasises the difficulties involved in using the concept of thirst in explanations of behavior and of drug action.     

Effects of diazepam,FG 7142, and RO 15-1788 on schedule-induced polydipsia and the temporal control of behavior

Although benzodiazepine agonists and inverse agonists have opposite effects on drinking elicited by water deprivation, there is much less information about the effects of these drugs on nonhomeostatic drinking. In this experiment the effects of diazepam (0.3–5.0 mg/kg), a benzodiazepine receptor agonist, and FG 7142 (1.0–9.0 mg/kg), an inverse agonist, were determined on drinking elicited by a FT-60 schedule of food delivery (SIP). Both diazepam and FG 7142 dose-dependently reduced SIP, measured as either licking or volume consumed. In addition, diazepam reduced panel pressing for food, decreased locomotor activity, and changed the time course of each behavior. In contrast, FG 7142 reduced schedule-induced drinking without significantly altering other behaviors. The antagonist RO 15-1788, when given in combination with these drugs, only partially restored the reductions in licking produced by diazepam, but was much more effective in reversing the effects of FG 7142 at doses of the antagonist that failed by themselves to affect responding. The opposite pattern of effects was seen on the volume of water consumed. These effects are discussed in terms of the behavioral and pharmacological specificity of these drugs.     

Anxiolytic-like effects of alpha-2-adrenoceptor agonists on conflict behavior in the rat: pre- versus postsynaptic receptor mechanisms.

The effects of acute pretest administration and chronic posttest administration of clonidine or the selective alpha 2-adrenoceptor agonist UK-14,304 on conflict behavior were investigated. In daily 10-min sessions, water-deprived rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. Prior to treatment, subjects accepted 25-30 shocks/session (punished responding) and consumed approximately 12-15 ml/session (unpunished responding). Acute pretest administration of clonidine or UK-14,304 did not increase punished responding. In contrast, chronic posttest clonidine administration (40 micrograms/kg, IP, twice daily for 8 weeks) resulted in a robust and time-dependent increase in punished responding (60-70 shocks/session) relative to saline-treated controls. Moreover, the selective alpha 2-adrenoceptor agonist UK-14,304 also increased punished responding when administered chronically (1.0 mg/kg, BID). Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine HCl (DSP4, 65 mg/kg, IP) significantly decreased punished responding in control conditioned suppression of drinking sessions. The anticonflict effect associated with chronic posttest clonidine treatment was not altered by DSP4 pretreatment. These findings suggest that chronic posttest alpha 2-adrenoceptor agonist treatment produces an anticonflict effect independent of its actions at presynaptic alpha 2-adrenoceptors.     

Lack of central 5-hydroxytryptamine influence on the anticonflict activity of diazepam

This study examined the effects of various drug treatments (IP injections) proposed to modify central 5-hydroxytryptamine (5-HT) activity on a conditioned suppression of drinking behavior in water-deprived rats. The subjects were trained to drink their daily water requirement during a 10-min session. Intermittent tone periods of 7 s were then introduced, the last 5 s of which the drinking tube was electrified. The animals gradually suppressed tube contacts during the tone to a low constant level within 2 weeks of training. Diazepam increased punished responding dramatically. The 5-HT antagonists methysergide (1–18 mg/kg), cyproheptadine (1–18 mg/kg), metergoline (0,25–2.0 mg/kg) and cinanserin (10–100 mg/kg) failed to induce large, reliable increases in punished responding. When a low dose of diazepam was combined with 5-HT antagonists, only one treatment, methysergide at 3 mg/kg, potentiated the anticonflict activity of diazepam. Acute or chronic treatment with PCPA increased behavior suppressed by punishment, but this effect was weak, brief, and poorly related to the depletion of brain 5-HT. LSD (0.3–100 g/kg) administered 1,10, or 30 min before the test was ineffective in overcoming suppression by punishment. Mescaline (6–30 mg/kg) had no significant effect on punished responding. 5-HTP (18 mg/kg) decreased the number of shocks accepted, but not after pretreating with carbidopa. Pretreatment with carbidopa plus 5-HTP potentiated the anticonflict effect of diazepam. The 5-HT agonist mCPP (0.25–2.0 mg/kg) enhanced suppression due to punishment, but only in doses that interfered with unpunished responding. The 5-HT-releasing agent fenfluramine (0.25–1.0 mg/kg) did not affect this behavior. Amitriptyline pretreatment in a dose not affecting unpunished behavior (5.6 mg/kg) potentiated the diazepam-induced increase in punished responding. These results are difficult to reconcile with the proposal that suppression of behavior consequent to punishment is related to brain 5-HT activity.     

Effects of cocaine microinjections into the nucleus accumbens and medial prefrontal cortex on schedule-induced behaviour: comparison with systemic cocaine administration

The effects of cocaine HCl infusions into either the nucleus accumbens (NACC) or medial prefrontal cortex (PFC) were compared on the performance of schedule-induced polydipsia (SIP) and related behaviours. Food-deprived rats were exposed to a fixed-time 60-s schedule of food delivery in daily 30-min sessions until stable levels of behaviour were obtained (14 days). Rats were then bilaterally infused with cocaine into either the NACC or PFC via chronically indwelling guide cannulae. Each subject received a sequence of five cocaine infusions (0, 12.5, 25, 50, 100 µg) according to a Latin Square design. For comparison, following these intracranial infusions each rat received a sequence of five IP injections of cocaine (0, 2.5, 5, 10, 20 mg/kg) also in a counterbalanced order. NACC and PFC infusions of cocaine and IP cocaine dose-dependently reduced SIP. Cocaine infusions into the NACC, but not the PFC, increased locomotor activity but the characteristic temporal profile of locomotor activity during SIP was retained. IP cocaine also increased locomotor activity in a dose-dependent manner, but the temporal profile of activity was flattened following 20 mg/kg cocaine. NACC and PFC infusions of cocaine had little effect on the total number of panel presses to gain access to the food pellets, but did slightly decrease the high rates of responding immediately prior to the pellet delivery. IP cocaine increased the total number of panel presses at the higher doses, mainly by increasing the low rates of responding. The effects of cocaine infusions into the PFC were behaviourally the most selective, as they reduced SIP without having substantial effects either on locomotor activity or panel pressing. These data therefore implicate a role for the PFC in the performance of SIP.