The abolition of the partial reinforcement extinction effect (PREE) by amphetamine

The effects of amphetamine administration on the partial reinforcement extinction effect (PREE) at one trial a day, were examined. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasirandom 50% schedule. All animals were then tested inextinction. dl-Amphetamine 1.5 mg/kg was administered in a 2×2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction exhibited by PRF animals as compared to CRF animals, was obtained in animals that received saline in acquisition, independently of drug treatment in extinction. In contrast, amphetamine administered in acquisition abolished the PREE irrespective of drug treatment in extinction. In addition, amphetamine administered in extinction alone increased resistance to extinction in PRF animals.     

The effects of clonidine on the partial reinforcement extinction effect (PREE)

Clonidine has been reported to exert anti-anxiety effects in animals and man similar to those of benzodiazepines. The present experiment examined the effects of clonidine administration on the partial reinforcement extinction effect (PREE) which is known to be sensitive to benzodiazepine action. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Clonidine 50 g/kg was administered in a 2×2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction exhibited by PRF animals as compared to CRF animals, was obtained in animals that received saline in acquisition, independently of drug treatment in extinction, as well as in animals that received clonidine in both acquisition and extinction, but not in animals that received clonidine in acquisition alone. The administration of clonidine in extinction alone increased resistance to extinction in both the CRF and PRF animals. The increase in resistance to extinction, typically obtained with benzodiazepine treatment, indicates that clonidine exerts anxiolytic effects, supporting the involvement of the noradrenergic system in anxiety. However, clonidine did not fully reproduce the effects of benzodiazepines on the PREE, suggesting that the two classes of drugs may act via different noradrenergic mechanisms.     

Corticotropin releasing factor and amphetamine exaggerate partial agonist properties of benzodiazepine antagonist Ro 15-1788 in the conflict test

The central nervous system stimulants corticotropin releasing factor (CRF) and amphetamine were administered in combination with the benzodiazepine ligands Ro 15-1788 and FG 7142 in order to assess their benzodiazepine agonist and antagonist receptor properties in an operant conflict test in rats. Ro 15-1788, which was without behavioral activity in this test when given alone, reversed the suppression of punished responding produced by CRF and amphetamine in a dose-dependent manner. Chlordiazepoxide, which produced a release of punished responding by itself, also reversed the suppression of punished responding produced by CRF but not that of amphetamine. The benzodiazepine inverse agonist FG 7142, in contrast, enhanced the rate suppressing actions of both CRF and amphetamine. In a locomotor activity test, Ro 15-1788 failed to block the locomotor activation observed with CRF and amphetamine. The results suggest that anxiety or stress-enhancing compounds may enhance the partial agonist properties of Ro 15-1788 in certain test situations.     

The abolition of the partial reinforcement extinction effect (PREE) by amphetamine: disruption of control by nonreinforcement

Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received a food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. d-Amphetamine 1 mg/kg was administered to PRF animals in acquisition in a 2 X 2 design, i.e., drug-no drug on reinforced trials and drug-no drug on nonreinforced trials. In four CRF groups, the drug was administered in the same sequence as in the PRF groups. Following acquisition, all animals were given 4 days of CRF retraining and tested in extinction. No drug was given in retraining and extinction. The PREE, i.e., increased resistance exhibited by PRF animals as compared to CRF animals, was obtained in groups which received placebo on all acquisition trials or amphetamine on rewarded trials and placebo on nonrewarded trials. The PREE was abolished when amphetamine was administered throughout the acquisition trials or on nonrewarded trials, irrespective of drug treatment on rewarded trials.     

Ethanol consumption reduces the adverse consequences of self-administered intravenous cocaine in rats

Rationale Human drug users report that the initial positive effects of cocaine are followed by a dysphoric state characterized by anxiety and drug-craving. As a means of presumably attenuating these negative aftereffects, 50–90% of cocaine users choose to co-administer ethanol during cocaine binges. This co-administration reportedly prolongs the high and diminishes the low associated with cocaine use.Objective The current study was intended to assess whether this phenomenon could be modeled in the animal laboratory. We have previously shown that animals running a straight alley for an intravenous cocaine reward develop a unique approach-avoidance conflict behavior that is characterized by stop and retreat behaviors as the subjects approach the goal box. The retreats are thought to reflect the concurrent positive (reward) and negative (anxiety) associations with the goal box and can be dose-dependently reduced by pretreatment with diazepam, which presumably attenuates the anxiety stemming from the conflict.Methods To test the role of ethanol in reducing cocaine-induced anxiety, rats were trained to run a straight-arm alley for a single daily injection of cocaine (1.0 mg/kg IV).Results Rats that had the opportunity to then drink either an 8% or a 4% sucrose–ethanol solution immediately following their daily runway trial came to exhibit fewer retreats than rats that did not drink ethanol following their cocaine injection.Conclusions These results suggest that ethanol effectively reduces the development of approach-avoidance conflict in animals running an alley for IV cocaine, a result that may account for the prevalence of cocaine–ethanol co-administration in humans.     

Behavioural effects of intracerebral amphetamine in the marmoset

Marmosets were implanted bilaterally with guide cannulae so that d-amphetamine could be delivered to sites within the anterior neostriatum. Six animals received a series of bilateral amphetamine (20 g) and saline injections to six sites 1 mm apart on a line passing through the caudate and accumbens nuclei. A second group of six animals received a range of doses (0, 5, 10, 20, 40 g) of amphetamine bilaterally to one caudate and one accumbens site only. Drug injected into the accumbens produced a dose-related increase in checking (small head movements) and locomotion and a decrease in social interaction and inactivity. Drug injected into the caudate did not affect these behaviours, except for checking which was increased by the highest dose.     

Testing cyclic AMP mediation of memory: Reversal of α-methyl-p-tyrosine-induced amnesia

Treatments that increased intracellular cyclic 3, 5 adenosine monophosphate (cAMP) levels following catecholamine depletion caused by -methyl-p-tyrosine (AMPT) provided a prophylactic effect against AMPT-induced amnesia. This effect gives evidence that cAMP mediated the formation of memory. In Experiment I, the phosphodiesterase inhibitor papaverine (50 mg/kg), immediately after a one-trial acquisition task, functionally increased cAMP levels and prevented amnesia 3 h after treatment with AMPT (200 mg/kg) for New Zealand A strain (NZ/A) mice tested in a step-through passive avoidance apparatus. Retention test latencies 72 h later were significantly higher for animals that received only saline and for animals that received AMPT and papaverine than for animals that received AMPT and saline (the amnesic group). In a similar task (Experiment II), mice that received an intracerebroventricular injection of either 5 or 10 g dibutyryl cAMP immediately after acquisition and 3 h after AMPT administration showed significantly higher retention test latencies than animals that received AMPT and saline. The AMP plus 10 g dibutyryl cAMP group showed facilitated performance even compared to the saline plus saline group.     

Anxiolytic properties of amygdaloid kindling unrelated to benzodiazepine receptors

We investigated the possibility that repeated electrical stimulation of the basolateral amygdala (kindling) would increase punished behavior, a pre-clinical indicator of anti-anxiety activity. Male Sprague-Dawley rats, prepared with electrodes in the left basolateral nucleus and frontal cortex, were trained to bar-press under a multiple schedule in which either every 30th response produced food (no punishment) or every 10th response produce both food and a brief electric shock (punishment). Rates of punished responding were less than 10% of non-punished values. Brief electrical stimulation of the amygdala occurred biweekly, and the current levels were incremented from subconvulsive values (50 A) to suprathreshold levels (150 A). Electrical stimulation increased punished responding without concomitant changes in nonpunished behavior; increases were most pronounced in fully-kindled rats. Fullykindled animals also demonstrated the largest primary afterdischarge. Electrical stimulation of the frontal cortex induced similar seizure and convulsive patterns but did not increase punished responding. Anxiolytic activity of amygdaloid stimulation was not prevented by the selective benzodiazepine antagonist Ro 15-1788, which antagonized similar behavioral effects of chlordiazepoxide. Thus, kindling of seizures in the amygdala results in behaviorally and neuroanatomically specific antianxiety actions which do not depend upon receptor sites blocked by Ro 15-1788 (benzodiazepine receptors).Research was conducted in compliance with the Animal Welfare Act, and other Federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NIH publication 85-23. The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense, (para 4-3, ARR 360-5). A preliminary report of these results was published in Fed Proc 46: 1302 (1987)     

Paroxetine combined with a 5-HT1A receptor antagonist reversed reward deficits observed during amphetamine withdrawal in rats

Rationale Diminished interest or pleasure in rewarding stimuli is an affective symptom of amphetamine withdrawal and a core symptom of depression. An operational measure of this symptom is elevation of brain stimulation reward thresholds during drug withdrawal. Data indicated that increasing serotonin neurotransmission by co-administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the serotonin-1A receptor antagonist p-MPPI reversed reward deficits observed during drug withdrawal (Harrison et al. 2001).Objectives We tested the hypothesis that increased serotonergic and noradrenergic neurotransmission, using the SSRI paroxetine which also inhibits noradrenaline reuptake, would alleviate affective aspects of amphetamine withdrawal.Methods A discrete-trial, current-threshold, self-stimulation procedure was used to assess brain reward function. The effects of paroxetine and p-MPPI alone and in combination were assessed in non-drug-withdrawing animals. We assessed also the effects of paroxetine and p-MPPI alone and in combination on reward deficits associated with amphetamine withdrawal.Results Paroxetine or p-MPPI alone had no effect on thresholds, while the co-administration of p-MPPI (3 mg/kg) and paroxetine (1.25 mg/kg) elevated thresholds in non-withdrawing rats. Amphetamine withdrawal resulted in threshold elevations. The co-administration of p-MPPI and paroxetine reduced the duration of amphetamine-withdrawal-induced reward deficits.Conclusions Increased serotonergic and noradrenergic neurotransmission decreased reward function in non-withdrawing rats, while the same treatment reversed reward deficits associated with amphetamine withdrawal. Considering that paroxetine acts on both the serotonin and noradrenaline transporter, these results indicate that the affective symptoms of amphetamine withdrawal, similar to non-drug-induced depressions, may be, in part, mediated through reduced serotonergic and noradrenergic neurotransmission.     

The development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment

Two experiments were designed to assess the effect of a novel environment on the development of sensitization to the psychomotor activating effects ofd-amphetamine. In the first experiment, rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopamine system received ten daily injections of amphetamine (2 mg/kg), either in their home cages or in novel test cages. The home and novel cages were physically identical (cylindrical transparent buckets), but one group lived and were tested in these cages, whereas the other group was transported from the stainless steel hanging cages where they lived to these novel test cages, for each test session. The first injection of amphetamine produced significantly more rotational behavior in animals tested in a novel environment than in animals tested at home. In addition, animals tested in a novel environment showed greater sensitization than animals tested at home, so the difference between the two groups was even more pronounced following the last injection. In a second experiment, locomotor activity was quantified in rats that received ten injections of either saline or 1.5 mg/kg amphetamine, in their home cages or in a physically identical novel environment. Again, there was a significantly greater locomotor response to the first injection of amphetamine, and greater sensitization, in animals tested in a novel environment than in animals tested at home. These data indicate that environmental factors can exert a large effect on the susceptibility to sensitization, and mechanisms by which this may occur are discussed.     

Transient disruption of attentional performance following escalating amphetamine administration in rats

Rationale Attentional deficits are thought to be critically involved in the development of positive symptoms in schizophrenia. The present experiment tests the general hypothesis that sensitization of the mesolimbic dopaminergic system contributes to the attentional deficits in schizophrenia.Objectives The present study assessed attentional performance following administration of an escalating amphetamine regimen and subsequent challenge amphetamine administration in rats.Methods Rats were trained to perform a two-lever sustained attention task that involved discrimination of visual signals and no signal presentation. After reaching criterion, subjects were assigned to receive escalating amphetamine or saline. Attentional performance was assessed immediately following escalating amphetamine, following challenge amphetamine administration (1.0 mg/kg) to amphetamine-pretreated rats, and for 3 days after the challenge session. At the end of this experiment, a dose-response study was conducted with saline-pretreated rats to confirm the appropriateness of the challenge dose.Results Amphetamine-pretreated animals demonstrated a transient increase in errors on non-signal trials following escalating amphetamine administration. The latency to press a lever was decreased during and after challenge amphetamine administration. Administration of 1.0 mg/kg amphetamine did not alter accuracy of amphetamine-pretreated animals or of saline-pretreated animals in the dose-response experiment.Conclusions Prior escalating amphetamine administration transiently disrupted attention, increasing incorrect claims for a signal on trials when no signal was presented. The present data support the existing literature that escalating amphetamine regimens may be useful to model the attentional deficits that contribute to the psychotic symptoms in schizophrenia.     

Dissociation of learning in marihuana tolerant rats

Rats previously trained to climb a rope were injected daily with a marihuana extract; the drug initially impaired the performance but after 14 injections the animals became completely tolerant. The rats were then trained to press either one of the 2 bars of a Skinner box. On each day only one of the bars was activated to deliver the reward; 45 min before the experiment an injection of cannabis extract (left bar) or of control solution (right bar) was given. After 30 injections the animals learned which bar to press in order to obtain the reward, indicating that they were still using some effect of marihuana as a discriminative stimulus. This dissociation of learning produced in marihuana tolerant rats, (as measured by rope-climbing), indicates that tolerance is not complete. Furthermore, as dissociation of learning is not produced by peripheral effects of drugs, it is suggested that even after chronic treatment marihuana continues to act on the central nervous system.Work partially aided by FundaÇÃo de Amparo à Pesquisa do Estado de Sao PÃulo (FAPESP) and Conselho Nacional de Pesquisas (CNPq). Read before the Annual Meeting of the Brazilian Society of Pharmacology and Experimental Therapeutics, SÃo Paulo, May 1971.With fellowship from FAPESP.     

An evaluation of the young dopamine-lesioned rat as an animal model for minimal brain dysfunction (MBD)

Three main symptoms of minimal brain dysfunction (MBD), a common disorder in children, are hyperactivity, learning disabilities, and attention deficits. Drugs like amphetamine and methylphenidate have been demonstrated to produce a significant behavioral improvement in these children. The behavioral response of young rats (3–4 weeks), with selective lesioning of the central dopaminergic system, to a novel environment was analyzed. Both the frequencies and durations of eight mutually exclusive and complementary behavioral categories were scored. By analyzing the behavior in this way it appeared that considerable hyperactivity and leaning disabilities could be demonstrated in these rats. Moreover, the bout length of some behavioral categories was somewhat shortened, which might be an indication of deficits in attention. However, treatment of the animals with amphetamine did not produce any therapeutic effect on the three symptoms. Since pharmacotherapeutic support is, in our opinion, a conditio sine qua non for the validity of the model, we do not believe that the young DA-lesioned rat is an appropriate animal model for MBD.     

Behavioral interactions of fluoxetine and other 5-hydroxytryptamine uptake inhibitors with ethanol in tests of anxiety,locomotion and exploration

The effects of haloperidol 0.1 mg/kg on the partial reinforcement extinction effect (PREE) paradigm at one trial a day, were examined. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasirandom 50% schedule. All animals were then tested in extinction. Haloperidol 0.1 mg/kg was administered in a 2 × 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction of partially reinforced as compared to continuously reinforced animals, was obtained in all four drug conditions. The administration of haloperidol in acquisition increased markedly resistance to extinction in CRF animals. The administration of the drug in extinction decreased resistance to extinction in both CRF and PRF animals. The results are explained in terms of two independent actions of haloperidol: the well-known effect of reduction in the effectiveness of reinforcement as well as enhancement of the effectiveness of nonreinforcement.     

Self-injection of amphetamine directly into the brain

Rats learned to self-administer d-amphetamine (10 g/l) through a cannula implanted in the nucleus accumbens. They responded more frequently for 65±15 nl of amphetamine than for equal amounts of saline. When presented with two levers (one amphetamine, one blank) they responded more on the correct lever for amphetamine. They would also switch levers, when necessary, to maintain access to the drug. When half the usual drug intake was given automatically, animals reduced their response rate by half, thus self-regulating the total amount of amphetamine they received. In tests for leakage into the ventricles, eight rats that self-injected with an accumbens cannula showed response extinction when switched to a ventricular cannula. We conclude that amphetamine self-injected into the accumbens is a positive reinforcer. This localization of amphetamine reward suggests that the nucleus accumbens contains a synaptic mechanism underlying amphetamine abuse and, perhaps, also natural reinforcement of behavior.     

Registration of choice direction in a T-maze in rats under the influence of N-methyl-4-piperidyl cyclopentyl methylethynyl glycolate (PCMG), a centrally acting cholinolytic

Groups of 10 rats, trained to alternate their choices (left-right) during successive trials in an enclosed T-maze at an intertrial interval of 2 h, were treated according to a 4×4 Latin square scheme, either with the short acting cholinolytic PCMG (0.5 mg/kg i.p.) or the vehicle 40 min after trial I. The animals received either 3 trials with an intertrial interval of 1 h or 2 trials with an intertrial interval of 2 h. There were 2 experiments: the first was run in four replications, the second in 2 replications, the only difference being two forced repetition trials immediately following trial I during the second experiment. The direction chosen, the duration of running and the behaviour shown in the various parts of the maze were analysed. In contrast to the first experiment the second experiment demonstrated that it is possible to insert a drug trial between two non drug trials without influencing the alternation of choice directions shown during the non drug trials. Both pre-choice and post-choice behaviour were markedly changed, except for the actual running. These changes were interpreted as an intensification of conflicts already existing in normal animals, between opposing tendencies under the influence of the drug. The results are discussed in relation to existing hypotheses about the behavioural action of cholinolytics.     

Role of brain amines in learning associated with “amphetamine-state”

Conditional avoidance responses acquired under amphetamine were recalled without deficit only when tested under amphetamine (amphetaminestate dependent learning). Hydroxyamphetamine was devoid of this property. Dihydroxyphenylalanine (DOPA) but not 5-hydroxytryptophan (5-HTP) substituted for amphetamine while reserpine but not syrosingopine eliminated the amphetamine-state. DOPA and 5-HTP, only when given together, restored the amphetamine-state in reserpinized animals. DOPA alleviated the deficit in retention which was caused by methyl-p-tyrosine. 5-HTP alleviated the similar deficit caused by p-chlorophenylalanine. Chlorpromazine or cyproheptadine antagonized the amphetamine-state. It is suggested that amphetamine, but not hydroxyamphetamine is capable of producing an asymmetric behavior-controlling state. The amphetamine-state is related to the stimulation of central and not peripheral amine-receptors and depends on newly synthesized catecholamines which stimulate central catecholamine receptors through serotonin modulation in this case.     

Effects of H1-receptor antagonists on responding punished by histamine injection or electric shock presentation in squirrel monkeys

Squirrel monkeys were trained to press a key under a two-component schedule of food presentation. In the presence of either green or red stimulus lights, the 30th response produced a food pellet (fixed-ratio schedule). During the red stimulus lights (punishment component), the first response of each fixed ratio produced either an IV injection of histamine (100.0 g/kg/inj) or a brief electric shock (3.0 mA). Responding was selectively suppressed in either punishment component. Presession IM administration of chlorpheniramine (0.1 and 0.3 mg/kg), diphenhydramine (1.0 and 3.0 mg/kg), or pyrilamine (0.1 and 0.3 mg/kg) increased rates of responding punished by histamine but not those punished by electric shock. Presession administration of promethazine (0.1–3.0 mg/kg) or tripelennamine (0.1 and 0.3 mg/kg) also increased rates of responding punished by histamine in all subjects and response rates punished by electric shock in one of three subjects. Chlordiazepoxide (3.0–56.0 mg/kg) increased rates of responding punished by either histamine or electric shock. These results suggest that the punishing effects of histamine injection are mediated by H₁ receptors and that H₁-receptor antagonists increase rates of responding suppressed by punishment only under limited conditions including those in which histamine is the punishing stimulus.     

Effects of haloperidol and d-amphetamine on perceived quantity of foods and tones

The hypothesis that dopamine (DA) receptor agonists and antagonists affect hedonia associated with natural rewards was tested, using a psychophysical procedure previously shown to be sensitive to both the sweetness of food and the motivational state of rats. Rats were first trained to discriminate between two different quantities of a rewarding stimulus by pressing one of two levers. Perceived quantity was subsequently derived from generalization trials of intermediate quantities. Haloperidol (0.03–0.083 mg/kg), a DA receptor antagonist, did not influence perceived food quantity, an indirect marker of hedonic value. On the other hand, d-amphetamine (0.25–1.0 mg/kg) affected perceived food quantity in a dose-dependent fashion, and in the same direction as occurs after increasing hunger or food sweetness. Both haloperidol and amphetamine influenced the perceived quantity of a stimulus without natural reinforcing properties (a tone), but the effect of amphetamine on the perceived quantity of this initially neutral stimulus was opposite in direction to that observed with food. These results suggest that whereas amphetamine affects hedonic processes, haloperidol does not. In addition, it seems that haloperidol probably produces its actions through effects on motor mechanisms or by interfering with the response-facilitating properties of rewards.     

Anxiolytic-like action of the 3-PPP enantiomers in the Vogel conflict paradigm

The effect of the (+)- and (-)-enantiomers of 3-PPP [conventional and atypical dopamine (DA)-receptor active agent, respectively] were investigated in a commonly used animal model of anxiety: the Vogel licking-conflict test. Low doses (0.5 mg/kg SC) of both 3-PPP enantiomers resulted in anti-conflict (=anxiolytic-like) actions in this test. (-)-3-PPP proved to be almost as potent as apomorphine in releasing the punished responding (minimum effective doses; (-)-3-PPP: 0.016, and apomorphine: 0.006 mg/kg SC), whereas (+)-3-PPP was about 10 times less effective than apomorphine. In the higher dose range (1.0 mg/kg), both 3-PPP enantiomers instead induced an apparent pro-conflict effect; i.e. decreased responding to a level significantly below baseline, thus resulting in a biphasic dose-response curve. Simple alterations in the animals' motivation to drink, in shock threshold or in motor capabilities did not seem to be major explanatory factors either for the anti- or for the pro-conflict effects. With regard to the latter, the possibility is discussed of an interaction between the experimental test situation and non conflict-related effects of the drugs, thus interfering with the punished drinking. The findings are interpreted within the concept that low doses of the 3-PPP enantiomers, in particular (-)-3-PPP, may attenuate anxiety-elicited increases in the neurotransmission in certain meso-cortical/limbic DA pathways, i.e. consistent with the previously shown preferentially limbic net antidopaminergic profile of action of (-)-3-PPP. The results support an active role for DA in conditions associated with anxiety and reinforce the view that novel putative anxiolytics might be found among selective DA-modulating agents like, e.g. the atypical DA receptor agonist (-)-3-PPP.