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PubMed1979

The effects of schedule of reinforcement on stimulus overselectivity in autistic children.

Recent research demonstrated that when autistic children are presented a discrimination task with multiple cues, they typically respond to an abnormally limited number, usually one, of the available cues. This phenomenon, termed "stimulus overselectivity," has been implicated as a possible basis for many of the behavioral deficits characteristic of autism. The present investigation was conducted to systemically analyze the effects of changing the schedules of reinforcement during discrimination training on subsequent stimulus overselectivity. Twelve autistic children were taught a discrimination involving multiple visual cues, with a CRF schedule of reinforcement. The children were then overtrained on either the same (CRF) schedule or on a partial (VR:3) reinforcement schedule. Subsequent overselectivity on single-cue test trials was then assessed. Results suggested that significantly less overselectivity occurred when the children were presented with the VR:3 reinforcement schedule during overtraining. These results are discussed in terms of variables influencing overselectivity and in terms of implications for designing treatment procedures for autistic children.

Adolescent↗

PubMed1991

Beta-endorphin-induced locomotor stimulation and reinforcement are associated with an increase in dopamine release in the nucleus accumbens.

In vivo microdialysis was used to compare the effects of beta-endorphin upon dopamine (DA) release in the nucleus accumbens (NAC) of anesthetized versus freely moving rats, and to examine the role of the mesolimbic DA system in mediating both the motoric and secondary reinforcing effects of this peptide. Microdialysis probes were inserted into the NAC and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using a reversed phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (ICV) administration of beta-endorphin (2.5 and 5.0 micrograms) increased DA release and metabolites in both freely moving and anesthetized rats. This effect was of greater magnitude and duration in freely moving rats and was accompanied by stimulation of locomotor activity. The 5 micrograms dose also functioned as a secondary reinforcer in a conditioned place preference paradigm. A higher dose of beta-endorphin (7.5 micrograms) stimulated DA release and metabolites in anesthetized rats but failed to affect these parameters in freely moving rats. At this dose, catalepsy and a loss of the reinforcing effects of this peptide were observed. These data demonstrate marked differences in the effects of beta-endorphin upon DA release in the awake versus anesthetized rat. Further, the finding that the reinforcing and locomotor stimulating effects of beta-endorphin only occur at those doses which stimulate DA release suggest that this action is critical for the expression of both behavioral effects.

Anesthesia↗

PubMed1990

Reinforcing effects of peripherally administered substance P and its C-terminal sequence pGlu6-SP6-11 in the rat.

Reinforcing effects of intraperitoneally (IP) administered substance P (SP1-11), its amino-terminal fragment SP1-7 (SPN) and an analog of the carboxy terminus (pGlu6-SP6-11: SPC) were studied in rats. Two conditioned place preference paradigms were used. After three pairings of the drug with a certain environment the effect of the treatment was evaluated in the drug-free state during a test trial. The reinforcing effects of SP (37 nmol) and the equimolar dose of SPC were expressed by a significant increase in the amount of time the animals spent in the treatment environment. Other doses of SP (3.7 and 185 nmol) and SPC (7.4 and 185 nmol) and none of the doses of SPN (37, 185, 370 nmol) influenced the place preference behavior of the rats. The reinforcing effects of SP parallel the known facilitating effects of peripherally administered SP on memory. The amino acids that encode the reinforcing effects of SP may lie within the C-terminal sequence of the SP molecule.

Animals↗

PubMed1994

Amphetamine-induced disruptions of latent inhibition are reinforcer mediated: implications for animal models of schizophrenic attentional dysfunction.

Latent inhibition (LI) is a phenomenon observed when repeated, non-reinforced presentation of a stimulus results in a retardation of subsequent conditioning to that stimulus. Several recent experiments have suggested that LI is abolished in conditioned suppression paradigms following acute, low doses of amphetamine given during pre-exposure and conditioning. Experiment 1 sought to increase the generality of this finding in an appetitive LI paradigm, using a dose of amphetamine previously shown to disrupt the LI effect in an aversive paradigm (Killcross and Robbins 1993). However, no evidence for any disruption of LI was found. Experiment 2 extended this investigation to additional, higher doses of d-amphetamine, and also examined the role of reinforcer magnitude in the effect. A non-significant trend towards an attenuated LI effect was found, which was reversed by decreases in the concentration of the sucrose reinforcer. Experiments 3 and 4 investigated the influence of systemic amphetamine in aversive paradigms, with specific attention to the increased response to the aversive foot-shock reinforcer found in amphetamine-treated animals. These experiments revealed that the influence of amphetamine on the LI effect in conditioned suppression paradigms could be reversed by reducing the intensity of footshock used in conditioning, thereby paralleling the effect found in the appetitive paradigm. Therefore it is unlikely that a simple attentional account of the abolition of the LI effect in previous experiments can be sustained.

Amphetamine↗

PubMed1992

Oral self-administration of triazolam, diazepam and ethanol in the baboon: drug reinforcement and benzodiazepine physical dependence.

Reinforcing and physical dependence-producing effects of oral diazepam and triazolam (0.01-1.28 mg/ml) were studied in four non-water-deprived baboons in daily 2-3-h sessions. Drinking initially was food-induced, but subsequently it was maintained for greater than year without the inducing procedures; drug intake greater than 10 mg/kg per session was attained. Triazolam and diazepam reinforcement (compared to vehicle) was concluded for only one baboon for each drug under a single-spout procedure and for two baboons for each drug under a two-spout procedure. However, all baboons showed ethanol reinforcement under a two-spout procedure. When a lever-pressing requirement was imposed for each drink (one-spout procedure), ethanol maintained requirements of 128 or 256 responses/drink, and volume of ethanol consumed was greater than vehicle. Neither benzodiazepine maintained lever pressing better than vehicle at any response requirement and drinking was suppressed by requirements of 1-32. Physical dependence to triazolam and diazepam developed after approximately 1 month of daily ingestion, evidenced by a precipitated withdrawal syndrome after injection of the benzodiazepine antagonist flumazenil. A mild spontaneous withdrawal syndrome occurred after substitution of vehicle for triazolam or diazepam. These data indicate a clear dissociation between the reinforcing and physical dependence-producing effects of triazolam and diazepam.

Animals↗

PubMed1995

Ro 15-4513 selectively attenuates ethanol, but not sucrose, reinforced responding in a concurrent access procedure; comparison to other drugs.

The experiments described in this report used a concurrent access procedure to study ethanol reinforcement. Rats were trained to lever press for a 10% sucrose solution and a 10% ethanol/10% sucrose mixture, and both reinforcers were available on variable-interval 5-s schedules. In baseline and vehicle injection sessions, the animals distributed their responding between both solutions. When injected with the partial inverse benzodiazepine agonist Ro 15-4513 (3, 9, and 18 mg/kg), responding for the ethanol solution decreased while responding for sucrose remained intact. Ethanol injections (0.5 and 1.0 g/kg) engendered a similar profile. Chlordiazepoxide led to an increase in ethanol mix responding at 2 mg/kg and a decrease in ethanol mix responding at higher doses; no dose affected sucrose responding. Morphine (0.5-16 mg/kg) decreased responding for both the ethanol mix and sucrose solutions, more or less simultaneously. Naloxone (0.125-20 mg/kg) selectively reduced ethanol mix responding at low doses, and decreased responding for both reinforcers at high doses. In another group of animals, isocaloric alternatives were concurrently available: 10% ethanol/0.25% saccharin versus 14% sucrose. Injections of Ro 15-4513 and chloridiazepoxide produced similar results as in the first group of rats: an increase in ethanol mix responding with low dose chlordizepoxide, and a decrease in ethanol mix responding with Ro 15-4513. However, naloxone injections did not selectively affect responding for either of the reinforcers when they were isocaloric. These results are discussed in terms of ethanol's neuropharmacological actions.

Animals↗

PubMed1995

Overnight caffeine abstinence and negative reinforcement of preference for caffeine-containing drinks.

It has been suggested that liking for the taste, flavour and aroma of, for example, coffee and tea is acquired through the process of classical conditioning, involving association of these orosensory cues with the psychopharmacological consequences of caffeine ingestion. Accordingly, this study investigated caffeine reinforcement by assessing changes in preference for a novel drink consumed with or without caffeine. Particular care was taken to use "ecologically valid" procedures; that is, overnight caffeine abstinence followed by a cup-of-coffee equivalent dose of caffeine (70 mg) at breakfast. Caffeine had no significant effects on drink preference or mood in subjects with habitually low intakes of caffeine. In contrast, moderate users of caffeine developed a relative dislike for the drink lacking caffeine and showed somewhat lowered mood following overnight caffeine abstinence (e.g., less lively, clearheaded and cheerful), which was significantly improved by caffeine. These together with other recent results strongly suggest that, in everyday life, caffeine reinforcement can occur as the result of the alleviation by caffeine of the adverse effects of overnight caffeine abstinence (negative reinforcement). They also demonstrate the utility of this flavour-conditioning procedure, which could be applied in the wider investigation of the reinforcing properties of drugs.

Adolescent↗

PubMed1996

Orally delivered methadone as a reinforcer in rhesus monkeys.

Methadone usually is taken orally for drug abuse treatment in humans but oral methadone self-administration by laboratory animals has not been investigated extensively. The present study examines acquisition and maintenance of oral methadone maintained responding in four adult male rhesus monkeys. Drug solution was available from one liquid delivery system and water from a second system during daily 3-h sessions. Locations of liquids were reversed each session, and liquid (0.65 ml per delivery) was delivered according to a fixed-ratio reinforcement schedule. Initially a test for the reinforcing effects of 0.00625-0.4 mg/ml methadone solutions was carried out but a consistent preference for drug over water was not seen. To establish methadone as a reinforcer, a fading procedure was used in which responding was first maintained by solutions of methadone (0.00625-0.4 mg/ml) combined with ethanol (0.0325-2.0% w/v). Subsequently, the concentration of the ethanol in the combination was gradually reduced to zero. Methadone-maintained responding (0.4 mg/ml) persisted when ethanol was no longer present. To confirm that the drug was serving as a reinforcer, the dose was varied: (a) by changing the volume delivered while the concentration was held constant and (b) by changing the concentration of the methadone while the volume per delivery was held constant. Over a wide range of doses, deliveries of methadone solution usually exceeded deliveries of concurrently available water. Orderly relationships were observed among methadone dose, response rate, and drug intake. The study of oral self-administration of opioid drugs by nonhuman primates may be a useful strategy for the development and evaluation of new drug substitution or replacement therapies.

Administration, Oral↗

PubMed1995

Haloperidol differentially affects reinforcement and motivational processes in rats running an alley for intravenous heroin.

The role of drug-paired environmental stimuli in opiate self-administration was investigated by exposing animals to discrete cues that were predictive of the availability or unavailability of heroin reinforcement. Rats were trained to traverse a straight arm runway for a reinforcement consisting of a single 0.1 mg/kg intravenous infusion of heroin delivered upon entrance to the goal box. On each trial, one of two discriminative olfactory stimuli (orange and almond) was used: one which signaled the availability of heroin in the goal box (S+), and one which signaled its absence (S-). The effect of dopamine (DA) receptor antagonism on reinforcement and motivational processes was investigated by pretreating subjects with 0.0, 0.15 or 0.30 mg/kg of the DA receptor antagonist drug, haloperidol. Haloperidol had no effect on operant runway performance (i.e. goal time) in any condition. However, 24 h later, on the first post-treatment trial, those haloperidol animals that received heroin in the goal box on the previous trial (i.e. the S+ condition) ran reliably more slowly than subjects that received vehicle on the previous S+ trial. These results suggest that haloperidol does not affect the motivational properties of stimuli which predict the availability of heroin, while it does diminish the reinforcing effects of actually receiving heroin.

Analysis of Variance↗

PubMed1996

Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil.

Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central alpha 1-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil, l-ephedrine and d-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by alpha 1-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil and l-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil-required very high doses: modafinil was over 200 times less potent than d-amphetamine and was also less potent than l-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.

Adrenergic Agents↗

PubMedDate not supplied

Monoaminergic control by amygdalar nuclei of the reinforcing action of conditional stimuli.

The influence of microinfusion of 5-HT, NE, and DA into the amygdalar nuclei on the accomplishment of conditioned reinforcing and conditioned trigger reflexes which are constituents of the CADR was studied in cats with a developed conditioned alimentary discrimination reflex (CADR) in response to two conditional light stimuli set apart on different sides of a box. It was established that 5-HT in doses of 30-50 micrograms in a volume of 5 microliters elicits inhibition; the same doses of NE, by contrast, induces the "hanging-up" of the animals on conditional and conditional--unconditional stimuli which possess the property of reinforcement during the execution of the CADR. The microinfusion of DA in doses of 30-60 micrograms recalls, from animal to animal, the action of 5-HT and NE. It is hypothesized that the inhibitory functions of 5-HT and the activating actions of NE in the amygdalar nuclei support this structure's control of reinforcing conditional and conditional--unconditional reflexes and the perception of the reinforcing action of conditional stimuli. It is hypothesized that the DAergic innervation of the amygdala does not participate directly in conditioned reflex activity.

Amygdala↗

PubMedDate not supplied

Characteristics of the chemical sensitivity of cerebral cortical neurons at the stages of food-procuring behavior of cats as a function of the quality of reinforcement.

The chemical sensitivity to the principal neuromediators of neurons of the visual area of the cerebral cortex was investigated at sequential stages of instrumental behavior in this study using the method of the microiontophoresis, in two experimental situations. In the first of these a portion of milk was used as the reinforcement; in the second, a portion of meat powder. It was demonstrated that the number of universal neurons decreases against the background of the application of norepinephrine and acetylcholine in behavioral acts with qualitatively different food reinforcements. At the same time, the number of neurons that are areactive at all stages of the behavior increases in the situation involving milk reinforcement, while it decreases in the situation involving meat reinforcement.

Acetylcholine↗

PubMedDate not supplied

Neural substrates of olfactory discrimination learning with auditory secondary reinforcement. I. Contributions of the basolateral amygdaloid complex and orbitofrontal cortex.

The basolateral amygdaloid complex (BLA) and orbitofrontal cortex (OFC) share extensive reciprocal connections, and interactions between these regions likely contribute to both mnemonic and affective processes. The present study examined the potential differential contributions of the BLA and OFC to performance of an olfactory discrimination task that incorporates auditory conditioned reinforcement and to expression of immediate post-shock freezing behavior. Damage to the BLA had little effect on performance of the conditioned reinforcement task but abolished immediate post-shock freezing behavior. In contrast, damage to OFC resulted in both a mild but significant performance decrement in the conditioned reinforcement task and a significant attenuation of immediate post-shock freezing behavior. These findings suggest that immediate post-shock freezing behavior is likely critically dependent upon interactions between the BLA and OFC. However, although mnemonic processes underlying accurate performance of the conditioned reinforcement task might be supported by OFC in part, such processes are independent of either the BLA or interactions between these two regions.

Acoustic Stimulation↗

PubMedDate not supplied

Increased regularity of activity of cortical neurons in learning due to disinhibitory effect of reinforcement.

This paper reviews the author's studies on neurophysiologic mechanisms of conditioned reflex learning. Electroencephalograms, evoked potentials, activity of neocortical and hippocampal neurons and the rabbits' behavior in the course of elaboration of defensive and inhibitory conditioned reflexes to light flashes have been recorded. Electric shock (ECS) applied to the paw served as reinforcement. The study demonstrated three types of reinforcement effect on the activity of cortical neurons: activating, disinhibitory, and inhibitory. EEG activation due to reinforcement is accompanied by a change in phasic cortical neuronal activity from chaotic or irregular, typical of rest or inhibition, to regular tonic discharges (in neocortex and hippocampus) and group discharges in the stress rhythm, 5-7 Hz in the hippocampus. Following a number of conditioning trials, the effect of reinforcement is simulated by the effect of a conditioned stimulus. With EEG activation and increased regularity in impulses, facilitation of motor reactions is observed.

Animals↗

PubMed2002

Antalarmin, a putative CRH-RI antagonist, has transient reinforcing effects in rhesus monkeys.

RATIONALE: During the course of our investigation of antalarmin, a corticotropin-releasing hormone (CRH) antagonist, in rhesus monkeys, we noticed that large, intravenous doses of antalarmin resulted in behavioral changes that resembled intoxication. OBJECTIVES: Antalarmin was evaluated in rhesus monkeys for its reinforcing effectiveness as well as for its effects on hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS: Twelve monkeys, each with a surgically implanted indwelling venous catheter, were trained to respond for and receive the short-acting barbiturate, methohexital. Monkeys responded on one of two schedules: a fixed ratio (FR) 10 (30 or 100), timeout (TO) 10 s schedule on which they received methohexital, antalarmin, vehicle or saline injections; or an FR30, TO 45 s during which saline, vehicle, or four different doses of methohexital or antalarmin were available. Each dose was available during a 25-min period separated by a 10-min TO. Blood samples were obtained from three monkeys before, during and after the self-administration sessions and assayed for ACTH and cortisol. RESULTS: Antalarmin initially served as a reinforcer in 11 of 12 monkeys, although its reinforcing effects dissipated after three to four exposures under both operant schedules. Self-injection of antalarmin did not produce any change in cortisol levels, although methohexital did attenuate ACTH and cortisol release. CONCLUSIONS: This study provides the first evidence for transient reinforcing properties of a putative centrally acting CRH-R1 selective antagonist.

Adrenocorticotropic Hormone↗

PubMed2002

Blockade of ionotropic glutamatergic transmission in the ventral tegmental area reduces heroin reinforcement in rat.

RATIONALE: While the role of the mesocorticolimbic (MCL) dopamine (DA) system in mediating the reinforcing properties of drugs of abuse has been well established, how and where other neurotransmitter systems interact to modify this system is less well understood. OBJECTIVES: The present study sought to assess whether blockade of ionotropic glutamate receptors in the ventral tegmental area (VTA) would modulate heroin self-administration (SA) behavior in rats. METHODS: The effects of systemic or regional administration of ionotropic glutamate receptor antagonists into the VTA on the maintenance of heroin SA were assessed. Rats were reinforced each time they responded on a lever with a single injection of intravenous heroin. To determine the specificity of their effects on heroin SA, the ability of these antagonists to modify locomotion and food-reinforced behavior was also examined. RESULTS: Systemic or regional administration of the non-competitive NMDA antagonist dizocilpine into the VTA significantly increased the rate of heroin SA and shifted the heroin dose-response curve to the right. Similarly, when systemically administered, ketamine, another non-competitive NMDA antagonist, also increased the rate of heroin SA. However, when administered directly into the VTA, ketamine or AP5 [ D-(-)-2-amino-5-phosphonopentanoic acid, a competitive NMDA antagonist], dose-dependently blocked heroin SA. In contrast, 6,7-dinitroquinoxaline-2,3-dione (DNQX), an AMPA/kainate receptor antagonist, significantly increased heroin SA. CONCLUSION: These data suggest that ionotropic glutamate receptors in the VTA, presumably by modulating MCL DA efferents and/or tegmental interneurons, modulate opiate reinforcement.

2-Amino-5-phosphonovalerate↗

PubMed2003

Effects of a non-drug reinforcer, saccharin, on oral self-administration of phencyclidine in male and female rhesus monkeys.

RATIONALE: Previous research with male subjects has demonstrated that alternative non-drug reinforcers reduce self-administration of drugs of abuse under a wide variety of conditions. Recent findings indicate sex differences in drug self-administration, and females may be more responsive to the suppressive effects of pharmacological treatment strategies than males; however, it is not known whether or not there are similar sex differences in the effect of behavioral interventions, such as non-drug reinforcers, on drug self-administration. OBJECTIVES: The goal of this research was to determine whether the suppressive effects of non-drug reinforcers vary as a function of sex using behavioral economic measures in rhesus monkeys. METHODS: During daily 3-h sessions, seven male and seven female adult rhesus monkeys orally self-administered concurrently available phencyclidine (PCP) and water, PCP and saccharin, or saccharin and water, from two separate spouts, under a series of fixed-ratio (FR) values. The FR value was varied from 4 to 8, 16, 32, 64, and 128, and the demand (consumption x FR) for PCP was measured in order to determine the effect of concurrent access to saccharin (versus water). RESULTS: The availability of saccharin resulted in reduced PCP self-administration compared with the condition when water was available in both males and females. Consumption of PCP and saccharin was similar between the sexes under the two conditions when water was concurrently available. When saccharin was available with PCP, PCP responses and deliveries were reduced in both sexes at low to intermediate FR values, but the amount of PCP consumed (mg/kg) was reduced significantly more in females than in males only at FR 32. CONCLUSIONS: . Non-drug reinforcers are an effective treatment for drug abuse in females as well as males over a range of PCP FR values. Males show elevated drug-maintained responding compared with females, but when differential body weights are considered (mg/kg) females consume more than males only under limited schedule parameters.

Administration, Oral↗

PubMed2004

Reinforcing effects of methylphenidate: influence of dose and behavioral demands following drug administration.

RATIONALE: The reinforcing effects of stimulant drugs such as D-amphetamine, caffeine, and cocaine are modulated by behavioral demands following drug administration. OBJECTIVE: The objective of this study was to assess the reinforcing effects of methylphenidate under different behavioral demands using a modified progressive-ratio procedure. METHODS: The reinforcing effects of oral methylphenidate (0, 10, 20, and 40 mg) were assessed in seven healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems for three 50-min blocks. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room for three 50-min blocks. Two sampling sessions (one performance and one relaxation session) always preceded two self-administration sessions (one performance and one relaxation session) and the order of relaxation and performance sessions was constant within a dose condition. RESULTS: Methylphenidate significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Methylphenidate produced comparable stimulant-like subject ratings under both the performance and relaxation conditions. CONCLUSION: The findings of the present experiment suggest that the reinforcing effects of methylphenidate, like D-amphetamine and cocaine, are influenced by behavioral demands following drug administration.

Administration, Oral↗