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Reinforcing effects of oral cocaine: contextual determinants.

RATIONALE: Although the behavioral, subjective, and physiological effects of oral cocaine have been investigated, its reinforcing effects have not been demonstrated. OBJECTIVE: The primary aims of this study were to examine the reinforcing effects of oral cocaine and determine whether such effects can be influenced by manipulating behavioral requirements following drug ingestion. METHODS: Nine adult volunteers with histories of cocaine abuse were trained to discriminate between orally administered cocaine (100 mg/70 kg) and placebo capsules under double-blind conditions. Following acquisition of cocaine vs placebo discrimination (80% correct), the reinforcing effects of cocaine were determined using two different choice conditions (dependent and independent). Volunteers were first exposed to cocaine and placebo once each with a relaxation activity (sitting in a cushioned chair) and a vigilance activity (performing a computer task). Following exposure to each drug with each activity, volunteers began the dependent choice condition. Every 2 days volunteers chose which drug (cocaine or placebo) they ingested with the vigilance and relaxation activities. Volunteers could not choose the same drug with both activities. This procedure occurred 5 times over a 10-day period. The independent choice condition took place over 2 days. On one day, volunteers chose which drug (cocaine or placebo) they ingested with the relaxation activity and, on the other day (in counterbalanced order), which drug they ingested with the vigilance activity. Volunteers were allowed to select the same drug with both activities. RESULTS: All volunteers successfully acquired the cocaine vs placebo discrimination. In the dependent choice condition, all volunteers significantly chose cocaine over placebo with the vigilance activity and chose placebo over cocaine with the relaxation activity. In the independent choice condition, volunteers significantly chose cocaine over placebo with the vigilance activity (i.e., cocaine functioned as a positive reinforcer in the vigilance context). Interestingly, the independent choice condition also showed that volunteers chose placebo over cocaine with the relaxation activity (i.e., cocaine functioned as a negative reinforcer because it was avoided relative to placebo). CONCLUSION: The study shows that the behavioral requirements following drug ingestion can be a determinant of whether or not oral cocaine functions as a reinforcer in volunteers with histories of cocaine abuse.

Administration, Oral↗

Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules.

RATIONALE: Recent reports have indicated that the gamma-aminobutyric acid (GABA)B agonist baclofen attenuates the reinforcing effects of cocaine. OBJECTIVES: To further evaluate the effect of baclofen on cocaine self-administration under a fixed ratio (FR) and progressive ratio (PR) schedule of reinforcement. METHODS: In the first series of experiments, three dose-response curves were generated that examined the effect of three doses of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) against four unit-injection doses of cocaine (0.19, 0.38, 0.75, and 1.5 mg/kg per injection) reinforced under a FRI schedule. For comparison, an additional group of rats was pretreated with haloperidol (32, 56, or 100 microg/kg, i.p.). A separate experiment examined the effect of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) on responding for concurrently available cocaine or food reinforcement. RESULTS: Under the FR1 schedule, baclofen suppressed intake of low but not high unit injection doses of cocaine. In contrast to haloperidol, baclofen had no effect on the distribution of inter-injection intervals and, instead, produced long pauses in cocaine self-administration. Baclofen dose dependently reduced cocaine-reinforced responding on a PR schedule; concurrent access to a food-reinforced lever demonstrated that the animals retained the capacity to respond at high rates. CONCLUSION: The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule.

Animals↗

The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice with varying delays of reinforcement.

Impulsive behaviour is an important component of many psychiatric syndromes. It is often expressed as aggressive or violent behaviour, but may also be non-violent. One important factor which might lead to aggression or violence is an inability to tolerate a delay of gratification, leading to frustration and aggressive outbursts. In animals and in man, tolerance to delay of gratification can be studied using delay of reinforcement (also known as self-control) procedures. Experiments with delay of reinforcement in rats show that serotonergic mechanisms may be involved in this form of impulsive behaviour, which seems to support clinical findings in this area. The present experiment examined the effects of a series of psychoactive drugs on delays of reinforcement using a steady state operant procedure involving lever-pressing by rats. Rats were trained to choose between one food pellet delivered immediately and three or five pellets delivered after varying delays which increased during the course of the session. Using this procedure the rats remained sensitive to within-and between-session variations in delay of reinforcement even after long periods of testing. It was used to demonstrate an increase in impulsivity (after d-amphetamine) and a reduction in impulsivity (after diazepam and metergoline), indicated by shifts in the choice/delay function. The other drugs tested, imipramine, citalopram, haloperidol and carbamazepine, had no consistent effects although tested at doses which are active in other procedures. This method has proved to be a useful way of examining the effects of drugs on choice of delay of reinforcement in the rat. Although the behavioural basis of tolerance to delay of reinforcement (self-control) has received considerable attention, little is yet known about the biological basis. The present data indicate that the procedure described here can be used to elucidate the pharmacological basis of this aspect of impulsive behaviour.

Animals↗

High and low temperatures have unequal reinforcing properties in Drosophila spatial learning.

Small insects regulate their body temperature solely through behavior. Thus, sensing environmental temperature and implementing an appropriate behavioral strategy can be critical for survival. The fly Drosophila melanogaster prefers 24 degrees C, avoiding higher and lower temperatures when tested on a temperature gradient. Furthermore, temperatures above 24 degrees C have negative reinforcing properties. In contrast, we found that flies have a preference in operant learning experiments for a low-temperature-associated position rather than the 24 degrees C alternative in the heat-box. Two additional differences between high- and low-temperature reinforcement, i.e., temperatures above and below 24 degrees C, were found. Temperatures equally above and below 24 degrees C did not reinforce equally and only high temperatures supported increased memory performance with reversal conditioning. Finally, low- and high-temperature reinforced memories are similarly sensitive to two genetic mutations. Together these results indicate the qualitative meaning of temperatures below 24 degrees C depends on the dynamics of the temperatures encountered and that the reinforcing effects of these temperatures depend on at least some common genetic components. Conceptualizing these results using the Wolf-Heisenberg model of operant conditioning, we propose the maximum difference in experienced temperatures determines the magnitude of the reinforcement input to a conditioning circuit.

Adenylyl Cyclases↗

Response-reinforcement relationships in chronic pain syndrome: applicability of Herrnstein's law.

The quantitative relationship between chronic pain behavior and reinforcement has been generally found to be positive. Herrnstein's statement of the law of effect adds a qualification: it predicts that response rate varies hyperbolically with contingent reinforcement, and that response rate is also negatively related to extraneous reinforcement. The present study is an original investigation of the first of these assertions with regard to the naturally occurring behaviors in chronic pain syndrome. It was found that the stereotypic pain behaviors of 12 chronic pain patients were hyperbolically rather than proportionally related to contingent reinforcement from their significant others. Likewise, healthy behaviors in the same group were a hyperbolic function of contingent reinforcement. Estimates of extraneous reinforcement were also obtained for each category of behaviors. As a group, the subjects showed an inverse relationship between pain behaviors and healthy behaviors, consistent with previous research in the pain area. The present findings add generality to Herrnstein's matching law which serves as a descriptive model of target behaviors in chronic pain patients. The findings also have prescriptive implications for the modification of behavior among chronic pain sufferers.

Adult↗

The role of spouse reinforcement, perceived pain, and activity levels of chronic pain patients.

Levels of pain, activity, marital satisfaction, and contingent reinforcement for expressions of pain and suffering were assessed in chronic pain patients. In addition, spouses' marital satisfaction, mood, life control, and self-reported responses to the patient's pain were examined. Multiple regression analyses revealed that spouse reinforcement of overt expressions of pain was significantly related to both perceived pain and activity levels of chronic pain patients. The best predictor of patients' pain and activity levels was patients' perception of spouse reinforcement, followed by spouses' self-reported responses to the patients' pain. Spouse reinforcement of pain was not associated with spouses' marital satisfaction or perception of patients' pain levels. Rather, spouse reinforcement was associated with high interference of patients' pain with spouses' lives, spouses' positive mood, spouses' perception of more life control, as well as longer duration of the pain problem. The data support the importance of the spouse as a potential source of reinforcement of pain behavior.

Adult↗

Haloperidol induces a partial reinforcement extinction effect in rats: implications for a dopamine involvement in food reward.

The hypothesis that dopamine antagonist drugs attenuate the reinforcing properties of food was investigated in hungry rats trained to traverse a straight runway for food reward. Testing consisted of a single trial per day during which latencies to leave the start box and to traverse the alley were recorded. In each experiment, a reinforcement phase lasting 30 consecutive days was immediately followed by a 21 day extinction phase. The runway responses of animals that experienced intermittent food reward during the reinforcement phase of the experiments, was later found to be more resistant to extinction than those of continuously reinforced animals. This "partial reinforcement extinction effect" (PREE) was also observed in animals that experienced periodic reductions in the quantity, but not quality, of food reward. Intermittent pretreatment with 0.15 mg/kg of haloperidol during the reinforcement phase produced a PREE that was indistinguishable from that produced by reward omission on those same trials. Control groups for motor debilitation and for non-associative drug effects did not demonstrate a PREE. These results are consistent with the view that central dopamine substrates play a role in the neural basis of food reward.

Animals↗

Operant responding controlled by milk or milk contaminated with alcohol as positive reinforcers in infant rats.

Infant rats during the first, second, or third week of life were tested in operant conditioning with uncontaminated milk or milk supplemented with 6.0% v/v absolute ethanol (EtOH) as the reinforcer. Relative to yoked controls, pups of each age group reinforced on a response-contingent basis exhibited a significantly higher rate of responding with either reinforcer. In terms of amount of reinforcement, milk induced a higher rate of lever pressing than did the EtOH-contaminated compound. Age-related differences in the onset of differential responding for plain milk and EtOH-contaminated milk suggested developmental changes in the effects of alcohol. In a second experiment, forced drinking of milk and EtOH-contaminated milk was compared in similar age groups. Patterns of intake resembled the patterns of operant responding controlled by the same substance in the first experiment. These experiments indicate that the presence of alcohol in milk partially inhibits the reinforcing capacity of uncontaminated milk. Nevertheless, the former compound is still effective as a positive reinforcer during the first weeks of life.

Animals↗

The effects of delay of reinforcement and dose on the self-administration of cocaine and procaine in rhesus monkeys.

Delays of reinforcement were imposed while three rhesus monkeys intravenously self-administered either cocaine or procaine to determine whether the magnitude of delay-induced reductions in infusion frequency were dose- or drug-dependent. Drug-maintained baselines demonstrating the greatest resistance to change under delay conditions might be conceptualized as involving the greatest strength of responding and include drug reinforcers with the greatest efficacy. Under baseline conditions, cocaine or procaine was infused contingent upon lever pressing according to fixed ratio 10 schedules during daily, 1-h experimental sessions. Under delay conditions, a 120-s delay of reinforcement was inserted between the completion of each fixed ratio contingency and infusion delivery. Tests under baseline and delay conditions alternated until several doses of cocaine (3, 10, 33, 100, and 300 micrograms/kg), and subsequently, of procaine (33, 100, 300, 1000, and 3000 micrograms/kg) were tested. The results indicated that during both baseline and delay conditions increases in dose of either drug resulted in increases followed by decreases in the number of infusions obtained. Introducing delays of reinforcement resulted in decreases in the number of infusions obtained at a given dose. Generally, however, when reinforcement delays were imposed the decreases in infusion number, as a percentage of baseline number, were less at the higher doses of both drugs. The doses of procaine which were maximally effective as reinforcers (i.e. during which infusion number was minimally reduced by delay) were as effective as the maximally effective doses of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Relative reinforcing effects of different doses of orally delivered cocaine.

The relative reinforcing effects of different doses of oral cocaine were investigated in two adult male rhesus monkeys. In the first experiment, a range of cocaine doses (0.1-0.8 mg/ml) was studied with drug and water concurrently available for 3 h each day under identical and independent fixed-ratio schedules. The side positions of the drug and vehicle were alternated from session to session. Drug deliveries always exceeded vehicle deliveries, i.e., orally delivered cocaine functioned as a reinforcer. The highest rates of responding occurred at either the lowest or next to lowest dose (0.1 or 0.2 mg/ml). In the second experiment, pairs of different cocaine doses were systematically presented under identical and independent fixed-ratio schedules. The higher of two concurrently available doses usually maintained the higher response rate. These findings suggest that the relative reinforcing effects of orally delivered cocaine increase with dose. Absolute response rates obtained with single cocaine doses and water concurrently available do not always reflect the magnitude of the reinforcing effects indicated when pairs of cocaine doses are studied together. The results of this study are in agreement with earlier investigations in which the relative reinforcing effects of pairs of intravenous cocaine doses or oral pentobarbital doses were studied. Taken together these findings indicate that, over a range of doses and across pharmacological classes and routes of administration, relative reinforcing effects of a drug increase directly as a function of increases in dose.

Administration, Oral↗

The concept of automatic reinforcement: implications for behavioral research in developmental disabilities.

Automatic reinforcement refers to situations in which behavior is maintained by operant mechanisms independent of the social environment. A number of difficulties exist in conducting an adequate functional analysis of automatically reinforced aberrant behavior. For example, sources of reinforcement are often difficult or impossible to identify, manipulate, or control. Further, the development of treatments is often difficult because many behavioral interventions, such as timeout, involve manipulation of the social environment--an approach that may be functionally irrelevant in the case of automatic reinforcement. This article discusses the problems inherent in the analysis of automatically reinforced behavior and reviews four classes of treatment that are compatible with that behavioral function. The four types of intervention reviewed include manipulations of establishing operations, sensory extinction, differential reinforcement, and punishment. Suggestions for future research are discussed.

Conditioning, Operant↗

The reinforcing property and the rewarding aftereffect of wheel running in rats: a combination of two paradigms.

Wheel running reinforces the behavior that generates it and produces a preference for the context that follows it. The goal of the present study was to demonstrate both of these effects in the same animals. Twelve male Wistar rats were first exposed to a fixed-interval 30 s schedule of wheel-running reinforcement. The operant was lever-pressing and the reinforcer was the opportunity to run for 45 s. Following this phase, the method of place conditioning was used to test for a rewarding aftereffect following operant sessions. On alternating days, half the rats responded for wheel-running reinforcement while the other half remained in their home cage. Upon completion of the wheel-running reinforcement sessions, rats that ran and rats that remained in their home cages were placed into a chamber of a conditioned place preference (CPP) apparatus for 30 min. Each animal received six pairings of a distinctive context with wheel running and six pairings of a different context with their home cage. On the test day, animals were free to move between the chambers for 10 min. Results showed a conditioned place preference for the context associated with wheel running; however, time spent in the context associated with running was not related to wheel-running rate, lever-pressing rate, or post-reinforcement pause duration.

Animals↗

"The stone which the builders rejected...": Delay of reinforcement and response rate on fixed-interval and related schedules.

The article deals with response rates (mainly running and peak or terminal rates) on simple and on some mixed-FI schedules and explores the idea that these rates are determined by the average delay of reinforcement for responses occurring during the response periods that the schedules generate. The effects of reinforcement delay are assumed to be mediated by a hyperbolic delay of reinforcement gradient. The account predicts that (a) running rates on simple FI schedules should increase with increasing rate of reinforcement, in a manner close to that required by Herrnstein's equation, (b) improving temporal control during acquisition should be associated with increasing running rates, (c) two-valued mixed-FI schedules with equiprobable components should produce complex results, with peak rates sometimes being higher on the longer component schedule, and (d) that effects of reinforcement probability on mixed-FI should affect the response rate at the time of the shorter component only. All these predictions were confirmed by data, although effects in some experiments remain outside the scope of the model. In general, delay of reinforcement as a determinant of response rate on FI and related schedules (rather than temporal control on such schedules) seems a useful starting point for a more thorough analysis of some neglected questions about performance on FI and related schedules.

Animals↗

Prefrontal cortex D1 modulation of the reinforcing properties of cocaine.

The involvement of the dopaminergic pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) in the reinforcing properties of many drugs of abuse is well established. Though the prefrontal cortex (PFC) exhibits significant influence over activity in this pathway, its role in drug abuse is less defined. The present experiment investigated the impact of PFC D1 activity on cocaine self-administration (0.25, 0.75 mg/kg/inj) under progressive (PR) and fixed ratio (FR) schedules of reinforcement by assessing immediate and delayed effects of bilateral intra-PFC infusions of a D1 agonist (SKF 38393; 0.23 microg/side) and antagonist (SCH 23390; 0.25 microg/side). Immediately following infusion of dopaminergic agents or vehicle, no significant changes in self-administration occurred under any tested condition. However, 24 h after intra-PFC antagonist treatment, significantly lower PR breakpoints were observed for low (0.25 mg/kg), but not moderate (0.75 mg/kg) unit doses of self-administered cocaine. Locomotor activity levels during these assessments were unaffected by intra-PFC treatments. On an FR-3 schedule of reinforcement, the 0.25 cocaine unit dose elicited higher total cocaine intake and hyperlocomotor activation during a shorter session, but intra-PFC treatment had no significant effects on the number of reinforced responses or behavioral activity. The observation of decreased cocaine breakpoints after intra-PFC DA antagonist treatment reflects decrements in cocaine reinforcement efficacy. This finding corresponds temporally with previous work showing increased NAcc DA levels after similar treatment. Current findings demonstrate that transient changes in PFC DA neurotransmission can specifically influence reinforced behaviors without affecting overall behavioral activation.

Animals↗

The neurotensin receptor agonist NT69L suppresses sucrose-reinforced operant behavior in the rat.

NT69L is a neurotensin analog that can be administered peripherally. It blocks amphetamine- and cocaine-induced hyperactivity in rats. It also blocks nicotine-induced locomotor activity and has shown sustained efficacy in a rat model of nicotine-induced sensitization. The present study tested the effect of NT69L on responding for sucrose reinforcement on a continuous reinforcement schedule (CRF) and incrementing (FR1-FR5) discrimination schedule. Male Sprague-Dawley rats, on restricted food intake, were trained to press a lever for sucrose pellets on a CRF and incrementing discrimination schedule of reinforcement. On the following day, the testing session was followed by an extinction session, where lever pressing was not reinforced. Immediately after extinction, a reversal to CRF was implemented to test for relapse. Trained rats were injected with NT69L (1 mg/kg) or saline 30 min before each testing session. Dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels were determined. NT69L significantly suppressed the lever pressing behavior for sucrose reinforcement on CRF which measures the "hedonic" value of the reward. NT69L also suppressed sucrose self-administration on the incrementing discrimination schedule of reinforcement (FR3-FR5) that is analogous to the motivational incentive. Reversal to CRF was significantly reduced by pretreatment with NT69L. The suppression of sucrose self-administration behavior by pretreatment with NT69L had a pattern similar to that for extinction. The effect of NT69L on dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels is discussed relative to changes occurring during extinction.

Animals↗

Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine.

Among drugs that can function as positive reinforcers, slower occupancy of central nervous system sites of action has been associated with diminished reinforcing strength. The present study examined the relative reinforcing strength of cocaine, and the rate of in vivo dopamine transporter binding, as a function of injection duration. Rhesus monkeys (N=5) were allowed to self-administer cocaine under a progressive-ratio schedule with doses injected over different times (10-600 s). An ex vivo dopamine transporter binding assay was used to examine kinetics of in vivo transporter occupancy by cocaine injected over the same times in rats. Cocaine was a weaker reinforcer, and dopamine transporter binding rate decreased, with slower injections. Maximum transporter binding was the same across injection durations. These results support the hypothesis that slower onset of action is associated with a slower transporter occupancy and diminished reinforcing strength. Relative strength as a reinforcer may not be determined by maximum occupancy, at least not exclusively.

Animals↗

Reinforcement as a means for quality improvement in management of coronary syndromes: adherence to evidence-based medicine.

OBJECTIVE: To study the effect of reinforcement as a quality improvement intervention in the evidence-based management of the coronary syndromes. METHODS: In the pre-intervention phase, the charts of 140 consecutive patients with ICD-9 codes 410-414 for coronary syndromes were reviewed for measurement of total cholesterol on admission and fasting low density lipoprotein (LDL) cholesterol, implementation of aspirin therapy on admission, beta-blockers' use during hospitalization, and treatment with angiotensin converting enzyme (ACE) inhibitors in patients with left ventricular systolic dysfunction. Reinforcement was used as an intervention for quality improvement. All personnel of Division of Cardiology including nursing staff, medical residents, cardiology fellows, and attending physicians were reinforced to adhere to the evidence-based management. In the post-intervention phase, charts of 140 consecutive patients with ICD-9 codes 410-414 for coronary syndromes were reviewed to assess the improvement in the same quality of care parameters. RESULTS: By reinforcement, a significant improvement was noted in all quality of care parameters studied. Proportion of patients who had total cholesterol measured on admission increased from 78% to 92% (P<0.005), and those who had fasting LDL cholesterol measured increased from 22% to 70% (P<0.0001). Use of aspirin at admission (in 74% of patients pre- vs. 80% of patients post-intervention, P<0.05), beta-blockers during hospitalization (in 62% of patients pre- vs. 78% of patients post-intervention, P<0.001), and ACE inhibitors in patients with left ventricular systolic dysfunction (in 58% of patients pre- vs. 89% of patients post-intervention, P<0.001) improved significantly after reinforcement to the medical personal. CONCLUSION: Reinforcement to adhere to the evidence-based management results in a significant improvement in the quality of care provided to the patients with coronary syndromes.

Adult↗

D1-like and D2 dopamine receptor antagonists administered into the shell subregion of the rat nucleus accumbens decrease cocaine, but not food, reinforcement.

Cocaine self-administration experiments were designed to assess the respective roles of D1-like and D2-like dopamine receptors in the ventral forebrain in cocaine reinforcement. D1-like or D2-like dopamine receptor antagonists were microinjected into the nucleus accumbens core, nucleus accumbens shell, neostriatum or lateral septum prior to sessions in which cocaine was self-administered under a progressive ratio schedule by rats. The results indicated that administration of a D1/5 (SCH-23390) or a D2/D3/D4 (eticlopride), but not a D3 (U99194A) or D4 (L-750,667), dopamine receptor antagonist into the core and shell of the nucleus accumbens decreased the reinforcing efficacy of cocaine. However, in control experiments intra-accumbal core administration of SCH-23390 or eticlopride decreased food self-administration, whereas administration of these drugs into the accumbens shell had no effect on food reinforcement. Neither SCH-23390 nor eticlopride influenced cocaine reinforcement when administered into the neostriatum or lateral septum. Collectively, these results indicate that D1-like and D2 dopamine receptors in the nucleus accumbens shell selectively modulate the reinforcing efficacy of cocaine, whereas D1-like and D2 dopamine receptors in the accumbens core have a more general influence on reinforced behaviors.

Animals↗