Stimulus compounding enhances conditioned suppression produced by cocaine-paired stimuli.

When 2 stimuli that occasion cocaine self-administration are presented in compound, their ability to increase cocaine-reinforced operant responding is substantially enhanced. The goal of the present experiment was to determine whether stimulus compounding could produce analogous enhancements of a classically conditioned drug effect. Food-maintained responding in rats was suppressed by a tone and a light that were individually paired with response independent cocaine (3 mg/kg iv). This conditioned suppression was significantly enhanced when the stimuli were presented together in a stimulus-compounding test. The magnitude of this enhancement was similar to that in previous studies in which responding was suppressed by shock-paired stimuli. These results demonstrate that multiple drug-related cues interact in a predictable manner to influence both operant and classically conditioned behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaine self-administration under conditions of restricted and unrestricted food access.

Four rhesus monkeys (Macaca mulatta), maintained at reduced body weight and restricted food availability, had access to a 0.8-mg/ml cocaine solution and vehicle under a concurrent fixed-ratio (FR) 8 schedule. Over days, the cocaine concentration was reduced (0.57, 0.4, 0.2, 0.1, 0.05, 0.025) and then returned, gradually over days, to 0.8 mg/ml. The ratio value was then varied (to 16, 32, 64, 128, and 8). Food access was unrestricted, and the ratio and the concentration manipulations were then repeated. During food restriction cocaine served as a reinforcer for all monkeys, whereas during free feeding cocaine functioned as a reinforcer for 3 of 4 monkeys; with these monkeys, the dose-response curve obtained under free feeding was shifted to the right of that obtained under food restriction. There were no differences in FR response curves obtained during food restriction and unrestricted feeding. These data suggest that food restriction increases cocaine's reinforcing effects and that the higher the cocaine dose, the greater are the reinforcing effects. A demand curve analysis was completed, and data are discussed in terms of microeconomic principles. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Potency of food deprivation intensity cues as discriminative stimuli.

Rats were trained to use stimuli arising from 0 and 24 hrs without food as discriminative signals for shock. In Exp 1, one group was shocked under 0-hr food deprivation and not shocked under 24-hr food deprivation. Another group received the reverse contingency. The groups received only 3 training trials under each deprivation level. Learning was revealed in a test phase when greater extinction of freezing was observed under the nonshocked than under the shocked deprivation level for both groups. A similar pattern of results was obtained in Exp 2 when auditory cues were also relevant throughout training. Furthermore, prior training with food deprivation cues seemed to reduce learning about auditory cues subsequently trained in compound with deprivation stimuli. The results indicate that food deprivation intensity cues can be potent discriminative stimuli. The idea that deprivation cues function as conditioned modulatory stimuli cues is also discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Instructions as discriminative stimuli in verbal conditioning and awareness.

This investigation was to study the effects of preconditioning instructions and type of reinforcer on level of awareness and extent of conditioning. Prior to a conditioning task, Ss in different experimental groups were given varying degrees of information concerning the nature of the reinforcement and the reinforcement contingency. In some groups of Ss the reinforcement consisted of E saying "good" while in other experimental groups the Ss received points as reinforcement. The results indicated that the degree of conditioning and level of awareness were partially dependent upon the amount of information in the preconditioning instruction. However, in experimental groups where only partial information was given, Ss who received points conditioned better than Ss who received "good" even though there were no differences in the level of awareness. The nature of the response class was also found to be an important variable that affected the level of conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interaction between drug discriminative stimuli and exteroceptive, sensory signals.

Interactions between drug discriminative stimuli based on 5.6 and 10 mg/kg sodium pentobarbital (ip) and exteroceptive stimuli (visual and auditory) were studied in 27 male Sprague-Dawley rats in a T-maze. In 3 groups, visual stimuli (light vs dark) were differentially paired with drug stimuli; the 4th group discriminated combinations of tonal frequencies (1 kHz or 10 kHz) and the presence or absence of pentobarbital (10 mg/kg). In general, visual stimuli controlled choice behavior (left or right turn) to a greater extent than did the drug training stimuli, whereas the auditory stimuli exerted no apparent control over the pentobarbital stimulus in Group 4. Tests with higher doses (13.75 and 17.5 mg/kg) indicated augmented stimulus control by the drug dimension in 2 groups (Group 1, 10 mg/kg pentobarbital vs saline; Group 2, 5.6 mg/kg vs 10 mg/kg pentobarbital) but not in the 3rd group (5.6 mg/kg pentobarbital vs saline) in the "conflict" situation, in which the exteroceptive conditions signaled one response whereas the drug stimulus signaled the opposite response. Discrimination training with only one of the stimulus dimensions resulted in stimulus control in the following order: 10 mg/kg vs saline?>?5.6 mg/kg vs saline?>?1 kHz vs 10 kHz. This indicates that the auditory stimuli were of marginal significance. It is concluded drugs can compete with exteroceptive, visual stimuli for associative strength. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug states as discriminative stimuli in a flavor-aversion learning experiment.

Injection of poison into rats after they drank in the presence of stimulus compounds of a drug state and a flavor resulted in little stimulus control by the drug state. In Exp I, half of the 16 male Sprague-Dawley rats were poisoned after drinking salt water while stimulated with amphetamine and after drinking sugar water while sedated with pentobarbital, but they were not poisoned after salt–pentobarbital (BY) or sugar–amphetamine (AX) combinations. The other half were subjected to counterbalanced procedures. Poisoning occurred after AX and BY stimulus combinations but did not occur after AY and BX combinations. In Exp II, 32 Ss were poisoned only after consuming a particular flavored solution (salt or vinegar) in a particular state (pentobarbital or undrugged); that is, if AX was poisoned, BX, BY, and AY were experienced without poisoning. There was complete counterbalancing of flavors and drug states. Exp II, with 23 Ss, was similar except that amphetamine was used instead of pentobarbital. In both experiments, there was some discrimination learning based on the drug state, but it was extremely weak. (21 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exposure to novel environmental stimuli decreases amphetamine self-administration in rats.

Researchers examined whether exposure to novel environmental stimuli reduces drug self-administration. Rats were trained to self-administer amphetamine on a fixed ratio (FR) 5 schedule of reinforcement and then were exposed to novel stimuli during the session. Responding was significantly decreased with exposure to novelty but returned to baseline levels on intervening nonexposure sessions. In 2 subsequent experiments, rats were exposed to novel plastic objects prior to the session. Immediately following exposure, rats were allowed to self-administer amphetamine on an FR 1 schedule, which was increased gradually to an FR 5 either using predetermined increments or on the basis of performance criteria. Exposure to the novel objects significantly decreased acquisition of amphetamine self-administration in both situations. Results suggest that exposure to novel environmental stimuli may be effective at reducing drug self-administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential control over drug-seeking behavior by drug-associated conditioned reinforcers and discriminative stimuli predictive of drug availability.

Conditioned stimuli (CSs) can control behavior either by activating responses when presented noncontingently or through their ability to maintain responding when presented contingently, that is, as conditioned reinforcers. In the present study, the extent to which drug-seeking behavior could be subject to these different types of stimulus control was studied by presenting to rats CSs that were either paired with each drug infusion or presented as discriminative stimuli (DSs) signaling the availability of drug. It was found that stimuli paired with either cocaine or heroin infusions increased drug seeking when presented contingent on responding, but not when presented noncontingently. By contrast, DSs that signaled cocaine availability increased drug seeking when presented either noncontingently or contingently. These results suggest that drug-seeking behavior can be influenced differentially by CSs and that conditioned reinforcers are especially important for maintaining prolonged sequences of drug-seeking behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaine use is associated with increased craving in outpatient cocaine abusers

Continuous treatment with transdermal nitroglycerin leads to tolerance development within the first day of application. Effective long-term therapy can be provided by interval treatment with nightly patch removal, but even during the hours of intermittent patch application there is rapid attenuation of initial effects. To assess whether an unattenuated antiischemic and antianginal efficacy during the hours of intermittent dosing can be maintained, a modified drug-release profile with increasing plasma concentrations was evaluated using a double-blind, placebo-controlled crossover protocol. Eleven patients with documented coronary artery disease received, in a randomized order, a total of four low-dose nitroglycerin patches (5 mg/24 h each) or placebo, respectively, at intervals of 3 hours. After a treatment interval of 12 hours, all patches were removed for an equally long patch-free interval prior to renewed application of one patch the next morning. At a comparable workload, reductions of ST-segment depression of 65%, 63%, and 56% were found at 2.5 hours, 8 hours, and 12 hours after application of the first patch on day 1, respectively (all significant vs. placebo; 2.5 hours vs. 12 hours, n.s.). On day 2, the comparable reduction of 63% at 2.5 hours after renewed application indicates prevention of tolerance development during subchronic treatment. Effects on exercise capacity and angina pectoris paralleled those on exercise-induced ST-segment depression. Plasma concentrations of nitroglycerin increased from 223 pg/mL to 558 and 803 pg/mL on day 1 and amounted to 205 ng/mL at 2.5 hours on day 2. Thus, interval therapy with increasing nitroglycerin concentrations provides unattenuated antiischemic and antianginal efficacy during the hours of treatment and circumvention of early tolerance during subchronic application. This modified pharmacokinetic profile can be regarded as a model for an improved dosage regimen in nitrate interval therapy.     

Cocaine craving, euphoria, and self-administration: A preliminary study of the effect of catecholamine precursor depletion.

The authors used the acute phenylalanine-tyrosine depletion (APTD) method to test the effect of transient catecholamine precursor depletion on cocaine craving, euphoria, and self-administration. Eight nondependent, nontreatment-seeking cocaine users self-administered 3 doses of cocaine (0.6, 1.5, 3.0 mg/kg, taken intranasally) following ingestion of (a) a nutritionally balanced amino acid mixture, (b) APTD, and (c) APTD followed by L-dopa/carbidopa (2 × 100 mg/25 mg). APTD decreased both cue and cocaine-induced drug craving but not euphoria or self-administration. APTD + L-dopa also decreased drug craving, possibly reflecting the ability of L-dopa to transiently decrease dopamine cell firing. Together, these preliminary results suggest that the craving elicited by cocaine and cocaine cues is related to changes in catecholamine neurotransmission. Euphoria and the self-administration of freely available drugs by regular users, in comparison, might be better accounted for by other mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Establishing morphine and U-50,488H as discriminative stimuli in a three-choice assay with pigeons.

Pigeons were trained in a 3-choice assay to discriminate among injections of 5.6 mg/kg U-50,488H, 5.6 mg/kg morphine, and vehicle solution. In dose-response tests, subjects rarely responded on the U-50,488H-appropriate key when morphine was administered or on the morphine-appropriate key when they received U-50,488H. A high dose of naltrexone (1.0 mg/kg) completely blocked the morphine cue but failed to block completely the U-50,488H cue. In generalization tests, d-amphetamine primarily engendered saline-appropriate responding. Ethylketazocine produced mixed results, in that moderate doses produced responding on both the morphine- and U-50,488H-appropriate keys, but 3.2 mg/kg engendered primarily morphine-appropriate responding. These results demonstrate the feasibility, but not necessarily the value, of 3-choice discrimination procedures involving mu and kappa agonists and vehicle. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of the relation between Pavlovian occasion-setting and instrumental discriminative stimuli: A blocking analysis.

Retracted October 1990. (See record 1991-03475-001.) Conducted 2 experiments with 72 male Sprague-Dawley rats, using a blocking design (A+, then AB+) to assess the relation between Pavlovian occasion-setting and instrumental discriminative stimuli. Prior conditioning of both associative and occasion-setting functions of A in a serial feature-positive procedure blocked acquisition of an instrumental discriminative function by a novel stimulus (B) trained in compound with A. Neither prior conditioning of only an A/unconditioned stimulus/stimuli (UCS) association nor prior conditioning of Stimulus A using a Pavlovian simultaneous feature-positive procedure, which does not endow A with an occasion-setting function, blocked acquisition of an instrumental discriminative function by B. Prior acquisition of an instrumental discriminative function by A blocked acquisition of a Pavlovian occasion-setting function by a novel stimulus (B) trained in compound with A but did not block acquisition of an association between B and the UCS. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned changes in dopamine oxidation currents in the nucleus accumbens of rats by stimuli paired with self-administration or yoked-administration of d-amphetamine

In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents corresponding to dopamine efflux in the nucleus accumbens of rats after presentation of a conditioned light stimulus repeatedly paired with either yoked- or self-administered intravenous injections of the psychostimulant d-amphetamine. Daily conditioning trials began with a non-contingent drug injection, paired with a conditioned stimulus consisting of a 5 s flashing light and 30 s lights out, after which a house light was illuminated during the 3 h session, signalling drug availability. Each subsequent injection of d-amphetamine was paired with the conditioned stimulus. Electrochemical measures were taken on conditioning trials 4-7, and on each trial, intravenous d-amphetamine (0.25 mg/kg per injection) self-administration produced a significant maximal increase in mean dopamine oxidation currents of approximately 8 nA above baseline. Dopamine oxidation currents in rats receiving yoked d-amphetamine were approximately 5 nA above baseline by the fourth day of drug administration and reached approximately 8 nA on the seventh and final day of drug administration. On day 9 the first presentation of the vehicle injection and conditioned stimulus, in combination with illumination of the house lights, induced an immediate increase in nucleus accumbens dopamine oxidation currents in all rats that had previously received d-amphetamine. Subsequent presentations of the conditioned stimulus at 30 min intervals induced further increases in extracellular dopamine oxidation currents in both drug-treated groups. By the end of the 3 h session, both groups had similar maximal conditioned increases in dopamine oxidation currents of approximately 6 nA. These data are discussed with relation to the neurochemistry of drug craving.     

Binge cocaine self-administration by humans: smoked cocaine

Tolerance develops to the cardiovascular and subjective effects of intravenous cocaine during single self-administration sessions, but diminishes within 3 h after the session ends. To examine whether a similar pattern of tolerance occurs to smoked cocaine, seven adult 'crack' cocaine users completed a protocol investigating changes in behavior during the repeated self-administration of smoked cocaine. During sessions, participants could self-administer up to 6 doses of smoked cocaine (50 mg per dose), one every 14 min. Both two- and three-day binge conditions were tested. During the two-day binge, a 2.5 h cocaine self-administration session began at 1200 h and again at 1600 h on two consecutive days, while during the three-day binge, self-administration sessions occurred at 1200 h and 1600 h on three consecutive days. The first one or two cocaine doses in each session increased cardiovascular and subjective effects ratings; subsequent cocaine inhalations during the session did not increase these measures further, suggesting the development of acute tolerance to these effects. Ratings of 'I want cocaine' decreased slightly across three days of repeated smoked cocaine self-administration, while anxiety scores increased slightly across three days, suggesting that some effects of smoked cocaine may persist beyond a binge.     

Discriminable stimuli produced by hallucinogens

Bison pancreatic ribonuclease was isolated by affinity chromatography. Thermolysin and tryptic digestion of denaturated protein, and subtilisin digestion of native protein yielded peptides, which were purified and submitted to amino acid analysis. These peptides, together with partial sequence data obtained by Stewart & Stevenson (16) overlap the entire amino acid sequence of bison ribonuclease. No differences with bovine ribonuclease were found, although there may be differences in state of amidation of some residues.     

Behavioral sensitization is induced by intravenous self-administration of cocaine by rats

Salicylate-kodein is a widely used analgesic agent, particularly in outpatient practice. Salicylates have been incriminated in hepatic injury while kodein may induce biliary spasm. We report here a case of granulomatous hepatitis attributed to prolonged intake of this combination, which has never been reported previously to our knowledge.     

The effect of increased response requirements on discriminative performance of the domestic hen in a visual acuity task

Six domestic hens were trained in a spatial discrimination task. A controlled reinforcement procedure insured that the ratio of scheduled and obtained reinforcement remained equal. Gray stimuli and gratings ranging in spatial frequency from 1 to 10 cycles per millimeter were presented in seven descending series of probes. The response requirement to the sample key was varied from fixed ratio 1 to fixed ratio 40 in seven experimental conditions. An increase in response requirements from fixed ratio 1 to fixed ratio 5 and fixed ratio 10 resulted in significantly higher accuracy at discriminable grating values. Further increases in response requirements did not consistently improve performance. Generally, response biases increased and occasionally became extreme for probes at finer gratings with increased response requirements.     

Intravenous preparations for self-administration of drugs by animals.

Describes the construction of the 5 components of iv drug self-administration preparations: (a) a chronically implanted venous catheter; (b) a harness worn by the animal; (c) a flexible leash, providing catheter protection, which is at tached at either end to the harness and to the cage wall; (d) a swivel joint in the leash allowing the animal to turn in the cage; and (e) an infusion pump. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaine seeking by rats is a goal-directed action.

In 2 experiments rats were trained to self-administer intravenous cocaine on chained schedules using different responses in the initial (drug-seeking) and terminal (drug-taking) links. In both between- (Exp 1) and within-subject designs (Exp 2), the drug-taking response was then either extinguished or reinforced in the absence of the opportunity to perform the seeking response. In a subsequent extinction test with the seeking manipulanda alone, the rate of drug seeking was reduced after the prior extinction of the associated taking response. An additional group trained with a sucrose reinforcer showed a comparable devaluation effect. These findings demonstrate that seeking responses for cocaine and food rewards are mediated by a representation of the contingency between seeking response and the opportunity to take the reward. (PsycINFO Database Record (c) 2010 APA, all rights reserved)