Priming effects with drugs and other reinforcers.

Abstinent drug users often report that taking even a small amount of their previously abused drug increases their desire for the drug and can lead to a full relapse. This apparent "priming" effect of drugs has been studied in both laboratory animals and humans. In animals trained to self-administer drugs, small amounts of a previously self-administered drug readily reinstate responding. In humans, administration of a previously abused drug increases self-reported craving and desire for the drug. Priming effects also occur with other reinforcers (e.g., presentation of a food stimulus increases food-reinforced responding). This article examines the generality of priming phenomena, and it examines some of the learned or unlearned processes that underlie the effect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

Fluvoxamine effects on concurrent ethanol- and food-maintained behaviors.

In previous studies, the selective serotonin reuptake inhibitor fluvoxamine preferentially reduced responding for ethanol compared with responding for food under conditions in which each was available alone in separate groups or in the same subjects under a multiple schedule in which baseline response rates were matched. The impact of providing concurrent access to food on pharmacological effects on ethanol self-administration remains largely unexplored. In this study, acute doses of fluvoxamine (3.0-17.8 mg/kg) were administered 30 min before the experimental session to Lewis rats responding under a concurrent fixed-ratio, fixed-ratio schedule of ethanol and food presentation. Ratios for food were adjusted for each subject to provide matched rates of food and ethanol reinforcement across the 30-min session. Although the number of ethanol and food deliveries did not significantly differ under baseline conditions, response rates did differ. Following fluvoxamine administration, responding for food was decreased more than responding for ethanol. This differential effect did not appear to be related to response rate or fixed-ratio size. Thus, the selectivity of fluvoxamine on ethanol- versus food-maintained responding depends on the context in which the behavior occurs. Such results may help explain inconsistencies between preclinical results and those in humans, and could provide insight into the behavioral determinants of pharmacological effects on ethanol self-administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The many facets of the locomotor response to a novel environment test: Theoretical comment on Mitchell, Cunningham, and Mark (2005).

Several animal studies have shown that there is a positive correlation between locomotor activity in response to a novel environment and acquisition of drug self-administration behavior. This finding led to the assumption that animals with heightened reactivity to novel environments are more sensitive to the rewarding effects of drugs compared with animals with reduced reactivity. But are these individuals really more responsive to drugs, or could they have enhanced sensitivity to rewards in general or even simply be better learners? In the previous issue of this journal, J. M. Mitchell, C. L. Cunningham, and G. P. Mark (2005) (see record 2005-03585-010), investigated these important matters. They reported that the locomotor response to a novel environment does not predict responding for cocaine but reflects overall differences in the ability to learn operant tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The observing-response procedure: A novel method to study drug-associated conditioned reinforcement.

In this experiment, the observing-response procedure was adapted for use with drug self-administration. Rats' responding for oral ethanol was sometimes reinforced on a random-ratio schedule, whereas at other times it had no effect (i.e., extinction). Behavior producing stimuli associated with the otherwise unsignaled random-ratio and extinction periods (i.e., observing behavior) was acquired and maintained. In a vehicle control condition, both self-administration and observing behavior decreased, but observing decreased less rapidly proportionally to baseline than vehicle consumption. Thus, conditioned reinforcers may have persistent effects that are relatively independent of the current status of the primary reinforcer. The procedure allows long-term study of drug-associated conditioned reinforcement and provides independent indexes of the conditioned reinforcing and discriminative stimulus effects of drug stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex differences in vulnerability to drug self-administration.

Recent evidence from both human and animal studies indicates that there are sex differences in all phases of the addiction process, including initiation and acquisition of use, patterns and levels of use, the progression to addiction, and relapse. This brief review summarizes a series of studies on sex differences in drug self-administration in rats on which the Wyeth Young Psychopharmacologist Award was based and relates these findings to human clinical data. Briefly, preclinical findings show that female rats acquire drug self-administration at a faster rate, work harder to obtain drug infusions, "binge" for longer initial periods of time and show a more diurnally dysregulated pattern of self-administration under extended-access conditions, and respond at higher levels under reinstatement testing conditions compared with male rats. Similar results have been reported in humans, suggesting a biological basis of sex differences in vulnerability to drug abuse. A number of biological mechanisms have been explored, and the results show that ovarian hormones play a critical role in modulating the reinforcing effects of drugs of abuse in females. Preclinical studies, in conjunction with human studies, should further inform a sex-specific model for differences in drug abuse, and such a model may be useful for developing prevention and treatment strategies for drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Telepathology diagnosis by means of digital still images: an international validation study

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.     

Saying versus doing and other methodological issues in the study of human drug self-administration.

Because experimental tests of drug reinforcement in humans expose participants to risks associated with the drug of interest, whether self-report or shorter testing periods could be used was examined. Across 5 studies of caffeine self-administration in humans, participants' self-reported preferences were discordant with their subsequent self-administration behavior on 8%–29% of occasions. This was due mostly to self-reports of preference for the caffeinated beverage followed by no greater actual self-administration. Correlational analysis and experimental tests also suggested shorter tests of self-administration produce some discordant results compared with longer tests. These results suggest that, at least for caffeine, self-reports and short self-administration tests are concordant with but are not complete substitutes for more extensive tests of drug self-administration in humans. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Environments as cues to smoke: Implications for human extinction-based research and treatment.

Animal research has shown that the environments, or contexts, in which drug use occurs can play a key role in how animals respond to drug-related cues. Less is known about the role of environmental contexts in human drug-dependence research. Traditionally, cue-based studies and treatments focus on conditioned cues most proximal to drug administration (e.g., lit cigarettes, pictorial stimuli of drug paraphernalia). However, there is reason to believe that more distal cues, such as the environments in which drugs were previously used, might similarly gain associative control over human responding. This article describes a body of systematic research aimed at identifying and studying the impact of environmental contexts on smokers' cue reactivity in the laboratory. Overall, results of this program of research demonstrate that exposure to environments associated with smoking, but completely devoid of proximal smoking cues, can function as conditioned stimuli capable of evoking strong subjective responding from abstinent smokers. Furthermore, more robust reactivity can be achieved if environmental context cues are personalized using novel techniques described in this article. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strain differences in maintenance of cocaine self-administration and their relationship to novelty activity responses.

The authors previously demonstrated that Fischer 344 (F344) and Lewis inbred rats differ in acquisition of cocaine self-administration. Other studies show that acquisition and maintenance of drug self-administration are predicted by locomotor activity in a novel environment among outbred Sprague-Dawley rats. The present study was designed to determine whether this relationship extended to F344 and Lewis rats. In Experiment 1, F344, Lewis, and Sprague-Dawley rats were trained to self-administer cocaine and tested with several doses under fixed- and progressive-ratio schedules of reinforcement. Self-administered infusions and ineffective active lever presses--those emitted during infusion and time-out periods--were assessed. In Experiment 2, separate sets of rats of each strain were examined for locomotor responses (distance traveled and center time) under novelty conditions. Results show that F344 rats self-administer more cocaine than Lewis or Sprague-Dawley rats under both schedules and emit more ineffective lever presses--a possible measure of craving. Strain comparisons of locomotor responses suggest that center time, not activity, relates to self-administration behavior. Maintenance studies of cocaine self-administration rather than acquisition may better reflect vulnerability to addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration.

Extinction of classically and instrumentally conditioned behaviors, such as conditioned fear and drug-seeking behavior, is a process of active learning, and recent studies indicate that potentiation of glutamatergic transmission facilitates extinction learning. In this study, the authors investigated the effects of the Type-5 metabotropic glutamate receptors (mGluR5) positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction of cocaine-seeking behavior in rats with a history of intravenous cocaine self-administration. To assess its effects on acquisition and consolidation of extinction learning, CDPPB (60 mg/kg) or vehicle was administered either 20 min prior to, or immediately following, each of 10 extinction sessions, respectively. When administered prior to each extinction session, CDPPB produced a significant reduction in the number of active lever presses on all 10 days of extinction training as compared to vehicle-treated animals. When administered following each extinction session, a significant reduction in the number of active lever presses was observed on the 2nd through 10th day of extinction. Both treatment regimens also reduced the number of extinction-training sessions required to meet extinction criteria. Pre- or postextinction-training administration of CDPPB did not alter responding on the inactive lever and had no effects on open field locomotor activity. These data indicate that positive allosteric modulation of mGluR5 receptors facilitates the acquisition and consolidation of extinction learning following cocaine self-administration and may provide a novel pharmacological approach to enhancing extinction learning when combined with cue exposure therapy for the treatment of cocaine addiction. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Reinforcing effects of stimulants in humans: Sensitivity of progressive-ratio schedules.

Drug self-administration methodologies have been developed for use in humans to model naturalistic stimulant drug-taking behaviors. These methodologies use a number of schedules of reinforcement, including progressive-ratio schedules. As the name implies, in a progressive-ratio schedule, the response requirement for each subsequent delivery of drug increases, and the primary outcome variable is often the break point (i.e., the last ratio completed to receive a drug delivery). These schedules have been used in a number of human laboratory studies evaluating the reinforcing effects of stimulants. The results of these studies have demonstrated that progressive-ratio schedules are sensitive to manipulation of a pharmacological variable, dose, and to nonpharmacological variables contributing to stimulant drug effects. In addition, findings with progressive-ratio schedules are largely concordant with clinical findings, suggesting that drug self-administration under these schedules has predictive validity in terms of drug abuse and dependence. Future research is necessary, however, to understand better how pharmacological factors like route of administration, onset of effects, and pretreatment influence the reinforcing effects of stimulants under progressive-ratio schedules. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Renewal of drug seeking by contextual cues after prolonged extinction in rats.

Contextual stimuli associated with drug exposure can modulate various effects of drugs, but little is known about their role in relapse to drug seeking. Using a renewal procedure, the authors report that drug-associated contextual stimuli play a critical role in relapse to drug-seeking previously maintained by a heroin-cocaine mixture (speedball). Rats were trained to self-administer speedball, after which drug-reinforced behavior was extinguished over 20 days in the self-administration context or in a different context. On the test day, rats exposed to the drug-associated context, after extinction in a different context, reliably renewed drug seeking. The authors suggest that the renewal procedure can be used to study mechanisms underlying relapse to drug seeking elicited by drug-associated contextual stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats

Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex.     

Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats.

Estradiol benzoate (EB) facilitates the acquisition and reinstatement of cocaine-seeking behavior when administered to ovariectomized (OVX) rats. In contrast, progesterone (P) decreases acquisition of cocaine self-administration, but the effects of P on the reinstatement of drug seeking are not known. The purpose of the present study was to compare the effects of EB and P on the reinstatement of cocaine-seeking behavior in female rats. Rats received either OVX or sham surgery (SH) and were trained to lever press for intravenous cocaine infusions (0.4 mg/kg) under a fixed ratio 1, 20-s time-out schedule during daily 2-hr sessions. After 14 days of stable responding, saline replaced cocaine, and a 21-day extinction period began. After extinction, rats were separated into 5 treatment groups (OVX+EB, OVX+EB+P, OVX+vehicle [VEH], SH+P, or SH+VEH), and VEH, EB, or EB+P was administered 30 min prior to each session for 5 days. After 3 days of hormone treatment, rats received a saline or cocaine (10 mg/kg) injection, and reinstatement of lever responding was assessed. Reinstatement responding in the OVX+EB group was greater relative to the OVX+EB+P, SH+P, and OVX+VEH groups, which had low levels of cocaine-primed responding. The SH+VEH and OVX+EB groups displayed similar high levels of cocaine-elicited reinstatement. The suppression of cocaine-induced reinstatement following P treatment suggests a role for P in the prevention of relapse to cocaine self-administration in female cocaine users. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impulsive choice as a predictor of acquisition of IV cocaine self- administration and reinstatement of cocaine-seeking behavior in male and female rats.

Drug abuse and impulsive choice are related in humans. In female rats, impulsive choice predicted the rate of acquisition of IV cocaine self-administration. The objectives of the present experiments were to: (a) compare impulsive choice in males and females, (b) extend previous research on impulsive choice and acquisition of cocaine self-administration to males, and (c) compare males and females during maintenance, extinction, and reinstatement of cocaine-seeking behavior. Male and female rats were trained on an adjusting delay task in which a response on one of two levers yielded one food pellet immediately, and a response on the other resulted in three pellets after an adjusting delay that decreased after responses on the immediate lever and increased after responses on the delay lever. A mean adjusted delay (MAD) was used as the quantitative measure of impulsivity. In Experiment 1, MADs were analyzed for sex differences. In Experiment 2, acquisition of cocaine self-administration was examined in rats selected for high (HiI; MADs ≤9 seconds) or low (LoI; MADs ≥13 seconds) impulsivity. In Experiment 3, HiI and LoI groups were compared on maintenance and extinction of cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior. There were no sex differences in impulsive choice; however, HiI male and female rats acquired cocaine self-administration faster than their LoI counterparts. LoI females responded more on a cocaine-associated lever during maintenance and extinction than HiI females, but HiI females showed greater reinstatement of cocaine-seeking behavior than all other groups at the highest dose tested (15 mg/kg). Thus, individual differences in impulsive choice were associated with differences in cocaine-seeking behavior. Impulsive choice and sex may be additive vulnerability factors in certain phases of drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Potential Role of Drug Onset Cues in Drug Dependence and Withdrawal: Reply to Bardo (2004), Bossert and Shaham (2004), Bouton (2004), and Stewart (2004).

In responding to commentaries (M. Bardo, see record 2004-10475-002; J. Bossert and Y. Shaham, see record 2004-10475-003; M. Bouton, see record 2004-10475-004; J. Stewart, see record 2004-10475-005) on their original article (see record 2004-10475-001), the authors agree that the basic mechanisms underlying intra-administration associations may be extensible to a much wider range of phenomena, including both other examinations of conditioned drug effects (e.g., conditioned place preference) and human psychological disorders. The authors also address the concerns of a number of the commenting authors regarding discrepancies in the literature concerning the effects of drug priming in both human and animal studies of reinstatement of drug self-administration. Finally, the authors accept and endorse the calls by several of these commenting authors for further studies required to generate additional support for their model of conditioned drug effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Individual differences in the effect of novel environmental stimuli prior to amphetamine self-administration in rats (Rattus norvegicus).

These experiments determined whether individual differences in response to novelty subsequently predict the ability of novel stimuli, presented prior to the session, to decrease amphetamine self-administration. Using an inescapable locomotor test, the authors found that high-responder rats (Rattus norvegicus) showed a greater novelty-induced decrease in the acquisition of self-administration compared with low-responder rats. This effect was dose dependent and generalized to sucrose-reinforced responding. Using a free-choice place preference test, the authors found that high-novelty-seeking rats also showed a greater novelty-induced decrease in the acquisition of self-administration compared with low-novelty- seeking rats. Regardless of individual differences, novelty had little effect on amphetamine self-administration during the maintenance phase. These results suggest that exposure to novel environmental stimuli may reduce acquisition of drug-taking behavior, especially among high-novelty-seeking individuals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of phentermine on responding maintained under multiple fixed-ratio schedules of food and cocaine presentation in the rhesus monkey

Drugs that decrease drug-maintained responding at doses that do not decrease other behaviors in animals may be suitable candidates for development as medications to treat drug abuse in humans. The present study examined whether this effect could be obtained with phentermine, a drug that has been reported to decrease cocaine intake in humans. Rhesus monkeys were trained under multiple fixed-ratio 30-response schedules of food and i.v. cocaine delivery. Phentermine was always given as a slow, i.v. infusion. Acute treatment with phentermine (0.3-10 mg/kg) decreased cocaine-maintained responding at doses that did not decrease, or decreased less, food-maintained responding for each of three unit doses of cocaine (10-100 microg/kg/injection). Subacute treatment with phentermine (3 or 5.6 mg/kg, daily) also decreased cocaine-maintained responding more than food-maintained responding. After subacute treatment was terminated, rates of cocaine-maintained responding generally recovered to levels comparable to those seen during untreated control sessions. Phentermine (0.3-3 mg/kg) did not generally increase responding associated with a very low (1 microg/kg/injection) unit dose of cocaine, suggesting that the decrease in cocaine-maintained responding at higher unit doses was not the result of a leftward shift in the cocaine unit dose-effect function. Phentermine (0.1-3 mg/kg) decreased responding maintained by 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-[3-phenylpropyl] piperazine (GBR 12909) (30 microg/kg/injection) at doses similar to those that decreased food-maintained responding. These results show that phentermine is effective in decreasing cocaine self-administration and suggest that it may be an effective medication for cocaine abuse.     

Automatic processing of fundamental information: The case of frequency of occurrence.

Reviews the evidence that suggests that information about frequency of occurrence is stored in memory by an implicit or automatic encoding process. This evidence shows that frequency information is stored for a wide variety of naturally occurring events. Laboratory research shows that usually powerful task variables (e.g., instructions, practice) and S variables (e.g., age, ability) do not influence the encoding process. Evidence is also reviewed that either directly or indirectly implicates the use of frequency information across issues in psychology ranging from the acquisition and representation of knowledge domains to decision making to sex-role development. (120 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)