Modulation of cocaine- and methamphetamine-induced behavioral sensitization by inhibition of brain nitric oxide synthase

Evidence suggests the existence of multiple interactions between dopamine, glutamate and nitric oxide (NO) in brain structures associated with psychomotor stimulation. The present study was undertaken to investigate the effect of the relatively selective inhibitor of the neuronal nitric oxide synthase (NOS) isoform, 7-nitroindazole (7-NI), on the development of sensitization to the locomotor stimulating effect of cocaine and methamphetamine (METH). Male Swiss Webster mice that received 15 mg/kg cocaine once a day for 5 days developed a marked locomotor sensitization to a challenge cocaine (15 mg/kg) or cross-sensitization to a challenge METH (0.5 mg/kg) injection given after a 10-day drug-free period. This treatment also produced a context-dependent sensitization as evident by the sensitized response to a challenge saline injection. Pretreatment with 7-NI (25 mg/kg) 30 min before cocaine administration (5 days) completely blocked the induction of sensitization to cocaine, the cross-sensitization to METH and the conditioned locomotion induced by cocaine. 7-NI when given alone, either acutely or for 5 days, had no significant effect on the locomotor activity of animals. Animals treated with METH (1.0 mg/kg) for 5 days developed marked sensitization to challenge METH (0.5 mg/kg), cross-sensitization to challenge cocaine (15 mg/kg) and context-dependent locomotion. Pretreatment with 7-NI (25 mg/kg) attenuated the sensitized response to METH and the cross-sensitization to cocaine as revealed after a 10-day drug-free period. However, the METH-induced conditioned locomotion was unaffected by the pretreatment with 7-NI. The present study supports the role of brain NO in the development of sensitization to both psychostimulants, cocaine and METH. However, it appears that the inability of 7-NI to completely abolish the sensitized responses induced after METH administration is the result of the resistible conditioned locomotion caused by METH, but not by cocaine.     

The Discriminative Stimulus Effects of Cocaine in a Pavlovian Sexual Approach Paradigm in Male Japanese Quail.

Two groups of male Japanese quail (Coturnix japonica) to discriminate cocaine from saline in a conditioned approach procedure maintained by sexual reinforcement. For 1 group, cocaine (10 mg/kg ip) was administered prior to a conditioned stimulus (CS) that predicted copulation; saline followed by a CS predicted no copulation. A second group underwent the opposite training regimen. Results revealed apparent between-group differences in the rates of acquisition of the discrimination; however, during extinction trials, both groups responded more under the drug condition that predicted the female than to the condition that predicted no female. The results suggested that a drug discrimination may be maintained by sexual reinforcement. The findings are discussed with regard to interactions of cocaine and sexual reward, as well as to Pavlovian conditional stimulus control. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Transient inactivation of the ventral tegmental area selectively disrupts the expression of conditioned place preference for pup- but not cocaine-paired contexts.

The ventral tegmental area (VTA) plays a critical role in motivated behavior. However, it remains unclear whether intact VTA function is necessary for motivated behavior to seek contexts repeatedly paired with natural stimuli and/or pharmacological stimuli. In the present study, conditioned place preference (CPP) was induced with highly salient natural or drug stimuli attributed with strong incentive–motivational value in each of 2 female models: Postpartum females were conditioned to associate one unique context in the CPP apparatus with young offspring (pups) and a second context with a neutral stimulus, and virgin females were conditioned to associate unique contexts with cocaine (5 mg/kg ip) and saline injections. Immediately before CPP testing, each female received a microinfusion of bupivacaine bilaterally into the VTA to transiently inactivate the region; subjects were also tested after saline microinfusion into the VTA. Postpartum females’ preference for the pup-paired context was abolished by VTA inactivation but was restored to high control levels after saline microinfusion. In separate tests, VTA inactivation also reduced motivated pup licking and pup retrieval in postpartum females, suggesting that intact VTA function is required for the expression of both pup CPP and motivated pup-directed behaviors. Cocaine CPP remained unaffected by VTA inactivation. Locomotion was not affected by VTA microinfusions but was severely impaired by bupivacaine microinfusions into the substantia nigra. We concluded that the VTA is differentially involved in the expression of conditioned preference for contexts paired with pups, a salient natural stimulus, and contexts paired with cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Competition between the conditioned rewarding effects of cocaine and novelty.

Access to novelty might provide an alternative learning history that competes with conditioned drug reward. We tested this suggestion in rats using a place conditioning procedure with cocaine and novelty. In Experiment 1, rats were conditioned with cocaine to prefer one side of an apparatus. In a subsequent phase, cocaine exposure continued; however, on the unpaired side, separate group of rats had access to novel objects, cocaine injections, or saline with no objects. Pairings with novel objects or cocaine shifted a preference away from the cocaine-paired environment during drug-free and drug-challenge tests. Experiment 2 tested novelty's impact when cocaine exposure was discontinued. The identical procedures were used except drug exposure ceased on the cocaine-paired side during the second phase. Both groups expressed a preference for the cocaine compartment. This preference was maintained for rats that did not have novel objects; however, rats that experienced novelty spent similar amounts of time in both compartments during both tests. Overall, the conditioned rewarding effects of novelty competed with those of cocaine as evidenced by a change in choice behaviors motivated by drug reward. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"The Discriminative Stimulus Effects of Cocaine in a Pavlovian Sexual Approach Paradigm in Male Japanese Quail": Correction to Troisi and Akins (2004).

Reports an error in the original article by J. R. Troisi, II and Chana Akins (Experimental and Clinical Psychopharmacology, 2004, Vol. 12, No. 4, pp. 237-242). The first sentence of the abstract, "Two groups of male Japanese quail (Coturnix japonica) to discriminate cocaine from saline in a conditioned approach procedure maintained by sexual reinforcement," was incomplete. The correct wording is "Two groups of male Japanese quail (Coturnix japonica) were trained to discriminate cocaine from saline in a conditioned approach procedure maintained by sexual reinforcement." (The following abstract of this article originally appeared in record 2004-20800-003.) Two groups of male Japanese quail (Coturnix japonica) to discriminate cocaine from saline in a conditioned approach procedure maintained by sexual reinforcement. For 1 group, cocaine (10 mg/kg ip) was administered prior to a conditioned stimulus (CS) that predicted copulation; saline followed by a CS predicted no copulation. A second group underwent the opposite training regimen. Results revealed apparent between-group differences in the rates of acquisition of the discrimination; however, during extinction trials, both groups responded more under the drug condition that predicted the female than to the condition that predicted no female. The results suggested that a drug discrimination may be maintained by sexual reinforcement. The findings are discussed with regard to interactions of cocaine and sexual reward, as well as to Pavlovian conditional stimulus control (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Music-induced context preference following cocaine conditioning in rats.

Traditional models of drug-seeking behavior have shown that exposure to associated environmental cues can trigger relapse. These learned associations take place during repeated drug administration, resulting in conditioned reinforcement. Although considerable investigation has occurred regarding simple conditioned stimuli, less is known about complex environmental cues, particularly those that may be salient in human addiction. Recent studies indicate that music can serve as a contextual conditioned stimulus in rats and influence drug-seeking behavior during abstinence. The purpose of the present study was to further assess the effectiveness of music as a conditioned stimulus in rats, to determine rats' preferences for two contrasting pieces of music, and to determine rats' preferences for music versus silence. To this end, we created an apparatus that gave instrumental control of musical choice (Miles Davis vs. Beethoven) to the rats themselves. After determining baseline musical preference, animals were conditioned with cocaine (10 mg/kg) to the music they initially preferred least, with alternating conditioning sessions pairing saline with the music preferred most. The animals were subsequently tested in a drug-free state to determine what effect this conditioning had on musical preference. The results indicate that music serves as an effective contextual conditioned stimulus, significantly increasing both musical preference and locomotor activity after repeated cocaine conditioning. Furthermore, we found that rats initially favor silence over music, but that this preference can be altered as a result of cocaine-paired conditioning. These findings demonstrate that, after repeated association with reward (cocaine), music can engender a conditioned context preference in rats; these findings are consistent with other evidence showing that musical contextual cues can reinstate drug-seeking behavior in rats. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

A simple slide-rule method for the assessment of renal tubular reaborption of phosphate in man

Twenty-five male Sprague-Dawley rats were trained in five two-lever operant chambers on a DRL-15 sec schedule of positive food reinforcement to discriminate 10 mg/kg cocaine from 1 ml/kg saline. Following acquistions of discrimination a counterbalanced design of extinction tests was performed before and after repeated administration of 20 mg/kg cocaine or saline (three times a day at five hr intervals for seven days). The extinction tests consisted of testing responses of animals following 1 ml/kg saline, 2.5 mg/kg cocaine, or 5 mg/kg cocaine. The results showed no significant difference in animals' level choice before and after repeated injection with saline. However, the percent cocaine lever choice with the two doses of cocaine was lower after repeated administration of cocaine than before the repeated injections. This indicates tolerance developed to the discriminative stimulus properties of cocaine.     

Neonatal exposure to cocaine enhances the reward-potentiating properties of the drug in young adult animals.

Either cocaine (20 mg/kg) or saline vehicle was administered to rat pups once daily on postnatal days 1–8. The enhancement of braid stimulation reward (BSR) by acute administration of cocaine (2.5, 5, and 10 mg/kg ip) was assessed in adult offspring (70–90 days of age) using a rate-frequency curve-shift paradigm. Acute administration of cocaine produced orderly dose-related shifts of the rate-frequency function toward lower frequencies in all groups indicating a reward-enhancing effect of the drug on BSR. However, offspring neonatally exposed to cocaine displayed a greater drug-induced potentiation of BSR. Of particular note, the small but significant enhancement of the reward-potentiating properties of cocaine was more pronounced in female offspring neonatally exposed to the drug. These findings indicate that the rewarding properties of cocaine were altered by neonatal exposure to the drug in a sexually dimorphic fashion. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Thrombin induced inhibition of neurite outgrowth from dorsal root ganglion neurons

Adrenalectomy (ADX) is known to block the acquisition of intravenous cocaine self-administration. A previous study therefore examined whether ADX decreases sensitivity of the 'brain reward system' in general, or its response to cocaine in particular, by measuring thresholds for intracranial self-stimulation with and without concurrent cocaine administration. ADX had no effect on thresholds for lateral hypothalamic self-stimulation (LHSS) and did not alter the cocaine dose-response curve for lowering the LHSS threshold. This result suggested that ADX does not affect sensitivity of the brain reward system. However, medial prefrontal cortex (MPFC) appears to be an important site in the mediation of cocaine reinforcing effects, and MPFC self-stimulation (MPFCSS) is mediated by a neural substrate that is largely independent of that which mediates LHSS. The present study therefore assessed whether ADX diminishes cocaine facilitation of MPFCSS. It was found that the threshold-lowering effect of cocaine (5.0, 10.0 and 20.0 mg/kg, i.p. ) did not differ between ADX rats maintained on 0.7% saline, ADX rats maintained on corticosterone (50 microg/ml) in 0.7% saline, and sham-operated controls. However, there was a trend toward desensitization of MPFCSS, itself, following ADX in the group that did not receive corticosterone supplementation. Based on this observation, and the similar responses of MPFCSS and cocaine self-administration to noncontingent priming stimulation, stress, and NMDA receptor antagonism, it is speculated that acquisition of MPFCSS and cocaine self-administration may be dependent upon a common sensitization process that is regulated by corticosterone.     

Competition between novelty and cocaine conditioned reward is sensitive to drug dose and retention interval.

The conditioned rewarding effects of novelty compete with those of cocaine for control over choice behavior using a place conditioning task. The purpose of the present study was to use multiple doses of cocaine to determine the extent of this competition and to determine whether novelty’s impact on cocaine reward was maintained over an abstinence period. In Experiment 1, rats were conditioned with cocaine (7.5, 20, or 30 mg/kg ip) to prefer one side of an unbiased place conditioning apparatus relative to the other. In a subsequent phase, all rats received alternating daily confinements to the previously cocaine paired and unpaired sides of the apparatus. During this phase, half the rats had access to a novel object on their initially unpaired side; the remaining rats did not receive objects. The ability of novelty to compete with cocaine in a drug free and cocaine challenge test was sensitive to cocaine dose. In Experiment 2, a place preference was established with 10 mg/kg cocaine and testing occurred after 1, 14, or 28 day retention intervals. Findings indicate that choice behaviors mediated by cocaine conditioning are reduced with the passing of time. Taken together, competition between cocaine and novelty conditioned rewards are sensitive to drug dose and retention interval. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective absorption of radio frequency energy due to collective motion of charged domains: case of lysozyme crystal

The role of the N-methyl-D-aspartate (NMDA) receptors in cocaine conditioning and sensitization of locomotor activity was studied in four groups of Sprague-Dawley rats. A sub-motoric dose of the NMDA antagonist MK-801 (0.1 mg/kg, i.p.) was employed using a novel dual-compartment Pavlovian drug conditioning paradigm. The animals were placed sequentially in two different test environments in which locomotor activity was monitored. In the first compartment, the animals always received a non-drug test for 20 min. Upon completion of this test, the animals received either saline, cocaine (10 mg/kg i.p.), MK-801 or MK-801 plus cocaine depending on group assignment and were then placed immediately into the second compartment and again tested for 20 min. A total of six non-drug and six drug tests were conducted every other day over a 12-day period. Across all drug/saline treatment and post-treatment tests for conditioning, there were no statistical differences in locomotor activity among the saline and drug treatment groups in the non-drug test environment. In the drug/saline associated environment, however, cocaine had a reliable stimulant effect on locomotion when administered alone or in combination with MK-801. Following a 1-day and again after 21-days of withdrawal, all animals were administered a non-drug test for conditioning in which no injections were administered. On both tests, all groups had equivalent activity levels in the non-drug environment. In the drug/saline environment, only the cocaine group of the three drug treatment groups exhibited conditioned hyperlocomotion. Importantly, MK-801 blocked conditioned hyperlocomotion in the combined cocaine+MK-801 group. MK-801 did not alter serum or brain cocaine concentration or the cocaine effects on dopamine metabolism in limbic brain tissue. The co-administration of MK-801 with cocaine, however, blocked the corticosterone release effect of cocaine. Thus, the NMDA receptor site appears critical for cocaine induced conditioning and for corticosterone release.     

Cocaine-induced effects on isolation stress in neonatal rats.

The effects of cocaine administration on isolation-induced vocalizations and activity levels in 10-day-old rat pups were examined. Day 10 pups given cocaine (1.25, 2.5, 5, 10, and 20 mg/kg ip) vocalized significantly less than their caffeine- (10 mg/kg) and saline-administered siblings during a 5-min isolation period. Cocaine- and caffeine-administered pups also demonstrated a significant increase in overall activity compared with controls. In addition, ip administration of the dopamine antagonist haloperidol (0.5 and 1.0 mg/kg) before 1.25 and 2.5 mg/kg cocaine produced a significant elevation in vocalizations compared with saline pretreatment, which indicates a blocking of cocaine's effect on calling behavior. These results suggest that the endogenous dopamine system involved with reinforcement and reward may quell the stress of isolation in the infant rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned suppression of medial forebrain bundle and septal intracranial self-stimulation in the rat: Evidence for a fear-relief mechanism of the septum.

In 3 experiments, a conditioned emotional response (CER) paradigm was presented to 2 groups of male albino Sprague-Dawley rats (N?=?20) during intracranial self-stimulation (ICSS). One group barpressed for medial forebrain bundle (MFB) stimulation reward; the other group barpressed for septal stimulation reward. The MFB ICSS was found to be suppressed by the CER procedure, but this procedure failed to suppress septal ICSS. The difference between the 2 sites was found only when both MFB and septal ICSS current intensities were available at their optimal levels. When ICSS current intensities were lowered to either threshold or medium level, both groups exhibited the CER suppression effect. Ss were also tested for a possible analgesic effect produced by the ICSS. MFB stimulation was found to produce some degree of analgesia, but septal stimulation failed to produce any analgesic effect. Thus, the possibility that the attenuation of the CER suppression effect in the septal group was due to analgesia was excluded. The difference in MFB and septal ICSS behavior during the presentation of the aversive stimulus suggests a possible qualitative distinction between the reward functions of the 2 sites, and a possible fear-reduction property of the septal area. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

IgE levels in cord and capillary blood at 5 days of age

This study was designed to investigate the predictive validity of a recently described chronic mild-stress-induced anhedonia model of depression. In an intracranial self-stimulation (ICSS) paradigm, rats were allowed to self-stimulate in the ventral tegmental area. Stimulation frequency thresholds for ICSS responses were determined prior to, during, and after a 19-day period of exposure to a variety of mild, intermittent, unpredictable stressors. After nine days of mild stress, stimulation threshold was significantly increased, suggesting a gradual decrease in the rewarding properties of brain stimulation. This anhedonic state lasted throughout the stress period and slowly disappeared over a 10-day period after termination of the stress regimen. This stress-induced increase in ICSS threshold was not observed in rats that were stressed and concomitantly treated with the reversible inhibitor of monoamine oxidase type A (RIMA) moclobemide (20 mg/kg, b.i.d.). In nonstressed animals treated with vehicle or moclobemide, no significant change in ICSS occurred during the course of the experiment. These experimental results reinforce the value of this animal model with respect to its predictive and construct validity.     

Dissociation of conditioned locomotion and Fos induction in response to stimuli formerly paired with cocaine.

A discrete stimulus (flashing light) was paired with cocaine (20 mg/kg) to induce conditioned locomotion. To identify brain regions activated during this response, Fos was measured with immunohistochemistry. Although paired subjects displayed robust conditioned locomotion, Fos was not increased in any limbic brain regions analyzed. In contrast, pairing of cocaine with generalized contextual cues (whole room) produced conditioned locomotion and Fos activation in the prelimbic portion of prefrontal cortex and the nucleus accumbens core. These results suggest that the pattern of neuronal activation during cocaine-conditioned activity differs depending on whether a discrete or contextual stimulus is used as a conditioned stimulus. The possibility that expectancy and frustrative nonreward contribute to Fos expression in rats conditioned to contextual cues is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Regulation of gene expression in developing epidermal epithelia

Studies of conditioned locomotor activity typically use an entire environmental context as the conditioned stimulus. To determine whether conditioned locomotion can be elicited by specific, discrete stimuli similar to those used in traditional studies of classical conditioning, rats were injected intraperitoneally (i.p.) with saline before 30 min sessions in a locomotor activity chamber. Interspersed (one to two times a week) with these baseline sessions, the rats were injected with cocaine (20 mg/kg) and placed in the chamber with a tone or flashing light present. Although baseline levels of activity remained stable, locomotion increased (sensitized) over six drug-stimulus pairings. Conditioned locomotor activity was elicited when the stimuli were then presented in the absence of cocaine. When a cocaine challenge was administered, locomotor activity was higher in the presence of the conditioned stimuli than in their absence, indicating that conditioning contributed to sensitization. These conditioned effects did not occur in control groups in which cocaine was not associated with the stimulus. To determine whether reinforcing properties had been conditioned to the stimuli, the rats were then tested in an operant chamber where responding in one nose-poke hole produced a 2 s conditioned-stimulus presentation. Rats that had received stimulus-drug pairings responded at a higher rate in this hole than in another, inactive hole. Locomotor activity can thus be conditioned to discrete stimuli, and the reinforcing properties conditioned to these stimuli can transfer to other environments. In this respect, the drug-conditioning effects seen in rodents appear to be analogous to the conditioned responses observed when human drug abusers are presented with discrete, drug-related stimuli.     

Attenuation of cocaine kindling by 7-nitroindazole, an inhibitor of brain nitric oxide synthase

Recent studies suggest the involvement of the N-methyl-D-aspartate (NMDA) type of glutamate receptors and nitric oxide synthase (NOS) in the process of increased sensitivity to the convulsive effect of cocaine ("cocaine kindling"). The present study was undertaken to analyze the various behavioral stages in the development of cocaine kindling and to investigate the effect of 7-nitroindazole (7-NI), a relatively selective inhibitor of the neuronal NOS isoform, on the induction and expression of sensitization to the convulsive effect of cocaine. Also, the effect of 7-NI on responses produced by acute systemic administration of cocaine or N-methyl-D,L-aspartate (NMDLA) was investigated. Cocaine kindling was assessed on a five-stage scale following the administration of a sub-convulsant dose of the drug (35 mg/kg/day; i.p.) to Swiss Webster mice for 10 days. Stage 5 seizures developed following the 9th day of cocaine administration. Pre-treatment with 7-NI (25 mg/kg/day; i.p.) 15 min before cocaine for 10 days completely prevented the appearance of stage 4 and 5 seizures, and it significantly attenuated stage 3 behavior in response to a challenge cocaine dose (35 mg/kg) given either 24 hr or 10 days after 7-NI/cocaine administration was stopped. A single injection of 7-NI (25 mg/kg; i.p.) completely prevented the expression of cocaine kindled seizures. Whereas 7-NI had no effect on the responses elicited by acute cocaine administration (60 mg/kg; i.p.), this agent partially attenuated the effects induced by systemic administration of the NMDA receptor agonist NMDLA (250 mg/kg; i.p.). The present study indicates that 7-NI attenuates both the induction and expression of sensitization to the convulsive effect of cocaine. The findings that 7-NI attenuated cocaine kindling and partially blocked the effects produced by activation of the NMDA receptor, but not the effects induced by acute cocaine administration, support the role of the NMDA receptor and brain NOS in the development of cocaine kindling rather than in the acute effects of the drug.     

Intravenous gestational cocaine in rats: effects on offspring development and weanling behavior

Pregnant rats were injected with cocaine (CN; 6 mg/kg) or an equal volume of saline (SAL), via the tail vein, on gestation days 8-20. A third group was untreated (UT). Maternal weight gain was not affected by dam treatment despite slight differences in food intake. Litter characteristics (e.g., litter size, pup weight) did not differ among groups. Indices of fetal mortality were not affected by the treatments. Developmental tests, initiated on postnatal day (PND) 2, indicated slight delays in the negative geotaxic response and eye opening in cocaine-exposed pups. Open-field and tail-flick tests were performed on PND 21. Pups were acutely injected with cocaine (10 mg/kg, IP), saline, or received no treatment before placement in a novel open field; morphine (1.5 mg/kg, SC) or saline was injected prior to the tail flick test. Pups from CN dams exhibited a significant decrease in spontaneous exploratory behavior compared to both controls, and a time-dependent increase in rearing compared to pups from UT dams. The acute cocaine injection prior to placement in the open field did not alter locomotion or rearing among dam treatment groups. However, the acute cocaine injection did increase stereotypy ratings for female pups from CN dams compared to similarly treated males, and females from SAL and UT dams. No differences were observed among groups in the tail-flick test. These data suggest that the IV route of administration provides a viable method of cocaine delivery in pregnant rats, and provides further evidence of the developmental and behavioral teratogenicity of prenatal cocaine exposure.     

Conditioned Activity and Instrumental Reinforcement Following Long-Term Oral Consumption of Cocaine by Rats.

Food-reinforced conditioned activity and instrumental responding were measured in rats after 50 weeks of continuous access to a cocaine-saccharin solution in their home cages. The elevation of conditioned activity produced by acute access to the cocaine-saccharin solution in the home cage during testing was abolished by long-term preexposure to the cocaine solution, an effect that was reversed by systemic administration of cocaine immediately prior to testing. By contrast, chronic cocaine preexposure enhanced instrumental responding for both cocaine-sucrose and pure sucrose solutions. These results support the idea that long-term cocaine exposure enhances subsequent reinforcement. (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)