The consequences of different "lapses" on relapse to heroin seeking in rats.

Although human studies have shown that a lapse, the first violation of abstinence, often induces resumption of drug taking, or relapse, it is not known what aspect of a lapse is critical to relapse or whether this phenomenon can be studied in other species. Rats were trained to self-administer heroin accompanied by a discrete light stimulus. After extinction, different groups experienced different "lapses." Twenty-four hours later, all groups received a test for relapse. It was found that a lapse during which heroin was self-administered, or was presented in close temporal contiguity with lever pressing, induced subsequent heroin seeking. Simple exposure to heroin, or to heroin-related stimuli, during the lapse had little effect on responding in the test for relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lapses and reinstatement of heroin seeking in rats: Comment on Leri and Stewart (2002).

In an elegant series of experiments, F. Leri and J. Stewart (see record 2002-06535-001) report that exposure to heroin increases subsequent reinstatement responding if the animal has access to the drug lever during the lapse and if responding on the lever results in the presentation of conditioned cues. It is interesting that exposure to only these conditioned cues in the absence of heroin did not affect reinstatement responding on the following day. Although these are important experiments, the results should be interpreted with some degree of caution for several reasons. Nevertheless, the experiments described in this article represent the first attempt to address the effects of self-administered versus investigator-delivered heroin on subsequent reinstatement behavior. Future research should attempt to replicate these experiments taking these considerations into account. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A novel paradigm to investigate regulation of drug intake in rats self-administering cocaine or heroin intravenously.

The purpose of this experiment was to investigate the regulation of drug intake in rats (n?=?20) self-administering heroin or cocaine during daily 5-hr sessions. Operant chambers were equipped with 2 levers and associated stimulus lights. A response on the lever with stimuli signaling an increase in dose size increased the infusion duration by 3 s, and a response on the lever with stimuli signaling a decrease in dose size decreased the infusion duration by 3 s. Results showed that daily and hourly drug intake for cocaine and heroin groups were relatively constant. Significant correlation coefficients were obtained for heroin and cocaine groups for the relationship between interdose interval (IDI) and infusion duration (dose size). These findings indicate that subjects regulated their drug intake by adjusting IDI throughout drug self-administration sessions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug-induced reinstatement to heroin and cocaine seeking: A rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 μg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine-associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On the nature of the conditioned stimulus: Comment on Leri and Stewart (2002).

F. Leri and J. Stewart (see record 2002-06535-001) present convincing evidence that a relapse to heroin-seeking behavior is established when rats are given a momentary lapse in which they are allowed to respond while under the influence of heroin. Although exposure to a conditioned stimulus (CS) paired with heroin self-infusion did not induce a relapse, it was able to control responding. In addition to serving as both a discriminative stimulus and a conditioned reinforcer, it is argued in this article that the CS also may have positive hedonic value independent of its association with heroin and that this property should be considered in interpreting the results of future experiments. (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)     

Effects of acute and prolonged opiate abstinence on extinction behaviour in rats.

We examined the role of withdrawal in relapse to drug-seeking and drug-taking by testing the effects of opiate abstinence on extinction behaviour in rats trained to self-administer heroin. Male Long-Evans rats responded for IV heroin under a heterogeneous chain (VI 120 s; FR 1) schedule in which "seeking" responses preceded a "taking" response which produced a drug infusion. Responding was then measured in extinction during acute (6, 12, and 24 hr) and prolonged (3, 6, 12, and 25 day) abstinence. Sucrose consumption and somatic withdrawal were assessed at each testing period. During acute abstinence, responses on the "drug-seeking" manipulandum increased at 24 hr, whereas responses on the "drug-taking" manipulandum increased at 6 hr. Both responses were elevated during the 12-day abstinence test. Sucrose consumption was reduced and somatic withdrawal scores were increased in opiate-experienced rats at each test period. Results suggest that heroin abstinence has different effects on drug-seeking and drug-taking and that these effects do not temporally coincide with somatic measures of opioid withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antithrombotic agents in unstable angina. Review of clinical trials

The purpose of this experiment was to investigate the regulation of drug intake in rats (n = 20) self-administering heroin or cocaine during daily 5-hr sessions. Operant chambers were equipped with 2 levers and associated stimulus lights. A response on the lever with stimuli signaling an increase in dose size increased the infusion duration by 3 s, and a response on the lever with stimuli signaling a decrease in dose size decreased the infusion duration by 3 s. Results showed that daily and hourly drug intake for cocaine and heroin groups were relatively constant. Significant correlation coefficients were obtained for heroin and cocaine groups for the relationship between interdose interval (IDI) and infusion duration (dose size). These findings indicate that subjects regulated their drug intake by adjusting IDI throughout drug self-administration sessions.     

Fine structure of the pecten oculi of the barred owl (Strix varia)

Relapse prevention in abstinent cocaine addicts remains a major focus of drug addiction therapy. We used a rat model of cocaine addiction that focused on cocaine-seeking behavior elicited interoceptively and by conditioned stimuli. Each of 18 rats could self-administer a maximum of 20 intravenous cocaine injections (1.5 mg/kg) per session per day. To prevent initiation of responding by cocaine itself priming injections were never administered. Although cocaine was available beginning every session the rats displayed a self-imposed period of abstinence followed by a period of rapid consumption. The abstinence period was variable among rats but consistent for individual rats. In experiment 1 we studied the contribution of a CS+ (stimulus light and lever retraction) to the motivation to initiate and maintain a cocaine self-administration episode. We compared the number of responses the rats emitted to receive the first and subsequent injections of the day between a group responding on a fixed-ratio (FR) schedule (n = 6) and a group responding on a second-order (SO) schedule (n = 5) of reinforcement. For all rats the number of responses per injection was raised daily until a rat failed to consume more than four injections. The SO group was able to emit approximately four times as many responses as the FR group to obtain their first and subsequent injections. In experiment 2 (n = 7) responses during extinction were counted with and without the CS+. Responding was greater in the presence of the CS+ than in its absence. The present model demonstrates that the motivation to self-administer cocaine is variable and greatly enhanced by conditioned stimuli.     

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.     

Associative effects of US preexposure: Modulation of conditioned responding by an excitatory training context.

Conducted 2 experiments with 120 naive Sprague-Dawley rats to examine factors that contribute to retarded emergence of conditioned responding to a conditioned stimulus/stimuli (CS) trained in a context in which unsignaled unconditioned stimulus/stimuli (UCS) had previously been administered. In both experiments, water-deprived Ss were used in a conditioned lick suppression task to measure the conditioned response (CR) elicitation potential of the CS and the training context. From Exp I, it was determined that nonreinforced exposure to the excitatory context after UCS preexposure and prior to CS–UCS pairings in that context eliminated the CR deficit observed on a subsequent test of the CS. From Exp II, it was determined that the recovery induced by contextual deflation after CS training was specific to deflation of the context in which the CS was trained as opposed to another excitatory context. (28 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in pain reactivity induced by unconditioned and conditioned excitatory and inhibitory stimuli.

Investigated the effects of aversive-conditioning components on the reactivity of rats to pain. After training in Exp 1 with a discrete conditioned stimulus (CS) for a shock unconditioned stimulus (US), different groups were exposed to the CS, US, CS/US compound, just the training context, or none of those immediately prior to a hot-plate test assessing the latency of a paw-lick response. Relative to no exposure and context alone, the CS produced a shorter latency (sensitization effect), whereas the US produced a longer latency (hypoalgesic effect) that was actually augmented by the CS/US compound. Whereas the US-induced hypoalgesia was unaffected by naloxone, hypoalgesia produced by the CS/US compound was appreciably decremented by the drug. Exp 2 showed the same effects with parameters more typical of conditioning research. Exp 3 compared signals for the presence (CS+) and absence (CS–) of the US. The CS– did not itself affect pain reactivity, but it inhibited the effects of the CS+, US, and CS+/US compound. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pavlovian inhibitory conditioning and tolerance to pentobarbital-induced hypothermia in rats.

One group of rats (discrimination group) from an S pool of 96 male Sprague-Dawley rats received training in which, on alternate days, 1 conditioned stimulus (CS+) was associated with administration of 30 mg/kg pentobarbital (PBB), and a different CS (CS–) with saline. Controls received either exposure to both CSs but not the drug or to the drug but no CSs or to neither the CSs nor the drug. Subsequently, half the Ss in each group received injections of PBB in the presence of one of the CSs and the remaining half in the presence of the other CS. Results show that the discrimination group injected with PBB in the presence of CS+ displayed the most tolerance, whereas the discrimination group injected with PBB in the presence of CS– displayed the least tolerance. The attenuation of tolerance in the discrimination group injected in the presence of CS– provides evidence of inhibitory Pavlovian conditioning. Additional evidence of inhibitory conditioning was provided by the fact that CS? enhanced the hypothermic effects of PBB in the discrimination group, whereas CS? attenuated these effects. (30 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretraining Inactivation of the Caudal Pontine Reticular Nucleus Impairs the Acquisition of Conditioned Fear-Potentiated Startle to an Odor, but Not a Light.

Recent data from developing rats suggest that structures downstream from the amygdala are involved in the acquisition of conditioned fear-potentiated startle (FPS). The authors tested this idea in adult rats by temporarily inactivating the structure critical for FPS, the caudal pontine reticular nucleus (PnC), during fear conditioning. When the conditioned stimulus (CS) was an odor, rats displayed freezing, but not FPS, at test. This effect was not due to a decrease in footshock sensitivity. Further, no savings were evident on retraining. When the CS was a light, inactivation of the PnC had no effect on the acquisition of FPS. Thus, the PnC may be crucial for the acquisition of conditioned FPS to an odor, but not a light. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal lesions alter conditioning to conditional and contextual stimuli

The control of conditioned fear behaviour by a conditional stimulus (CS) and contextual stimuli (CXT) was compared in rats with lesions to the hippocampus (HPC) or neocortex (CO), and operated controls (OC). After classical fear conditioning in a distinctive context, rats were subsequently tested in the presence of the CS and CXT (CS + CXT), the CS alone (CS-only), or context alone (CXT-only). Two experiments were conducted in which conditioned fear was measured by an active avoidance response (experiment 1) or by response suppression (experiment 2). Groups did not differ in acquiring the conditioned fear response, as measured in the CS + CON test but, in both experiments, hippocampal (HPC) groups exhibited more conditioned fear behaviour than controls in the CXT-Only and CS-Only conditions. It was suggested that control rats conditioned the fear response to a stimulus complex that incorporated the CS and CTX. Rats with HPC lesions did not form this association between the stimulus elements; instead they segregated the CS and CXT and formed independent associations between the conditioned response (CR) and each component. In showing that HPC damage disrupts the process of forming associations between environmental stimuli and that the effect is not restricted to contextual cues, the results help to resolve apparently contradictory findings regarding the role of HPC in contextual information processing.     

Pairings of a drug or place conditioned stimulus with lithium chloride produce conditioned sickness, not antisickness.

In different experiments, pairings of a drug (pentobarbital or morphine) or place as the conditioned stimulus (CS) with lithium-induced sickness as the unconditioned stimulus (UCS) were given to rats to produce Pavlovian conditioning. Control rats received unpaired exposures. In the test, each rat was exposed to the CS, injected with lithium, and then offered food. If such pairings produce conditioning of antisickness (i.e., a compensatory response that opposes lithium sickness), then the experimental rats should eat more than the controls. The reverse occurred. Thus, pairings of a drug or place CS with a lithium UCS resulted in conditioned sickness rather than antisickness. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Double dissociation of the behavioural effects of R(+) 7-OH-DPAT infusions in the central and basolateral amygdala nuclei upon Pavlovian and instrumental conditioned appetitive behaviours

Dopaminergic cell bodies located within the ventral mesencephalon innervate the amygdaloid complex, a region critically involved in the attribution of affective significance to environmental stimuli. Recently, we have shown that post-session intra-amygdala administration of a D3 dopamine receptor agonist enhances selectively the acquisition of an appetitive conditioned response. In the present study, we have investigated the potential involvement of the central nucleus and the basolateral nuclei of the amygdala in mediating this effect. Thus, rats were trained to associate an arbitrary stimulus (CS+) with the availability of 10% sucrose reward. Post-session infusions of the D3 receptor-preferring agonist, R(+) 7-OH-DPAT, were made into either the central nucleus or basolateral nuclei. Acquisition of a conditioned approach response was enhanced by R(+) 7-OH-DPAT infusions within the central nucleus, but not within the basolateral nuclei. Drug infusions into either region failed to affect approach behaviour elicited by presentation of a control stimulus (CS-), explicitly unpaired with sucrose reward. The effects of pre-test infusions of R(+) 7-OH-DPAT on the instrumental properties of the stimuli were then determined. Rats were presented with two novel levers, depression of one lever resulted in presentation of the CS+, while presentation of the CS- was contingent upon depression of the other lever. Rates of response upon each lever as well as the ability of the conditioned stimuli subsequently to elicit conditioned approach behaviour were recorded. Data revealed a double dissociation of the effects of R(+) 7-OH-DPAT on the expression of the Pavlovian and instrumental properties of the reward-related stimulus. Thus, within the central nucleus R(+) 7-OH-DPAT dose-dependently attenuated expression of the conditioned approach response, but had no effect upon instrumental responding maintained by the conditioned reward. In contrast, within the basolateral nuclei, R(+) 7-OH-DPAT had no effect upon expression of conditioned approach behaviour, but abolished selectively the ability of the reward-associated stimulus to support the acquisition of a novel instrumental response. Hence, these data indicate that distinct regions of the amygdaloid complex process distinct aspects of conditioned appetitive behaviours.     

Alterations of immune functions in heroin addicts and heroin withdrawal subjects

Conflicting results, both decreased and increased, have been reported concerning the function of T-lymphocytes in heroin addicts. We investigated the alterations of T-lymphocyte proliferative responses and immunophenotypic markers on lymphoid cells in heroin addicts and during different periods of heroin withdrawal in addicted subjects. This study has demonstrated a decrease in the response of T-lymphocytes to 1.2, 2.5, 5 and 10 microg/ml of phytohemagglutinin stimuli in heroin addicts and 1- to 5-day heroin withdrawal subjects compared with controls. Similarly, in an in vitro study, 10(-4), 10(-6) and 10(-8) M concentrations of morphine were shown to suppress 0.6 and 2.5 microg/ml of PHA-stimulated T-lymphocyte obtained from naive subjects. This inhibitory effect of morphine on PHA stimulation was completely abolished by 100 microM naloxone. The immunological parameters of total T-lymphocytes (CD3), T-helper cells (CD4), cytotoxic T-cells (CD8), B-cells and natural killer cells that are the immunophenotypic markers studied by flow cytometric analysis were altered in heroin addicts, 15- to 21-day and 6- to 24-month heroin withdrawal subjects, when compared with controls. These results suggest that heroin addicts and short period (15 to 21 days and 6 to 24 months) of heroin withdrawal have decreases in their immune system functioning and that the heroin withdrawal subjects seem to gradually reverse their immunological parameters to normal levels when withdrawal was sustained >/=2 years. This is the first report examining immune function in heroin withdrawal subjects using the "cold turkey" method. The results are beneficial for further study of the mechanism responsible for the opioid-induced changes in immune function.     

Smoked heroin and cocaine based (speedball) combinations in Rhesus monkeys.

The purpose of this investigation was to compare the self-administration of heroin and cocaine base, alone and in combination, in rhesus monkeys (Macaca mulatta) self-administering a combination of heroin (0.1 mg/kg/delivery) and cocaine base (1.0 mg/kg/delivery) via the smoking route. Smoke deliveries were contingent on completion of a chained fixed ratio (FR; lever press), FR 5 (inhalation) schedule. The lever press FR values (64, 128, 256, 512, and 1,024) represented increasing drug price. Demand functions (Consumption x Price) were obtained for the heroin and cocaine combination and compared with previously determined demand functions for smoked heroin and cocaine alone. As the FR increased and the number of responses emitted increased, the number of drug deliveries decreased. The demand functions were not different for heroin versus cocaine alone or for cocaine alone versus the cocaine-heroin combination. However, the demand for heroin alone was significantly less than the demand for the cocaine-heroin combination, suggesting that smoked cocaine base enhances the behavioral effects of smoked heroin. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gustatory insular cortex lesions disrupt drug-induced, but not lithium chloride-induced, suppression of conditioned stimulus intake.

Rats suppress intake of a normally preferred 0.15% saccharin conditioned stimulus (CS) when it is paired with an aversive agent like lithium chloride (LiCl) or a preferred substance such as sucrose or a drug of abuse. The reward comparison hypothesis suggests that rats avoid intake of a saccharin cue following pairings with a drug of abuse because the rats are anticipating the availability of the rewarding properties of the drug. The present study used bilateral ibotenic acid lesions to examine the role of the gustatory cortex in the suppression of CS intake induced by cocaine, morphine, and LiCl. The results show that bilateral lesions of the insular gustatory cortex (1) fully prevent the suppressive effects of both a 15 and a 30 mg/kg dose of morphine, (2) attenuate the suppressive effect of a 10 mg/kg dose of cocaine, but (3) are overridden by a 20 mg/kg dose of the drug. Finally, these same cortical lesions had no impact on LiCl-induced conditioned taste aversion. The current data show that the insular taste cortex plays an integral role in drug-induced avoidance of a gustatory CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)