Biomedical subjects

Leigh V Panlilio

Publications and source records attributed to Leigh V Panlilio.

14 recordsLinked to original sources

PubMed2006

Cocaine self-administration under variable-dose schedules in squirrel monkeys.

Squirrel monkeys self-administered cocaine under a variable-dose schedule, with the dose varied from injection to injection. As in earlier studies with rats, post-injection pauses varied as a monotonic function of dose, allowing a cocaine dose-effect curve to be obtained during each session. These curves were shifted by pretreatment with dopamine antagonists, demonstrating that this procedure may provide an efficient means of evaluating treatments that affect drug self-administration. However, drug intake eventually became "dysregulated" after extensive training (100-300 sessions), with relatively short pauses following all doses. Dose-sensitivity was restored by adding a 60-s timeout period after each injection, suggesting that dysregulation occurred because the monkeys developed a tendency to self-administer another injection before the previous injection had been adequately distributed. Finally, when the response requirement under the variable-dose schedule was increased from 1 to 10, both the post-injection pause and the rate of responding following the pause ("run rates") were found to vary with dose. The dose-dependency of run rates suggests that post-injection pauses reflect not only motivational factors, such as satiety, but also the direct effects of cocaine on leverpressing.

Animals↗

PubMed2006

Previous exposure to THC alters the reinforcing efficacy and anxiety-related effects of cocaine in rats.

The hypothesis that prior cannabis exposure increases the likelihood of becoming addicted to other drugs can be evaluated by giving rats a history of tetrahydrocannabinol (THC) exposure, then allowing them to self-administer other drugs. In Experiment 1, THC pre-exposure did not alter the acquisition of cocaine self-administration or the amount of cocaine taken under a fixed-ratio 1 (FR1) schedule, with one response required for each injection. Under a progressive-ratio schedule, with the response requirement increasing exponentially with each injection, cocaine-seeking was significantly reduced in THC-exposed rats, suggesting that the regimen of THC exposure used in the present study caused cocaine to be devalued as a reinforcer. In contrast, in an earlier study that used the same regimen, a history of THC exposure did not alter the value of heroin as a reinforcer under the progressive-ratio schedule, but it increased heroin self-administration under the FR1 schedule. Experiment 2 examined how this regimen of THC pre-exposure alters the locomotor effects of cocaine and heroin. THC pre-exposure produced cross-tolerance to the motor-depressant effects of heroin; this may explain the shortened post-injection pauses exhibited by THC-exposed rats under FR1 heroin self-administration. When given cocaine, THC-exposed rats exhibited normal increases in locomotion, but they avoided the center of the open field, suggesting that this THC pre-exposure regimen enhances the anxiogenic effects of cocaine. This enhanced anxiogenic effect-which was verified in Experiment 3 using another model of anxiety, the light-dark test-may explain the reduced reinforcing value of cocaine observed in THC-exposed rats in Experiment 1.

Analgesics, Non-Narcotic↗

PubMed2006

Peri-response pharmacokinetics of remifentanil during a self-administration session indicates that neither blood nor brain levels are titrated.

An individual's drug abuse pattern is determined by a multitude of factors. Among these, simple pharmacological determinants of within-binge drug consumption are sorely underinvestigated. We therefore determined if within-session operant responsing to the ultra-short-acting mu opioid agonist remifentanil (RMF) was determined by blood or brain RMF levels or changes thereof. Our peri-response analysis did not detect any "threshold" RMF level, either in blood or in the nucleus accumbens (NAc) core as a deep brain region that might determine a rat's "decision" to re-emit a response during a multiple-injection drug self-administration session. The peri-response analysis also failed to find any peak RMF level, either in blood or in the NAc core, which could serve as a "ceiling" level. Thus, our findings strongly suggest that titration of blood or brain RMF levels does not determine a rat's intra-session operant response.

Animals↗

PubMed2005

A comparison of drug-seeking behavior maintained by D-amphetamine, L-deprenyl (selegiline), and D-deprenyl under a second-order schedule in squirrel monkeys.

L-Deprenyl (selegiline) is used in the treatment of Parkinson's disease and has been proposed as an aid for cigarette smoking cessation and a treatment for psychostimulant abuse. L-Deprenyl is metabolized in the body to L-methamphetamine and L-amphetamine, suggesting that it may have abuse potential. The current study assessed whether L-deprenyl or its isomer would maintain drug-seeking behavior on a second-order schedule and whether L-deprenyl would alter drug-seeking behavior maintained by D-amphetamine if given as a pretreatment. Squirrel monkeys learned to respond on a second-order schedule of reinforcement, where every tenth response was followed by a brief light flash, and the first brief light flash after 30 min was paired with intravenous (i.v.) injection of D-amphetamine (0.56 mg/kg), administered over a 2-min period at the end of the session. When responding was stable, saline or different i.v. doses of D-amphetamine (0.3-1.0 mg/kg), L-deprenyl (0.1-10.0 mg/kg), and D-deprenyl (0.1-3.0 mg/kg) were substituted for 10 days each. Subsequently, monkeys were pretreated with 0.3 or 1.0 mg/kg L-deprenyl intramuscularly 30 min prior to D-amphetamine baseline sessions. D-Amphetamine maintained high rates of drug-seeking behavior on the second-order schedule. D-Deprenyl maintained high rates of drug-seeking behavior similar to D-amphetamine. L-Deprenyl maintained lower rates of responding that were not significantly above saline substitution levels. Pretreatment with L-deprenyl failed to alter drug-seeking behavior maintained by D-amphetamine. These results indicate that D-deprenyl, but not L-deprenyl, may have abuse potential. Under conditions where drug-seeking and drug-taking behaviors are actively maintained by D-amphetamine, L-deprenyl, at doses that specifically inhibit type B monoamine oxidase, may not be effective as a treatment.

Animals↗

PubMed2005

Conditioned inhibition of cocaine seeking in rats.

Despite its potential relevance to the treatment of drug abuse, conditioned inhibition of drug seeking has not been systematically investigated before. In this study, rats could self-administer cocaine by lever pressing whenever a click or tone was present. Responding was not reinforced when a light was present. The light was presented simultaneously with the click (i.e., in an excitatory context) in 1 group, but the light was always presented alone in another group. When it was later presented in compound with the tone, the light was a highly effective conditioned inhibitor, suppressing cocaine seeking by 92% in the former group and by 74% in the latter. These results suggest ways to improve cue-oriented behavioral treatments for drug abuse.

Animals↗

PubMed2005

Human cocaine-seeking behavior and its control by drug-associated stimuli in the laboratory.

Second-order schedules of drug self-administration were developed to incorporate the effects of drug-related environmental stimuli into an animal model of drug abuse, making it more similar to human situations. Ironically, little is known about how human subjects behave under these schedules. In this study, human volunteers with a history of cocaine use worked on a second-order schedule in which every 100th lever response produced an auditory-visual brief stimulus (2 s). The first stimulus produced after 1 h was extended to 10 s and paired with an intravenous injection of cocaine (25 mg). Up to three injections were allowed per session. In different phases of the experiment, presentation of the brief stimulus was discontinued and/or saline solution (placebo) was injected instead of cocaine. Injections of cocaine were found to maintain responding even when the brief stimulus was not presented. Placebo injections alone did not maintain responding. In contrast, the brief stimulus maintained high levels of responding under placebo conditions, even though self-reports indicated that subjects could clearly discriminate that they were not receiving cocaine. These results demonstrate that drug-related environmental stimuli can maintain persistent drug seeking during periods of drug unavailability. As this procedure directly measures the effects of stimuli on drug seeking, it may provide a valuable complement to indirect measures, such as self-reports of craving, that are often used with human subjects. The similarity of the response patterns in humans and animals also supports the use of second-order schedules in animals as a valid model of human drug seeking.

Adult↗

PubMed2005

Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats.

Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin. In rats intravenously self-administering heroin, we investigated effects of cannabinoid CB1 receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide. The natural cannnabinoid CB1 receptor agonist delta-9-tetrahydrocannabinol (THC, 0.3-3 mg/kg i.p.) did not alter self-administration of heroin under a fixed-ratio one (FR1) schedule, except at a high 3 mg/kg dose which decreased heroin self-administration. Under a progressive-ratio schedule, however, THC dose-dependently increased the number of 50 mug/kg heroin injections self-administered per session and the maximal ratio completed (break-point), with peak increases at 1 mg/kg THC. In addition, 1 mg/kg THC increased break-points and injections self-administered over a wide range of heroin injection doses (25-100 microg/kg), indicating an increase in heroin's reinforcing efficacy and not its potency. The synthetic cannabinoid CB1 receptor agonist WIN55,212-2 (0.3-3 mg/kg i.p.) had effects similar to THC under the progressive-ratio schedule. In contrast, AM-404 (1-10 mg/kg i.p.), an inhibitor of transport of anandamide, and URB-597 (0.01-0.3 mg/kg i.p.), an inhibitor of the enzyme fatty acid amide hydrolase (FAAH) that degrades anandamide, or their combination, did not increase reinforcing efficacy of heroin at any dose tested. Thus, activation of cannabinoid CB1 receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid CB1 receptors and mu-opioid receptors and their signaling pathways, rather than by an opioid-induced release of endogenous cannabinoids.

Animals↗

PubMed2004

Lorazepam reinstates punishment-suppressed remifentanil self-administration in rats.

RATIONALE: We recently described a reinstatement procedure that models relapse to drug abuse in cases where abstinence results from aversive consequences of drug use. The potential value of this punishment-based model of relapse depends on its sensitivity to relapse-inducing events that are ineffective in the widely used extinction-based model. OBJECTIVES: It is known that certain drugs can have anti-punishment effects, but these drugs have not been tested in the punishment-based reinstatement procedure. Therefore, the effects of the benzodiazepine, lorazepam, were examined using punishment-based and extinction-based reinstatement procedures. METHODS: Rats self-administered the opioid, remifentanil (4 microg/kg per infusion). Two punishment groups were trained with response-contingent footshock that suppressed baseline rates of responding to zero. In an extinction group, remifentanil delivery was discontinued, and baseline responding stabilized at a low rate (mean=0.06 responses/min). Lorazepam (0.08-10 mg/kg, IP) was given during test sessions with the shock contingency discontinued for both punishment groups. Remifentanil delivery was maintained during testing in one punishment group but not the other. RESULTS: Lorazepam reinstated self-administration responding in both punishment groups but not in the extinction group. Priming injections of heroin reinstated responding in both the punishment and extinction groups, but combining heroin and lorazepam did not enhance reinstatement. CONCLUSIONS: This is the first demonstration that a trigger for relapse may have different effects depending on whether aversive conditioning contributed to the achievement of abstinence. It may be important to consider potential anti-punishment effects of both abused drugs and therapeutic agents in the treatment of individuals with a history of drug abuse.

Analgesics, Opioid↗

PubMed2004

Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers.

RATIONALE: Although numerous studies have documented that nicotine can function as an effective reinforcer of intravenous self-administration behavior in animals, it has not been clearly shown to maintain intravenous self-administration behavior above vehicle placebo levels in humans. OBJECTIVES: To compare the reinforcing effectiveness of nicotine versus saline placebo in human research volunteers responding under fixed-ratio (FR) schedules of intravenous drug self-administration while systematically increasing response requirements. METHODS: Eight male cigarette smokers resided in an inpatient research unit. During 3-h sessions, intravenous injections of nicotine and saline were available concurrently and were contingent on responding (pulling a lever). Nicotine dose (0.75, 1.5, 3.0 mg/injection), time out (TO) value after each injection (1-20 min) and FR response requirement (10-1600) were varied in different subjects over consecutive sessions. RESULTS: Number of nicotine injections/session significantly decreased as dose/injection increased and the number of self-administered nicotine injections was significantly greater than the number of self-administered saline injections across conditions. When FR value was progressively increased over sessions, response rates for nicotine, but not saline, injections increased, with maximal rates at the highest FR values. Rates of responding and injections/session were markedly and significantly higher for nicotine than for saline at FR values of 200 and above. Subjects rated effects of nicotine as both significantly more positive and more negative than saline placebo, with positive ratings significantly higher than negative ratings. CONCLUSIONS: Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session.

Adult↗

PubMed2003

Variability of drug self-administration in rats.

RATIONALE: Although temporal patterns of drug self-administration in animals are known to be highly regular, this regularity has rarely been quantified or systematically compared across reinforcers. OBJECTIVES: Over a range of unit doses, this study assessed: (1) the within-subject variability of inter-infusion intervals (latencies); (2) the estimated whole-body drug level at the time of self-infusion; (3) the within-subject variability of these drug levels; and (4) the statistical dependence between successive latencies, to determine whether regularity is maintained by compensatory, moment-to-moment adjustment of latencies. METHODS: Rats were trained with cocaine (10-1000 microg/kg per infusion, IV), remifentanil (an ultra-short acting opioid; 0.25-32 microg/kg per infusion, IV), or food (20-180 mg/delivery). RESULTS: Within subjects, latencies were most consistent from infusion to infusion at unit doses on the descending limb of the dose-response curve. However, the drug level at the time an infusion was initiated was actually least consistent at these doses. Sequential latencies showed only a weak autocorrelation for both drugs. CONCLUSION: These results suggest that highly consistent response patterns are not simply a product of precise titration of drug levels. The weak autocorrelation between sequential latencies suggests that temporal regularity of responding is not maintained through compensatory adjustments of post-infusion pauses.

Analgesics, Opioid↗

PubMed2003

Stimulus control of cocaine self-administration.

Environmental stimuli that set the occasion wherein drugs are acquired can "trigger" drug-related behavior. Investigating the stimulus control of drug self-administration in laboratory animals should help us better understand this aspect of human drug abuse. Stimulus control of cocaine self-administration was generated here for the first time using multiple and chained schedules with short, frequently-alternating components--like those typically used to study food-maintained responding. The procedures and results are presented along with case histories to illustrate the strategies used to produce this stimulus control. All these multicomponent schedules contained variable-interval (VI) components as well as differential-reinforcement-of-other-behavior (DRO) or extinction components. Schedule parameters and unit dose were adjusted for each rat to produce stable, moderate rates in VI components, with minimal postreinforcement (infusion) pausing, and response cessation in extinction and DRO components. Whole-body drug levels on terminal baselines calculated retrospectively revealed that all rats maintained fairly stable drug levels (mean, 2.3 to 3.4 mg/kg) and molar rates of intake (approximately 6.0 mg/kg/hr). Within this range, no relation between local VI response rates and drug level was found. The stimulus control revealed in cumulative records was indistinguishable from that achieved with food under these schedules, suggesting that common mechanisms may underlie the control of cocaine- and food-maintained behavior.

Animals↗

PubMed2002

Reinstatement of punishment-suppressed opioid self-administration in rats: an alternative model of relapse to drug abuse.

RATIONALE: Animal models of relapse to drug abuse typically assess the ability of various manipulations to reinstate responding that has ceased due to non-reinforcement (extinction). However, there is a lack of information concerning the reinstatement of responding that has ceased for reasons other than extinction. OBJECTIVES: This study examined the ability of response-independent reinforcer delivery (priming) to reinstate food- or drug-reinforced responding that had been suppressed by response-contingent footshock (punishment). METHODS: Nose-poke responding by separate groups of rats was reinforced with food (45 mg/delivery) or intravenous remifentanil (4 micro g/kg per infusion), a short-acting micro -opioid agonist. After either 3 or 27 days of training (with 100 reinforcers/day), a punishment contingency was introduced that rapidly suppressed responding. Then, the punishment contingency was discontinued, and half the rats received priming. RESULTS: Priming by non-contingent delivery of food or remifentanil significantly reduced the number of sessions required for responding to resume. There were no significant differences in this effect between short-term and long-term training or between food- and drug-trained groups. CONCLUSIONS: Self-administration responding that has been suppressed by punishment can be reinstated by priming, and it can eventually resume even without priming. Under the conditions studied here, priming after punishment had effects qualitatively similar to those typically seen after extinction. This punishment/reinstatement procedure may be useful for comparing the effects of other manipulations known to affect behavior in the extinction/reinstatement model of relapse.

Analgesics, Opioid↗

PubMed2002

Second-order schedules of drug self-administration in animals.

On a second-order schedule, a subject responds according to one schedule (the unit schedule) for a brief presentation of a stimulus such as a light. Responding by the subject on this unit schedule is then reinforced according to another schedule of reinforcement. Second-order schedules of drug injection allow the study of more complex behavioral sequences than do simple schedules and may more accurately reflect the human drug-abuse situation. Much of the early work in this area used primates as subjects and focused on the behavioral variables controlling responding. It was shown that long sequences of behavior could be maintained on second-order schedules with relatively infrequent injections of drug and that the second-order, brief-stimulus presentations were critical to the acquisition and maintenance of responding. Also, the continued presentation of the brief stimulus in extinction often led to prolonged extinction behavior. These studies clearly showed that environmental stimuli greatly influence drug self-administration behavior under second-order schedules. The focus of much of the more recent work with second-order schedules has been on the evaluation of pharmacological treatments for drug addiction, both as antagonist and substitution therapies. Both types of potential therapies have shown promise in these preclinical models of addictive behavior. The recent extension of second-order self-administration studies to rats as subjects has facilitated the investigation of neural mechanisms involved in this behavior. While this use of second-order schedules is a relatively recent phenomenon, significant contributions have already been made in identifying neural mechanisms critical to second-order schedule drug self-administration. This active area of research holds great promise for delineating specific brain regions critical to different aspects of drug addiction.

Animals↗

PubMed2002

Conditioned suppression of behavior maintained by cocaine self-administration.

Shock-paired stimuli have produced conditioned suppression of behavior maintained by a variety of reinforcers such as food, water, sucrose, and intracranial self-stimulation. With the ongoing pursuit of animal models for drug abuse treatment, it is surprising that this procedure for suppressing positively reinforced behavior has never been applied to drug-maintained behavior. The present study applied the conditioned suppression paradigm to behavior maintained by cocaine self-administration in rats. If shock-paired stimuli suppress ongoing cocaine self-administration, this would contrast with recent studies reporting that aversive stimuli can enhance the acquisition and reinstatement of behavior reinforced by cocaine. Rats were trained to bar-press for intravenous cocaine infusions on a variable-interval schedule. Then, a tone conditioned stimulus (CS) and a light CS were each paired with foot-shock while the rats were bar-pressing for cocaine. These CSs each came to reliably suppress responding in all subjects, just as shock-paired CSs suppressed responding by the positive reinforcers mentioned above. When the tone and the light were presented simultaneously in testing, suppression was significantly enhanced over that controlled by the single CSs. These results demonstrate that (1) cocaine-maintained behavior can be suppressed by environmental stimuli associated with non-drug reinforcers; and (2) combining stimuli that decrease drug self-administration can enhance their suppressive effects. Thus, the present findings can have implications for drug treatment.

Acoustic Stimulation↗