Biomedical subjects

L V Panlilio

Publications and source records attributed to L V Panlilio.

15 recordsLinked to original sources

PubMed2004

Exposure to delta-9-tetrahydrocannabinol (THC) increases subsequent heroin taking but not heroin's reinforcing efficacy: a self-administration study in rats.

One concern about the widespread use of cannabis is that exposure to its active ingredient, delta-9-tetrahydrocannabinol (THC), might increase future reinforcing effects of other abused drugs such as heroin. In this study, we investigated the effects of pre-exposure to THC on subsequent intravenous self-administration of heroin by Sprague-Dawley rats. In one group of rats, we studied (1) acquisition of heroin self-administration behavior using a continuous-reinforcement (fixed-ratio (FR) 1) schedule, (2) heroin dose-response relationships using an FR1/variable-dose schedule, and (3) reinforcing efficacy of heroin using a progressive-ratio schedule. The number of rats pre-exposed to THC that subsequently learned to self-administer 50 microg/kg injections of heroin within 10 daily sessions did not differ from vehicle-pretreated controls. In contrast, rats pre-exposed to THC subsequently self-administered significantly more heroin injections per session and showed significantly shorter post-injection pauses over a range of heroin doses (12.5-100 microg/kg/injection) using the variable-dose schedule. Interestingly, the maximum effort rats would exert to receive an injection of the different doses of heroin under the progressive-ratio schedule was not altered by THC pre-exposure. In a second group of rats, we varied the 'price' of heroin (responses required/dose), by manipulating FR response requirements at different doses of heroin across sessions, to calculate demand and response output curves. Again, consumption was significantly higher in the THC-treated rats at the lowest prices of heroin (FR1/100 microg/kg and FR1/50 microg/kg) but there were no differences in the reinforcing efficacy of heroin between THC- and vehicle-pretreated rats. Altogether, these results demonstrate that pre-exposure to THC alters some pharmacological effects of heroin that determine frequency of heroin taking, but offer no support for the hypothesis that pre-exposure to THC alters heroin's efficacy as a reinforcer.

Analgesics, Non-Narcotic↗

PubMed2003

The cannabinoid CB1 antagonist N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide (SR-141716A) differentially alters the reinforcing effects of heroin under continuous reinforcement, fixed ratio, and progressive ratio schedules of drug self-administration in rats.

Activation or blockade of cannabinoid CB1 receptors markedly alters many effects of opioids. In the present study, we investigated whether the cannabinoid antagonist (N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR-141716A) could alter the reinforcing effects of heroin in rats. A Delta9-tetrahydrocannabinol (THC) drug-discrimination procedure was first used to determine effective CB1 antagonist doses of SR-141716A and optimal pretreatment times for self-administration studies. Subsequently, Sprague-Dawley rats learned to self-administer heroin under three different schedules of intravenous drug injection: a continuous reinforcement schedule [fixed ratio (FR)1], a five-response, fixed ratio schedule (FR5), and a progressive ratio schedule. Then, SR-141716A (1 mg/kg i.p.) was administered 60 min before the start of the session for three consecutive daily sessions. SR-141716A markedly decreased heroin self-administration under the progressive ratio schedule at heroin doses ranging from 12.5 to 100 micro g/kg/injection. In contrast, SR-141716A had no effect on heroin self-administration under the FR1 schedule at heroin doses of 50 or 100 micro g/kg/injection, but produced small decreases in self-administration at lower doses (25 and 12.5 micro g/kg/injection). Consistent with a behavioral economics evaluation, SR-141716A produced a small but significant decrease in self-administration of the higher 50 micro g/kg/injection dose of heroin when the fixed ratio requirement was raised to five (FR5). Thus, blockade of CB1 receptors differentially decreased the reinforcing efficacy of heroin depending on the number of responses required for each injection (price). These findings indicate a facilitatory modulation of opioid reward by endogenous cannabinoid activity and provide support for the use of cannabinoid CB1 antagonists as medications for heroin addiction.

Analgesics, Opioid↗

PubMed2000

Self-administration of remifentanil, an ultra-short acting opioid, under continuous and progressive-ratio schedules of reinforcement in rats.

RATIONALE: Remifentanil is a mu-opioid agonist with an exceptionally short duration of action. Evaluating remifentanil's effects within the self-administration model of drug abuse may provide insight into the relationship between a drug's duration of action and its effectiveness as a reinforcer. OBJECTIVES: This study was conducted to establish a dose-effect function for intravenous remifentanil self-administration in rats and to assess the drug's ability to maintain responding under intermittent schedules of reinforcement. METHODS: Inter-infusion intervals were recorded under two continuous-reinforcement schedules of remifentanil self-administration. In the fixed-dose schedule, the unit dose (0.25-32 micrograms/kg) was held constant within sessions but varied across sessions. In the variable-dose schedule, four different doses were self-administered in random order within each session. For comparison, heroin (6.25-125 micrograms/kg) was studied with the variable-dose schedule. Remifentanil and heroin were also compared under a progressive-ratio schedule of reinforcement in which the response requirements increased exponentially with each successive infusion until responding ceased within each session. RESULTS: Under the continuous-reinforcement schedules, inter-infusion intervals for both drugs increased monotonically as a function of dose, with the remifentanil curve being considerably flatter. Under the progressive-ratio schedule, breaking points varied as an inverted-U shaped function, and the highest breaking points maintained by remifentanil and heroin were similar. At the doses that maintained the highest breaking points under the progressive-ratio schedule, post-infusion pauses under the continuous-reinforcement schedule were about three times shorter with remifentanil than with heroin. CONCLUSIONS: Although rates of self-administration are clearly influenced by a drug's duration of action, the ability to maintain responding under intermittent schedules of reinforcement may be independent of duration of action.

Analgesics, Opioid↗

PubMed2000

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

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

Animals↗

PubMed2000

Effects of compounding drug-related stimuli: escalation of heroin self-administration.

Previous experiments have demonstrated that presenting independently established discriminative stimuli in compound can substantially increase operant responding maintained by food reinforcement or shock avoidance. Recently, this phenomenon was also shown to occur with cocaine self-administration. The present study further assessed the generality of these stimulus-compounding effects by systematically replicating them with heroin self-administration. Rats' nose-poke responses produced intravenous heroin (0.025 mg/kg per infusion) on a variable-ratio schedule when either a tone or a light was present. In the absence of these stimuli, responding was not reinforced. Once discriminative control by the tone and light had been established, the stimuli were presented in compound under extinction (with heroin discontinued) or maintenance conditions (with heroin available during test-stimulus presentations). In extinction, the tone-light compound increased responding approximately threefold compared to tone or light alone. Under maintenance conditions, compounding increased heroin intake approximately twofold. These effects closely matched those obtained earlier with cocaine. This consistency across pharmacological classes and across drug and nondrug reinforcers further confirms that (a) self-administered drugs support conditioning and learning in a manner similar to that supported by other reinforcers; and (b) multiple drug-related cues interact in lawful and predictable ways to affect drug seeking and consumption.

Animals↗

PubMed1999

Blocking a selective association in pigeons.

Experiment 1 demonstrated for the first time a stimulus-reinforcer interaction in pigeons trained with free-operant multiple schedules of reinforcement. Pigeons that treadle pressed in the presence of a tone-light (TL) compound for food exhibited primarily visual stimulus control on a stimulus-element test, whereas pigeons that avoided shock in TL exhibited auditory control. In Experiment 2, this selective association was blocked in pigeons pretrained with the biologically contingency-disadvantage element of the compound (i.e., tone-food or light-shock) before TL training. When this pretraining preceded compound-stimulus training, control was now auditory in pigeons that treadle pressed for food and was visual in pigeons that avoided shock. Previous attempts at blocking this selective association were unsuccessful in pigeons (LoLordo, Jacobs, & Foree, 1982) but were successful in rats (Schindler & Weiss, 1985). Experiment 2 established that selective associations can be blocked in pigeons when the procedures that were effective with rats were systematically replicated. These results further demonstrate the cross-species generality of an associative attentional mechanism involving a biological constraint on learning in species with different dominant sensory systems.

Animals↗

PubMed1998

Motivational effects of compounding discriminative stimuli associated with food and cocaine.

In previous experiments, the compounding of two discriminative stimuli associated with the same reinforcer increased rats' responding approximately three-fold, regardless of whether the reinforcer was food, water, cocaine, or shock-avoidance. Compounding a discriminative stimulus associated with food with one associated with water increased responding two-fold. In the present experiment, compounding a discriminative stimulus associated with food with one associated with cocaine increased responding two-fold. These results support the hypothesis that 1) the effects of stimuli associated with reinforcers from the same incentive class (appetitive or aversive) are mutually enhancing, and 2) the combined effects of stimuli associated with two different reinforcers from within the same class are not as strong as those of two stimuli associated with the same reinforcer. These results also suggest that discriminative stimuli associated with non-drug reinforcers may increase the motivation to self-administer cocaine when encountered in combination with drug-related stimuli.

Acoustic Stimulation↗

PubMed1998

Effects of delivery rate and non-contingent infusion of cocaine on cocaine self-administration in rhesus monkeys.

The goal of this study was to determine whether slowly infused, response-independent cocaine would reduce cocaine self-administration in an animal model of drug abuse. Seven male rhesus monkeys self-administered i.v. cocaine on a fixed-ratio 30 schedule (5-min time-out). With unit dose (0.056 mg/kg per infusion for one monkey and 0.032 mg/kg per infusion for the rest) and infusion volume (0.5 ml) held constant, the rate of delivery was manipulated (0.125, 0.1875, 0.375, 0.75 and 3 ml/min, with infusions lasting 240, 160, 80, 40, and 10 s, respectively). Response rates increased monotonically as a function of delivery rate. Responding for cocaine at the slowest delivery rate did not differ from saline. The effects of infusing additional cocaine (starting 30 min prior to the session) at this non-reinforcing rate (0.125 ml/min) were then determined. Delivery rate of the self-administered infusion was manipulated as before. Non-contingent cocaine significantly increased responding for cocaine (at the fastest delivery rate) and for saline. While non-contingent cocaine reduced responding for cocaine in two of the seven monkeys, it also significantly reduced responding in three monkeys that responded for food on the same schedule. Plasma levels of cocaine delivered at rates of 0.125 and 3 ml/min were compared in five other monkeys. While a higher peak was reached with the faster infusion, levels did not differ after 5 min. Thus, when an infusion became available (after the 5-min time-out) in the self-administration experiments, plasma levels should not have differed regardless of the delivery rate. These results suggest that a low-dose, slow-delivery treatment with cocaine might prime or reinstate drug seeking rather than decrease it.

Animals↗

PubMed1997

Conditioned locomotor-activating and reinforcing effects of discrete stimuli paired with intraperitoneal cocaine.

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.

Animals↗

PubMed1996

Cocaine self-administration increased by compounding discriminative stimuli.

Presenting independently established discriminative stimuli in compound can substantially increase response rates under food and shock-avoidance schedules. To determine whether this effect extends to drug self-administration, rats were trained to press a lever to receive cocaine intravenously. A tone and a light were independently established as discriminative stimuli for cocaine self-administration, then presented in combination in a stimulus-compounding test. Compared to tone and light alone, the tone-plus-light compound stimulus increased responding approximately three-fold when cocaine was withheld during testing, and it increased drug intake approximately two-fold when cocaine was made available during testing. Compounding did not increase responding after training in a truly random control condition where tone and light were presented uncorrelated with the availability of cocaine. The results obtained with this animal model of drug abuse define conditions under which combinations of environmental stimuli might substantially increase human drug use.

Acoustic Stimulation↗

PubMed1993

Selective associations produced solely with appetitive contingencies: the stimulus-reinforcer interaction revisited.

In studies reporting stimulus-reinforcer interactions in traditional conditioning paradigms, when a tone-light compound was associated with food the light gained stimulus control, but when the compound was paired with shock avoidance the tone gained control. However, the physical nature of the reinforcer-related events (food vs. shock) presented in the presence of the tone-light compound was always confounded with the conditioned hedonic value of the compound's presence relative to its absence. When the compound was paired with shock, its presence was negative relative to its absence (which was shock-free). In contrast, when the compound was paired with food, its presence was positive relative to its absence (which was food-free). The present experiment dealt with this confounding effect by conditioning a tone-light compound to be positive or negative, relative to its absence, solely with food reinforcement. One group of rats received food for responding in the presence of the tone-light compound and no food in its absence. The other group also responded in the presence of the compound, but received food only in its absence. These rats were trained on a chained schedule in which responding in the presence of the tone-light compound produced a terminal link signaled by the absence of the compound; responding ceased in the terminal link because it delayed food delivery. In a test session to assess stimulus control by the elements of the compound, tone and light were presented separately under extinction conditions. Rats that had been exposed to a positive correlation between food and the compound emitted almost double the responses in the presence of the light as in the presence of the tone. In comparison, rats that had been exposed to a negative correlation emitted only two thirds as many responses in the presence of the light as in the presence of the tone. Because this selective association was produced using only food, it appears that the contingencies under which a reinforcer is presented, rather than (or as well as) its physical properties, can generate the selective associations previously attributed to "stimulus-reinforcer interactions." This could mean that regardless of the class of reinforcer that ultimately maintains responding (appetitive or aversive), the contingency-generated hedonic value of the compound stimulus may influence the dominant modality of stimulus control.

Animals↗

PubMed1993

Reversibility of single-incentive selective associations.

Rats were trained to press a lever in the presence of a tone-light compound stimulus and not to press in its absence. In each of two experiments, schedules were designed to make the compound a conditioned punisher for one group and a conditioned reinforcer for the other. In Experiment 1, one group's responding produced food in the presence of the compound but not in its absence. The other group's responding terminated the compound stimulus, and food was presented only in its absence. When tone and light were later presented separately, light controlled more responding than did tone in the former group, but tone gained substantial control in the latter. The same effects were also observed within subjects when the training schedules were switched over groups. In Experiment 2, two groups avoided shock in the presence of the compound stimulus. In the absence of the compound, one group was not shocked, and the other received both response-independent and response-produced shock. When tone and light were presented separately, the former group's responding was mainly controlled by tone, but the latter group's responding was almost exclusively controlled by light. These effects were also observed within subjects when the training schedules were switched over groups. Thus, these single-incentive selective association effects (appetitive in Experiment 1 and aversive in Experiment 2) were completely reversible. The schedules in which the compound should have been a conditioned reinforcer consistently produced visual control, and auditory control increased when the compound should have become a conditioned punisher. Currently accepted accounts of selective associations based on affinities between shock and auditory stimuli and between food and visual stimuli (i.e., stimulus-reinforcer interactions) do not adequately address these results. The contingencies of reinforcement most recently associated with the compound and with its absence, rather than the nature of the reinforcer, determined whether auditory or visual stimulus control developed.

Animals↗

PubMed1993

Single-incentive selective associations produced solely as a function of compound-stimulus conditioning context.

Barpressing was maintained in a tone-plus-light (TL) condition in 2 groups of rats by shock-related contingencies and in 2 other groups by food-related contingencies. Responding ceased in TL absence (TL). Contingency arrangements made TL hedonically positive, relative to TL, for 1 shock group and for 1 food group and hedonically negative for 1 shock group and for 1 food group. In a stimulus-element test, the visual modality was dominant when TL was hedonically positive, whereas auditory control increased when TL was negative, irrespective of the reinforcers involved. Within-incentive contingency manipulations produced selective associations hitherto ascribed to stimulus-reinforcer interactions, suggesting that biological constraints on learning may operate at the level of conditioned psychological states.

Animals↗

PubMed1992

Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist.

The external envelope glycoprotein (gp120) of the human immunodeficiency virus (HIV) has been shown to be toxic to neurons in culture. To further investigate the neurological effects of gp120, the involvement of this protein with the acquisition of spatial discrimination was assessed. Both native and recombinant gp120 were administered into the cerebral ventricles of adult rats and performance was evaluated in the Morris swim maze. Gp120 treatment retarded acquisition after daily administration of 12 ng. The specificity of this impairment was demonstrated in that the performance of animals given the same amount of gp160 from recombinant baculovirus was not different from animals given saline. Vasoactive intestinal peptide (VIP) has been shown to block gp120-induced neurotoxicity in culture and a VIP receptor antagonist has displayed toxic properties to neurons in culture. We show here that this antagonist, which competitively inhibits VIP binding and blocks VIP-mediated functions in cell cultures from the CNS, also produced an impairment of performance. This retardation was attenuated by cotreatment with VIP, supporting the specificity of the observed impairment. Thus, gp120 and the VIP antagonist produced similar retardation of spatial discrimination, suggesting that both may impair memory for spatially related stimulus control.

Animals↗

PubMed1992

FG 7142 selectively decreases nonpunished responding, but has no anxiogenic effects on time allocation in a conflict schedule.

Previous work (Thomas et al. 1990) showed that an anxiolytic benzodiazepine increased the time allocated to responding in a conflict situation (where responses were both food-reinforced and shock-punished) versus a nonpunishment situation. The present experiment tested whether a benzodiazepine-receptor inverse agonist (FG 7142, 1-30 mg/kg) would have the opposite effect (i.e., decrease time spent responding in a punishment situation). Chain pulls determined whether a rat's lever presses were reinforced on 1) a lean variable-interval schedule, or 2) a richer variable-interval schedule in which responding also produced shock intermittently. FG 7142 dose-dependently decreased nonpunished lever responding, but did not affect punished responding. The drug nonselectively decreased chain pulling (the schedule-switching response). Like chlordiazepoxide, FG 7142 increased the time spent in the punishment component, showing that not all effects of benzodiazepine-receptor agonists and inverse agonists are opposite. These results are inconsistent with expectations that anxiogenic actions of FG 7142 should 1) decrease punished responding; 2) increase the rate of responses that terminate the punishment condition; and 3) decrease time spent in the punishment component. Rather, nonsuppressed responding seems most sensitive to decreases by FG 7142.

Animals↗