Effects of serotonergic manipulations on cocaine self-administration in rats

Rats were trained to self-administer cocaine (0.5 mg/kg/infusion) and were then pretreated with the 5-HT1A agonist 8-OH-DPAT (0.125, 0.25 or 0.5 mg/kg, SC). 8-OH-DPAT pretreatment produced a decrease in reinforced response rates. When the effect of 8-OH-DPAT (0.5 mg/kg, SC) on responding for a range of cocaine doses was assessed, the drug produced a decrease in response rates when lower doses of cocaine served as the reinforcer. Fluoxetine (10 mg/kg, IV), an indirect 5-HT agonist, also reduced reinforced response rates for a low dose infusion of cocaine. Rates of responding for infusions of higher cocaine doses were not affected by fluoxetine pretreatment during an FR1 schedule of reinforcement. When an FR10 schedule of reinforcement was imposed, reinforced response rates for infusions of higher doses of cocaine were also reduced. Thus, under conditions that produce high rates of responding (low dose infusion or high ratio requirements for an infusion) fluoxetine reduced responding. This effect may be due to the effects at the 5-HT1A receptor, since 8-OH-DPAT produced a similar effect on cocaine self-administration. Given that the effects of these 5-HT agonists are observed only when low doses of cocaine serve as the reinforcer or when task demands are high, it is possible that the suppression of responding reflects an effect that is not specific to the reinforcing impact of cocaine. An alternative explanation for these effects incorporates a concept of unit cost/cocaine infusion that allows for direct comparison across studies that employ different reinforcement schedules.     

Schedule induction conditions not only exaggerate intake but also enhance drug solution choice

In previous research, rats exposed to daily, 3 h sessions of schedule-induced polydipsia (SIP) self-administered high doses of cocaine orally. However, a strong and durable preference for cocaine solution to water requires training in addition to mere oral self-administration exposure. If cocaine is dissolved in a preferred vehicle solution, and the vehicle is subsequently faded to water, then a strong preference for cocaine remains. A similar preference can be instituted for lidocaine solution. Such preferences may develop because the gustatory property of a drug becomes associated with the preferred vehicle and remains to function as a durable conditioned reinforcer after vehicle fading. To determine if drug preference is solely a function of this posited conditioning mechanism, or whether it also depends upon the SIP condition, rats were exposed to daily, 3 h sessions of single-ration feeding, rather than the SIP condition. A preferred vehicle (glucose/saccharin solution) was slowly faded from a 0.19 mg/ml lidocaine solution, which was presented concurrently with a choice for water. Although a preference for lidocaine solution to water could be generated, it occurred for only 5 out of 9 rats, and the preference was relatively unstable. By contrast, in two previous studies using SIP, 26 out of 27 rats maintained a preference for lidocaine solution. Thus, SIP not only exaggerates the amount of drug solution ingested but also contributes to the fixation of the associative drug solution choice.     

Oral cocaine self-administration in rhesus monkeys: Strategies for engendering reinforcing effects.

Orally delivered cocaine was established as a reinforcer for 8 rhesus monkeys (Macaca mulatta). Initially, each monkey was given a choice between the water vehicle and a 0.2 mg/ml cocaine concentration. The 0.2 mg/ml solution was not consumed in preference to water. One or more acquisition procedures were used with each monkey to establish orally delivered cocaine as a reinforcer. A common feature of all but one procedure was environmental situations that lead to the elective drinking of the cocaine solution. Evidence confirming the establishment of cocaine's reinforcing effects was obtained by testing each monkey across a broad range of cocaine concentrations under conditions of concurrent access to the cocaine solution and vehicle. Over a range of concentrations, the monkeys obtained greater cocaine than vehicle deliveries. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaine self-administration under conditions of restricted and unrestricted food access.

Four rhesus monkeys (Macaca mulatta), maintained at reduced body weight and restricted food availability, had access to a 0.8-mg/ml cocaine solution and vehicle under a concurrent fixed-ratio (FR) 8 schedule. Over days, the cocaine concentration was reduced (0.57, 0.4, 0.2, 0.1, 0.05, 0.025) and then returned, gradually over days, to 0.8 mg/ml. The ratio value was then varied (to 16, 32, 64, 128, and 8). Food access was unrestricted, and the ratio and the concentration manipulations were then repeated. During food restriction cocaine served as a reinforcer for all monkeys, whereas during free feeding cocaine functioned as a reinforcer for 3 of 4 monkeys; with these monkeys, the dose-response curve obtained under free feeding was shifted to the right of that obtained under food restriction. There were no differences in FR response curves obtained during food restriction and unrestricted feeding. These data suggest that food restriction increases cocaine's reinforcing effects and that the higher the cocaine dose, the greater are the reinforcing effects. A demand curve analysis was completed, and data are discussed in terms of microeconomic principles. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of D-cycloserine on the extinction of appetitive operant learning.

Four experiments with rat subjects examined whether D-cycloserine (DCS), a partial NMDA agonist, facilitates the extinction of operant lever-pressing reinforced by food. Previous research has demonstrated that DCS facilitates extinction learning with methods that involve Pavlovian extinction. In the current experiments, operant conditioning occurred in Context A, extinction in Context B, and then testing occurred in both the extinction and conditioning contexts. Experiments 1A and 1B tested the effects of three doses of DCS (5, 15, and 30 mg/kg) on the extinction of lever pressing trained as a free operant. Experiment 2 examined their effects when extinction of the free operant was conducted in the presence of nonresponse-contingent deliveries of the reinforcer (that theoretically reduced the role of generalization decrement in suppressing responding). Experiment 3 examined their effects on extinction of a discriminated operant, that is, one that had been reinforced in the presence of a discriminative stimulus, but not in its absence. A strong ABA renewal effect was observed in all four experiments during testing. However, despite the use of DCS doses and a drug administration procedure that facilitates the extinction of Pavlovian learning, there was no evidence in any experiment that DCS facilitated operant extinction learning assessed in either the extinction or the conditioning context. DCS may primarily facilitate learning processes that underlie Pavlovian, rather than purely operant, extinction. (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.     

Gestational methylmercury exposure selectively increases the sensitivity of operant behavior to cocaine.

Developmental methylmercury (MeHg) exposure alters dopamine neurotransmitter systems, but the selectivity of this and the effects of low, environmentally relevant MeHg exposure regimens are poorly understood. In previous reports, some including littermates of animals studied here, chronic, low-level exposures affected performance on reversal tasks and enhanced reinforcer efficacy. Using high- and low-rate operant behavior under a fixed interval (FI) schedule, sensitivity was examined to drugs that target noradrenergic and dopaminergic neurotransmitter systems. Female rats were exposed in utero to 0, 0.5, or 5 ppm of mercury, as MeHg, via maternal drinking water. Selenium (Se) is thought to attenuate MeHg's neurotoxicity, so animals consumed a diet containing 0.06 or 0.6 ppm of Se. At 11 months, they lever-pressed under a FI 120” schedule of sucrose reinforcement. Acute dose-effect curves were generated with cocaine, desipramine, SKF-38393, quinpirole, SCH-23390, and sulpiride. As compared with unexposed animals, those exposed to 5 ppm mercury, regardless of Se exposure, were 2 to 3 times more sensitive to the rate-reducing effects of high doses of cocaine and did not show increased responding earlier in the interval following moderate cocaine doses. Cocaine's effects in the 0.5 ppm Hg groups depended on dietary Se: low Se diet resulted in a rightward shift in the DEC compared to controls, whereas a high Se diet did not. No differential effects of MeHg were seen with the other drugs. Gestational MeHg exposure produces irreversible sensitivity to dopamine, but not norepinephrine, reuptake inhibitors and not to drugs that target D1 or D2 receptors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

AMPA receptors and motivation for drug: effect of the selective antagonist NBQX on behavioural sensitization and on self-administration in mice

A series of experiments was carried out in which the potency of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (10-100 mg/kg) on locomotor activity was investigated, in mice. NBQX reduced all forms of activity studied, but its potency to do so varied according to the conditions of the experiment. The smallest dose of NBQX significantly reducing spontaneous or cocaine-induced activity was 100 mg/kg. Mice that had been repeatedly treated with 16 mg/kg cocaine once per week, for 7 weeks, showed a sensitized locomotor response to a challenge dose of cocaine (16 mg/kg). NBQX reversed the sensitized response at 30 and 100 mg/kg. The pattern of results obtained leaves open the role that AMPA-receptors may have in the expression of behavioural sensitization. In two further experiments, mice were trained to self-administer cocaine (30 micrograms per reinforcer) via intravenous catheters, using an operant lever pressing technique. When the amount of cocaine per reinforcer was doubled (to 60 micrograms) or halved (to 15 micrograms) the mice adapted lever pressing rates to maintain some constancy of self-dosing (but not at 7.5 micrograms per reinforcer) and when saline was substituted for cocaine, response rates increased considerably (extinction bursting). NBQX (10 and 30 mg/kg) reduced the self-administration of 30 micrograms reinforcers of cocaine, but only during the first 30 min of the test session. There was no evidence that NBQX specifically antagonized the reinforcing effect of cocaine, as responding was similarly reduced on both the reinforced and the non-reinforced lever, nor did the response to NBQX mimic behaviour seen following changes in the concentration of the reinforcer. The results of the locomotor experiments and the self-administration experiments are discussed together, in terms of current hypotheses about glutamatergic mechanisms involved in motivation for drug.     

Limitations to the generality of cocaine locomotor sensitization.

Repeated exposure to cocaine often leads to tolerance to effects on operant behavior, whereas sensitization often develops to effects on locomotor activity. The purpose of the present set of experiments was to examine if locomotor sensitization to cocaine would develop in the presence or absence of an operant contingency in rats. In Experiment 1, rats lever pressed on an FR schedule of reinforcement, and were administered chronic cocaine. Tolerance to effects of cocaine on lever pressing developed in most subjects. No subjects developed locomotor sensitization even when the operant contingency was removed. Experiment 2 examined effects of chronic cocaine administration in rats with no exposure to an operant contingency. Tolerance developed to locomotor effects of cocaine in some subjects, but none developed sensitization. In Experiment 3, rats were exposed to a shorter drug regimen, and given time off before a sensitization-test session. Some, but not all subjects showed locomotor sensitization during the test session. The present results, therefore, show that locomotor sensitization to cocaine is not an inevitable consequence of repeated exposure to the drug. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned reinstatement of drug-seeking behavior with a discrete compound stimulus classically conditioned with intravenous cocaine.

The present study investigated the ability of a light and tone (LT) compound stimulus paired with cocaine infusions to reinstate cocaine-seeking behavior. Rats were trained to self-administer cocaine in the presence or absence of the LT during daily 3-hr sessions (maintenance). During Maintenance Days 5 and 10, rats underwent classical conditioning, whereby passive cocaine infusions were paired with either short-delayed, random, or no presentations of an LT. After extinction sessions, rats underwent test sessions in which the LT was presented in a noncontingent or response-contingent manner to measure conditioned cocaine-seeking behavior. The results demonstrated that response-contingent LT presentations significantly increased cocaine-seeking behavior and that the LT trained in a classical conditioning format transferred to an operant secondary reinforcer. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of hepaplastintest for liver disease. Effect of vitamin K administration on values of hepaplastintest (author''s transl)

A procedure for studing intravenous drug self-administration in the cat is described. Ten cats were given 24-h access to methamphetamine reinforcement (0.04 mg/kg/inj). The subjects maintained a significantly higher response rate for drug reinforcement than for saline. The pattern of self-administration over days alternated between periods of high and low drug intake. Six additional cats were used to study the effect of dose per injection on methamphetamine self-administration under conditions of limited access. When methamphetamine was subtituted at various doses per infusion in animals maintained on cocaine reinforcement, response rate was shown to be an inverted U-shaped function of dose. These studies demonstrate that methamphetamine is a reinforcer in the cat and its patterns of intake under conditions of 24-h and limited access resemble other species.     

Dopamine agonists prevent or counteract the suppression of brain stimulation reward by fenfluramine

Eighteen male subjects participated in a clinical study to examine a skin patch method of monitoring drug use. On the first day of each of two periods, 14 Band-aid type collection devices (sweat patches) were applied to a subject's torso, biceps, and back. On the following day, the subject took 50 or 126 mg cocaine hydrochloride intranasally. A 1-week interval separated treatment periods, and the order of dose levels was counterbalanced. On the days subjects received cocaine, one patch was removed before treatment, and five were removed after treatment. Subjects then returned over the next 7 days for removal of the remaining patches. They provided urine samples immediately after each patch removal. A group of 18 nondrug users also wore patches for up to 12 days. Analysis of the patch content yielded cocaine levels from the cocaine subjects that accurately reflected usage. Mean levels for 16 subjects were significantly different for the two treatment doses. However, given the between-dose and between-subject variability, the data cannot be used to determine either dose or time of use. The data do indicate, however, that the patch technology can be used to diagnose a single episode of cocaine use as far back as 7 days.     

Self-administered cocaine causes long-lasting increases in impulsive choice in a delay discounting task.

Cocaine use is associated with high levels of impulsive choice (preference for immediate over delayed rewards), but it is not clear whether cocaine use causes elevated impulsive choice, or whether elevated impulsive choice is solely a predisposing factor for cocaine use. This study examined the effects of prior cocaine self-administration on rats performing a delay discounting task commonly used to measure impulsive choice. Male Long-Evans rats were implanted with intravenous catheters, and following recovery, were trained to self-administer 30 mg/kg/day cocaine HCl (approx. 0.5 mg/kg/infusion) for 14 consecutive days (a control group received yoked intravenous saline infusions). Following three weeks of withdrawal, all rats were food-restricted and began training on the delay discounting task in standard operant chambers. On each trial, rats were given a choice between two levers. A press on one lever delivered a small food reward immediately, and a press on the other delivered a large food reward after a variable delay period. Rats that self-administered cocaine displayed greater impulsive choice (enhanced preference for the small immediate over the large delayed reward, as reflected by shorter indifference points) compared to controls, but were no different from controls on a “probabilistic discounting” task in which they chose between small certain and large uncertain rewards. These data suggest that self-administered cocaine can cause lasting elevations in impulsive choice, and that the high levels of impulsive choice observed in human cocaine users may be due in part to long-term effects of cocaine on brain function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaine cue in rats as it relates to subjective drug effects: a preliminary report

Using a food-reinforced two-lever operant method, rats (n=5) could be trained to discriminate 10 mg/kg cocaine from saline. Stimulus generalization experiments with lower doses (0.31-5.0 mg/kg) revealed that the cocaine cue is a dose-related phenomenon. Neuroleptic drugs were found relatively ineffective as possible antagonists of the cocaine cue, and no antagonistic effect whatsoever was obtained with dibenamine, propranolol, cyproheptadine and methysergide. iamphetamine (1.25 mg/kg) and apomorphine (0.31 mg/kg) were generalized with cocaine, and a dopaminergic involvement is discussed.     

Locomotor Activity Predicts Acquisition of Self-Administration Behavior but Not Cocaine Intake.

The current study investigates locomotor activity in a novel environment and correlates these activity levels with cocaine self-administration in rats that were either trained or untrained on a lever-pressing task prior to cocaine self-administration. The authors report that it is the rate of learning the lever-pressing task, not cocaine self-administration, that correlates with locomotor activity. The results suggest that a correlation between locomotor activity and cocaine self-administration is secondary to a link between locomotor activity and rate of learning to lever press for a reward. The authors conclude that locomotor activity is not necessarily an indicator of propensity to self-administer cocaine and demonstrate that environmental novelty and rate of learning an operant task are important considerations when designing experiments on drug-seeking behaviors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The visual acuity for the lateral visual field of the pigeon (Columba livia)

Previous studies on pigeons indicated that the visual acuity for the frontal visual field was much higher than that for the lateral one. Suspecting that the poor values for the lateral field were due to suboptimal testing conditions, we determined the lateral field acuity in eight head-fixed pigeons with high-contrast square-wave gratings. An instrumental conditioning task with water as reinforcer and mandibulation as an operant was used. Subjects achieved a mean acuity value of 12.6 c/deg. The results show that the acuity of the lateral visual field is only slightly lower than that of the frontal field. These data provide a psychophysical basis for ecological observations that pigeons and most other birds gaze laterally when scrutinizing small and distant objects.     

Ethanol and cocaine intake by rats selectively bred for oral opioid acceptance

Lines which accept or reject the potent opioid etonitazene, and a randomly bred control line, were assessed for the specificity of selective breeding. Drug-naive subjects from generation 8 were offered a continuous choice between water and 10% ethanol for 20 days. There was no difference between the accepting and rejecting lines in preference for one fluid, or in amount of ethanol consumed. The same rats were then given a choice between water and increasing concentrations (0.08-0.64 mg/ml) of cocaine, 7 days at each concentration. There were no differences among the lines in preference for the drug, but the rejecting line drank more of the cocaine solution than the accepting line. Finally, these rats were subjected to the regimen used in choosing rats for selective breeding, 4 days of a water-etonitazene choice. In their preference for etonitazene the order of the lines was as expected: accepting > control > rejecting. In addition, the accepting line drank more of the etonitazene solution than the other two lines. These data suggest that selection has been rather specific and not for a generalized tendency to become intoxicated.     

Regulation of intravenously self-administered nicotine in rats.

Ten male Wistar rats had access to 9 doses of nicotine (0.01–0.10 mg/kg iv) during daily 5-hr sessions. Once responding for nicotine stabilized, nicotine infusions were replaced with either cocaine infusions (0.0–2.4 mg/kg) or saline infusions. Saline substitution results indicate that nicotine functioned as a reinforcer. Regulation of nicotine intake was compared with that of cocaine by obtaining the correlation between mean interdose interval and preceding dose size. Results reveal that although this correlation was significant for both nicotine and cocaine self-administration, nicotine self-administration was less precisely regulated than cocaine self-administration. This procedure suggests that there are differences in regulation among self-administered drugs and that it may serve as a useful baseline for studying differences in vulnerability to drug abuse and potential treatment strategies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clinical and radiological assessment of proximally coated stems in growth in total hip replacement]

Although cocaine is a powerful reinforcer, it has been reported to produce anxiety in humans and anxiogenic-like behavior in animals. The goal of this study was three-fold: (1) to determine the doses of cocaine that induce anxiogenic-like behavior in the elevated plus-maze in rats, (2) to determine if cocaine-associated contextual cues are capable of eliciting anxiogenic-like behavior in the absence of the drug, and (3) to identify possible mechanisms through which cocaine-associated cues affect behavior in the elevated plus-maze. Measurement of the amount of time that the animals spend exploring the open arms of the maze provides a sensitive index of anxiogenic-like behavior in rats. In experiment 1, rats were injected with 10 mg/kg, 20 mg/kg, or 30 mg/kg cocaine HCl or saline for 6 days. On day 6, the rats were tested in the elevated plus-maze 25 min after injection with cocaine or saline. The animals chronically treated with the three doses of cocaine exhibited a dose-dependent increase in anxiogenic-like behavior in the elevated plus-maze, compared to the saline-treated group. In experiment 2, cocaine-induced (30 mg/kg) conditioning was achieved using a simple contextual design. On the final day of the experiment (day 6), after 5 days of conditioning, the rats were exposed for 25 min to the cocaine-associated contextual cues, then placed in the elevated plus-maze. Animals that had been exposed to cocaine-associated contextual cues prior to being placed in the elevated plus-maze exhibited a significant increase in anxiogenic-like behavior compared to the control groups. However, pretreatment of the rats with the CRF antagonist, alpha-helical CRF9-41 (1 microg, i.c.v.), on the test day, prior to exposure to cocaine-associated contextual cues, attenuated the subsequent anxiogenic-like behavioral response in the elevated plus-maze (experiment 3). The results suggest that contextual cues associated with repeated treatment with 30 mg/kg cocaine are capable of eliciting anxiogenic-like behavior in the absence of the drug and that CRF mediates the expression of anxiogenic-like behaviors in the elevated plus-maze following exposure to cocaine-associated cues. The conditioned anxiogenic action elicited by cocaine-associated cues may have relevance for understanding the complex addictive nature of this drug and some of the clinical phenomena related to its use.     

Adolescent cocaine residually impairs working memory and enhances fear memory in rats.

The residual effects of cocaine during adolescence on memory in male young adult rats were studied. Animals were injected with 20 mg/kg cocaine on postnatal Days 28 through 35, whereas lab-chow (LC) and pair-fed (PF) control subjects received saline. Assessment of spatial working and long-term memory in the Morris water maze, and 72-h retention of an inhibitory avoidance task was conducted at about 5 and 9 weeks postcocaine, respectively. Relative to PF control subjects, cocaine-treated subjects showed impairments in the water maze when required to swim to the hidden platform placed in a quadrant diagonal from the location of its original location (i.e., on reversal learning). These same drug-treated animals, however, exhibited enhanced inhibitory avoidance retention relative to both control groups. These seemingly disparate findings are seen as being consistent with previous data showing that cocaine during adolescence residually impairs spatial memory and leads to enhanced fear responses. Moreover, when taken with previous findings from our laboratory, the present water maze data indicate that the deleterious effects of cocaine, when administered during adolescence, is delayed until 5 weeks after initiation of abstinence. It is speculated that alterations to limbic circuitry, especially those associated with the amygdala, account for the behavioral results observed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)