Cocaine and level of arousal: effects on vigilance task performance of rats

Rats were food-reinforced for pressing one of two levers in an operant chamber, with the correct lever being indicated by the position of a briefly illuminated light. After stable accuracy levels were achieved, the rats were tested after an injection of either saline or cocaine (2.5 mg/kg) under two conditions. In the "low arousal" condition, animals were tested during the light phase of a 12-hr light-dark cycle and were fed approximately 5 hr prior to testing. In the "high arousal" condition, animals were tested during the dark phase after approximately 28-hr food deprivation. As expected, accuracy was higher and median choice and food retrieval latencies were shorter under the high arousal condition. Contrary to predictions, cocaine enhanced accuracy under both conditions. These results indicate that cocaine-enhanced performance in some tasks is not necessarily dependent on the animal performing at suboptimal arousal levels.     

Impulsive choice as a predictor of acquisition of IV cocaine self- administration and reinstatement of cocaine-seeking behavior in male and female rats

Drug abuse and impulsive choice are related in humans. In female rats, impulsive choice predicted the rate of acquisition of IV cocaine self-administration. The objectives of the present experiments were to: (a) compare impulsive choice in males and females, (b) extend previous research on impulsive choice and acquisition of cocaine self-administration to males, and (c) compare males and females during maintenance, extinction, and reinstatement of cocaine-seeking behavior. Male and female rats were trained on an adjusting delay task in which a response on one of two levers yielded one food pellet immediately, and a response on the other resulted in three pellets after an adjusting delay that decreased after responses on the immediate lever and increased after responses on the delay lever. A mean adjusted delay (MAD) was used as the quantitative measure of impulsivity. In Experiment 1, MADs were analyzed for sex differences. In Experiment 2, acquisition of cocaine self-administration was examined in rats selected for high (HiI; MADs < or =9 seconds) or low (LoI; MADs > or =13 seconds) impulsivity. In Experiment 3, HiI and LoI groups were compared on maintenance and extinction of cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior. There were no sex differences in impulsive choice; however, HiI male and female rats acquired cocaine self-administration faster than their LoI counterparts. LoI females responded more on a cocaine-associated lever during maintenance and extinction than HiI females, but HiI females showed greater reinstatement of cocaine-seeking behavior than all other groups at the highest dose tested (15 mg/kg). Thus, individual differences in impulsive choice were associated with differences in cocaine-seeking behavior. Impulsive choice and sex may be additive vulnerability factors in certain phases of drug abuse.     

Effects of cocaine and d-amphetamine on sustained and selective attention in rats

The effects of cocaine and d-amphetamine were compared in two attention-loading tasks. Cued by the position of a light, rats were food-reinforced for pressing one of two levers in a 2-choice, discrete-trial procedure. In the "sustained attention" task, the cue light was illuminated for a brief period (1.8 sec or less) at the beginning of each trial. In the "selective attention" task, the cue light remained on until a level press, while a blinking light over the incorrect lever served as a distractor. In the sustained attention task, low doses of d-amphetamine (0.25 mg/kg SC) and cocaine (2.5 mg/kg SC) enhanced accuracy; some doses of d-amphetamine (0.75 mg/kg SC) and cocaine (1.25 and 2.5 mg/kg SC) also reduced choice latencies. In the selective attention task, the lower doses of these drugs had no effect on accuracy, the highest dose of d-amphetamine (1.25 mg/kg SC) disrupted accuracy, and all doses of the drugs reduced choice latencies. The time to retrieve food was increased in a dose-dependent fashion by both drugs in both tasks. These results indicate that, other than differences in potency, cocaine and d-amphetamine induce similar behavioral effects in attention-loading tasks, with improvement or interference with performance dependent on the dose and the type of attention demanded of the task.     

Assessment of drug effects on memory by delayed discrimination responses in rats

Delayed discrimination experiments were conducted to examine drug effects on memory in rats. Three kinds of experimental situations: a Y-maze, an operant chamber with two retractable levers, and an operant chamber with two fixed levers were used. A discriminative stimulus light either on the left or the right side of a stimulus panel was presented for a brief period in each situation. After a certain delay time following extinguishment of the light, a choice response to the previously lighted side was termed as a correct choice. Scopolamine at 0.015-0.06 mg/kg, s.c., decreased the correct choice ratio in trials with a delay time of 0 sec in the Y-maze situation and in trials with longer delay times in the operant chamber situations. Nicotine at 0.06-1 mg/kg, s.c., decreased the correct choice ratio in trials with a delay time of 0-4 sec in the Y-maze situation, a delay time of 4 sec in the retractable-lever operant chamber situation, and a delay time of 0.1 sec in the fixed-lever operant chamber situation. Using this delayed discrimination procedure, drug effects on the relationship between delay time and correct choice ratio were observed. From these results, the present procedure was found to be useful for the evaluation of drug effects on memory in rats.     

The role of the ascending 5-hydroxytryptaminergic pathways in timing behaviour: further observations with the interval bisection task

This experiment examined the effect of destroying the 5-hydroxytryptaminergic (5HTergic) pathways on rats' ability to discriminate between two durations. Rats received injections of 5,7-dihydroxytryptamine into the median and dorsal raphe nuclei or sham lesions. They were trained to press lever A following a 2-s presentation of a light and lever B following an 8-s presentation of the light. For some rats, the levers were inserted into the chamber immediately after stimulus presentation (no-poke-requirement); for others, the levers were not inserted until a flap covering the food tray positioned midway between the levers had been depressed (poke-requirement). When stable performance was attained, probe trials were introduced in which the light was presented for intermediate durations. Logistic functions were derived relating percent choice of lever B to log stimulus duration. Under the no-poke-requirement condition, the bisection point (duration yielding 50% choice of lever B) was shorter in the lesioned rats than in the control rats. Under the poke-requirement condition, this effect of the lesion was attenuated. There was no effect of the lesion on the Weber fraction under either condition. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. It is proposed that rats may attain accurate timing under the interval bisection task by moving from one lever to the other during stimulus presentation; this movement may be facilitated by destruction of the 5HTergic pathways. Accurate timing is still possible when this movement is suppressed by the introduction of a poke requirement; however, in this case timing is not affected by 5HT depletion.     

Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement

In these experiments we sought to establish the intravenous (IV) self-administration of cocaine under a second-order schedule of reinforcement in order: (i) to obtain reliable, drug-free levels of responding with cocaine as a reinforcer, and (ii) to enable investigation of the neural mechanisms by which arbitrary cues gain motivational salience and, as conditioned reinforcers, control over drug-seeking behaviour. Initially, each infusion of cocaine was made contingent upon a response on one of two identical levers and was paired with a 20-s light conditioned stimulus (CS). Responses on the second lever were recorded, but had no programmed consequence. When rats acquired stable rates of self-administration, a second-order schedule of the type FRx(FRy:S) was introduced, with values of x being increased progressively to 10 and then y from 2 through 8. Priming (i.e. non-contingent) infusions of cocaine were never given. Once the first infusion was obtained under the second-order schedule, further infusions were made contingent on each response (to a maximum of ten infusions/day). Each stage was repeated daily until the first infusion of each session was achieved within a 5-min criterion. Rats with bilateral, excitotoxic lesions of the basolateral amygdala readily acquired the IV self-administration of cocaine under a continuous reinforcement schedule, initially administering more infusions and maintaining a slightly elevated level of self-administration than controls. Despite increased numbers of CS/drug pairings, basolateral amygdala-lesioned rats were severely impaired in the acquisition of the second-order schedule of IV cocaine reinforcement. Lesioned rats showed a cocaine dose-response function that was shifted upwards relative to control subjects. There was no significant difference between drug-naive amygdala-lesioned and control animals in the locomotor response to intraperitoneal injections of cocaine. These experiments indicate the feasibility and utility of second-order schedules in studying the neurobehavioural basis of cocaine-seeking behaviour. They suggest a dissociation in the neural mechanisims underlying cocaine-taking and cocaine seeking behaviour, and demonstrate the potential importance of the basolateral amygdala in the processes by which previously neutral stimuli gain control over drug-seeking behaviour.     

Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement

In these experiments we sought to establish the intravenous (IV) self-administration of cocaine under a second-order schedule of reinforcement in order: (i) to obtain reliable, drug-free levels of responding with cocaine as a reinforcer, and (ii) to enable investigation of the neural mechanisms by which arbitrary cues gain motivational salience and, as conditioned reinforcers, control over drug-seeking behaviour. Initially, each infusion of cocaine was made contingent upon a response on one of two identical levers and was paired with a 20-s light conditioned stimulus (CS). Responses on the second lever weee recorded, but had no programmed consequence. When rats acquired stable rates of self-administration, a second-order schedule of the type FRx(FRy:S) was introduced, with values of “x” being increased progressively to 10 and then “y” from 2 through 8. Priming (i.e. non-contingent) infusions of cocaine were never given. Once the first infusion was obtained under the second-order schedule, further infusions were made contingent on each response (to a maximum of ten infusions/day). Each stage was repeated daily until the first infusion of each session was achieved within a 5-min criterion. Rats with bilateral, excitotoxic lesions of the basolateral amygdala readily acquired the IV self-administration of cocaine under a continuous reinforcement schedule, initially administering more infusions and maintaining a slightly elevated level of self-administration than controls. Despite increased numbers of CS/drug pairings, basolateral amygdala-lesioned rats were severely impaired in the acquisition of the second-order schedule of IV cocaine reinforcement. Lesioned rats showed a cocaine dose-response function that was shifted upwards relative to control subjects. There was no significant difference between drug-naive amygdala-lesioned and control animals in the locomotor response to intraperitoneal injections of cocaine. These experiments indicate the feasibility and utility of second-order schedules in studying the neurobehavioural basis of cocaine-seeking behaviour. They suggest a dissociation in the neural mechanisims underlying cocaine-taking and cocaine seeking behaviour, and demonstrate the potential importance of the basolateral amygdala in the processes by which previously neutral stimuli gain control over drug-seeking behaviour.     

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on performance on two operant timing schedules

RATIONALE: Previous experiments have shown that the disruptive effect of central 5-HT depletion on interval timing behaviour is critically dependent upon the particular timing schedule used. However, it is not known how acute disruption of 5-HTergic function brought about by drugs acting at 5-HT receptors affects timing. OBJECTIVE: To examine the effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on performance on two quantitative timing schedules, a free-operant schedule in which rats were trained to distribute their responses differentially between two levers during the course of a 50-s trial (free-operant psychophysical procedure) and a discrete-trials schedule in which rats were trained to discriminate the durations of light stimuli (interval bisection task). METHODS: In experiment 1, rats were trained under the free-operant psychophysical procedure to respond on two levers (A and B) in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half, of the trial. For one group, repetitive switching between levers was permitted; for another group, it was prevented. In experiment 2, rats were trained to press lever A after a 2-s stimulus and lever B after an 8-s stimulus, and were then tested with stimuli of intermediate durations. For one group, a 'poke response' (depression of a central tray flap) was required after stimulus presentation to effect lever presentation; for the other group this requirement did not operate. In both experiments, quantitative indices of timing were derived from the psychophysical functions (%B responding vs time). RESULTS: In experiment 1, 8-OH-DPAT (25, 50, 100 and 200 microg kg(-1) s.c.) displaced the psychophysical curve to the left in both versions of the schedule. In experiment 2, 8-OH-DPAT increased the Weber fraction in both versions of the task without displacing the curve. CONCLUSIONS: These results show that 8-OH-DPAT disrupts timing behaviour. The results of experiment 1 are consistent with the proposal that 5-HTergic mechanisms help to regulate the period of the hypothetical pacemaker. However, the results of experiment 2 do not support this suggestion. Taken together, the results support the notion that different neural mechanisms may be involved in timing tasks involving temporal distribution of responding and discrimination of the durations of exteroceptive stimuli.     

Heightened cocaine and food self-administration in female rats with neonatal isolation experience.

Previously, we demonstrated that the early life stress of neonatal isolation facilitates acquisition of cocaine and food self-administration in adult female rats. We now test whether it enhances responding for these reinforcers after operant performance is established. Adult female rats were derived from litters that were either subjected to neonatal isolation (1 h/day isolation; postnatal days 2-9) or were nonhandled and assigned to one of two experiments. In Experiment 1, female rats well trained to self-administer cocaine were tested under a fixed-ratio 3 (FR3) schedule with several cocaine doses (0.0625-1.0 mg/kg/infusion) and under a progressive-ratio (PR) schedule (0, 0.5, and 1.0 mg/kg/infusion cocaine). In Experiment 2, female rats well trained to respond for food reinforcers under an FR15 schedule were tested under two PR schedules. Results show that neonatal isolation enhanced responding for cocaine under both schedules of reinforcement and increased responding for food under a PR schedule of reinforcement. These data extend our previous acquisition study in female rats to show that neonatal isolation enhances responding under maintenance conditions. These enduring behavioral changes may relate to the ability of neonatal isolation to increase striatal dopamine responses to psychostimulants, effects we showed previously in infant and juvenile rats.Neuropsychopharmacology (2006) 31, 70-76. doi:10.1038/sj.npp.1300779; published online 1 June 2005.     

Impulsivity (delay discounting) for food and cocaine in male and female rats selectively bred for high and low saccharin intake

Previous research in rats indicates that delay discounting for food, a model of impulsivity, predicted the rate of acquisition of cocaine self-administration. In other studies, rats bred for high saccharin intake (HiS) acquired cocaine self-administration at higher rates than those with low saccharin intake (LoS), and female (F) rats acquired cocaine self-administration more rapidly than males (M). The purpose of this study was to examine a possible connection between impulsivity, saccharin intake, and sex by comparing M and F rats from the HiS and LoS selectively bred lines on measures of impulsivity; i.e., their rate of delay discounting for food or i.v. cocaine infusions. The adjusting delay procedure allowed rats access to 2 response levers, and a pellet dispenser or an i.v. drug infusion pump. In 4 groups (HiS M, HiS F, LoS M, LoS F) responses under a fixed-ratio (FR) 1 schedule on one lever resulted in one 45 mg pellet immediately, and responses on the other lever resulted in 3 or 6 pellets after a delay. Four additional groups received either a small cocaine (0.2, 0.4, or 0.8 mg/kg) infusion immediately or a delayed larger infusion (3x the amount of the small infusions). The delay to the larger reinforcer began at 6 s and increased or decreased by 1 s following responses on the delay or immediate levers, respectively. A mean adjusted delay (MAD) was calculated over 30 choice trials during each daily 3-hour session, and it was used as a quantitative measure of impulsivity. In groups maintained by food, HiS rats were more impulsive (lower MADs) than LoS rats, and LoS females were more impulsive than LoS males. There were no phenotype or sex differences in delay discounting for cocaine. Understanding the relationship between impulsivity and other predictors of drug abuse (e.g., sex, saccharin intake) is important in developing prevention and treatment strategies.     

The effect of d-amphetamine on performance on two operant timing schedules

RATIONALE: Previous experiments have shown that d-amphetamine disrupts timing behaviour in rats. It has been proposed that d-amphetamine's effects reflect a reduction in the period of the pacemaker of the hypothetical internal clock. However, some studies have obtained conflicting results. OBJECTIVE: To examine the effects of d-amphetamine (0.2, 0.4, 0.8 mg kg(-1) i.p.) on performance on two quantitative timing schedules: a free-operant schedule, in which rats were trained to distribute their responses differentially between two levers during the course of a 50-s trial (free-operant psychophysical procedure), and a discrete-trials schedule, in which rats were trained to discriminate the duration of light stimuli (interval bisection task). METHODS: In experiment 1, rats were trained under the free-operant psychophysical procedure to respond on two levers (A and B) in 50-s trials in which reinforcement was provided intermittently for responding on A during the first half and on B during the second half of the trial. For one group, repetitive switching between levers was permitted; for another group, it was prevented. In experiment 2, rats were exposed to press lever A after a 2-s stimulus and lever B after an 8-s stimulus, and were then tested with stimuli of intermediate duration. For one group, a 'poke response' (depression of a central tray flap) was required after stimulus presentation to effect lever presentation; for the other group, this requirement did not operate. In both experiments, quantitative indices of timing were derived from the psychophysical functions (%B responding vs time). RESULTS: In experiment 1, d-amphetamine increased the Weber fraction and displaced the psychophysical curve to the left in both versions of the schedule, as well as producing rate-dependent suppression of responding. In experiment 2, d-amphetamine increased the Weber fraction in both versions of the task without displacing the curve. CONCLUSIONS: These results confirm the disruptive effect of d-amphetamine on timing. The results of experiment 1 are consistent with the proposal that the drug reduces the period of the hypothetical pacemaker. However, the results of experiment 2 do not support this suggestion. Taken together, the results support the notion that different neural mechanisms may be involved in timing tasks involving temporal distribution of responding and discrimination of the duration of exteroceptive stimuli.     

The relationship between the locomotor response to a novel environment and behavioral disinhibition in rats

Behavioral disinhibition, a component of impulsivity, has been associated with cocaine abuse and dependence. To examine the relationship between behavioral disinhibition and vulnerability to cocaine use disorders, we employed the high responder (HR)/low responder (LR) rodent model, in which rats that exhibit high levels of activity in response to a novel environment are more sensitive to the effects of psychostimulants. In Experiment 1, performance under a differential reinforcement of low-rate (DRL) schedule was used as a measure of behavioral disinhibition in HR and LR rats. The HR rats displayed more behavioral disinhibition relative to LR rats on the DRL 20- and 35-s schedules. In Experiment 2, rats were divided into groups with high disinhibition (HD) and low disinhibition (LD) based on DRL 20-s performance, then challenged with cocaine. Rats characterized as HD and LD had similar DRL 20-s performance to rats characterized as HR and LR (Experiment 1), respectively, but did not differ in their response to cocaine. The results of this study suggest that the HR phenotype may also be characterized by greater behavioral disinhibition, and that the DRL task is a suitable animal model to investigate the role of behavioral disinhibition in vulnerability to the behavioral effects of cocaine.     

Prenatal cocaine effects on fear conditioning: exaggeration of sex-dependent context extinction

Prenatal cocaine exposure results in deficits in sensory preconditioning, discrimination reversal, and spatial navigation, tasks that require input from the hippocampus. However, there are no previous studies concerning prenatal cocaine effects on contextual fear conditioning, another hippocampal-dependent task. The present experiments tested whether chronic subcutaneous administration of 40 mg/kg of cocaine HCl to pregnant rats, from gestational day (GD) 8 through 20 would lead to disruption of contextual fear conditioning in adult male and female offspring. Offspring of saline-injected/pair-fed and untreated dams served as controls. Experiment 1 used a one-trial context conditioning preparation. Rats received a 2-s, 1-mA footshock in either the test context or a novel context, or received no shock on the day prior to the no-shock test. Defecation and freezing were measures of fear. Experiment 2 used a multiple measures protocol to optimize detection of prenatal treatment effects and was preceded by an open-field test. Rats received a 2-s, 0.8-mA footshock or no shock once daily over 4 days of conditioning. During 3 days of extinction, access to an adjacent chamber enabled the observation of four additional measures of fear: side crossing, latency, nose crossing, and side-differential. There were gender-dependent effects of conditioning on freezing and the four added measures of fear. Males showed higher levels of context conditioning and extinguished more slowly than females. The measures of nose crossing and side-differential revealed that prenatal cocaine exposure exaggerated gender-specific effects of context conditioning. The effects of prenatal cocaine exposure on context extinction are sexually dimorphic.     

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats

 Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex. Received: 8 November 1996 / Final version: 30 July 1997     

Outcome specificity in deepened extinction may limit treatment feasibility: Co-presentation of a food cue interferes with extinction of cue-elicited cocaine seeking

Background

We previously showed that presenting two cocaine cues simultaneously during extinction deepens the extinction of cue-elicited cocaine seeking (Kearns et al., 2012). The present study investigated whether compounding a non-drug appetitive cue with a cocaine cue would similarly deepen extinction.

Methods

In Experiment 1, tone and click were each first established as discriminative stimuli for cocaine-reinforced responding and light was a cue for food-reinforced responding. In an initial extinction phase, all stimuli were presented individually. Then, during an additional compound extinction session, rats received 8 presentations of one of the cocaine cues (counterbalanced over subjects) simultaneously with light and 8 presentations of the other cue alone. A spontaneous recovery test was used to evaluate the effectiveness of the extinction treatments. Experiment 2 was performed under conditions designed to match those of Experiment 1, except food was the reinforcer in tone and click instead of cocaine.

Results

In Experiment 1, the cocaine cue compounded with the food cue during extinction controlled greater spontaneous recovery of cocaine seeking than the cocaine cue always presented alone. In contrast, Experiment 2 demonstrated deepened extinction of responding to a food cue when both compounded cues were food cues.

Conclusions

Results suggest that deepened extinction depends on the compound presentation of cues associated with the same reinforcer. Compound presentation of cues associated with different reinforcers could lead to an enhancement of responding. Care is urged in attempts to deepen the extinction of cue-elicited drug seeking by compounding drug cues with non-drug cues.     

Effect of destruction of the 5-hydroxytryptaminergic pathways on temporal memory: quantitative analysis with a delayed interval bisection task

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on memory for duration, using a delayed interval bisection task. Rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats, were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset a response on a panel placed midway between the two levers was required in order to initiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a ‘correct’ response, reinforcer delivery. When > 90% correct choices had been attained, an 8-s (phase I) or a 12-s (phase II) delay was interposed between stimulus offset and lever presentation in 50% of the trials, and probe trials (10% of both non-delay and delay trials) were introduced in which the light was presented for intermediate durations. Logistic functions were derived relating percent choice of lever B to stimulus duration. In both groups, the imposition of post-stimulus delays displaced the bisection point (duration yielding 50% choice of lever B) towards longer durations; this effect was significantly greater in the lesioned group than in the control group. Imposition of post-stimulus delays resulted in increases in the Weber fraction, which did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. Received: 30 April 1996 / Final version: 20 August 1996     

Effect of rate of delivery of intravenous cocaine on self-administration in rats

Many studies of drug self-administration in primates have shown that faster infusions of a drug are more reinforcing than slower infusions. Similar effects have not been shown in rats. We assessed the influence of delivery rate by allowing rats to choose between the same doses of intravenous cocaine delivered over two different infusion speeds. Rats were trained in chambers containing two nose-poke response devices. In Experiment 1, responses in one nose-poke delivered 0.3 mg/kg/injection of cocaine over 10 s, and responses in the other delivered the same dose over 100 s. In Experiment 2, the same procedure was used, but with 1.0 mg/kg/injection dose delivered over 1.7 versus 100 s. During acquisition, most rats preferred the faster infusion. When the delivery rates associated with the nose pokes were reversed, rats trained with 0.3 mg/kg/injection failed to switch nose-poke preference, but half the rats trained with 1.0 mg/kg/injection did switch. In Experiment 3, the choice was between 1 mg/kg cocaine delivered over 1.7 s and no reinforcement. Here, rats quickly learned to respond in the nose-poke associated with cocaine and quickly switched their choice during reversal. In Experiment 4, two groups of rats were allowed to choose between food delivered with a delay of 1 versus 5 s or 1 versus 10 s, respectively. Rats preferred the shorter delay during initial training. In reversal, some rats in the 1 vs 5 s group failed to reverse, while all the rats in the 1 vs 10 s group reversed. These results show that faster infusions of cocaine are clearly more reinforcing during acquisition, but delivery rate may not be as important to the maintenance of self-administration once it has been established. The results with food suggest that these findings represent general principles of behavior and are not unique to drug self-administration.     

Effects of delay, intertrial interval, delay behavior and trimethyltin on spatial delayed response in rats

Working memory was modeled in rats using a delayed response task with spatial location as the discriminative cue. Rats received food for pressing 1 of 2 retractable levers in the choice phase of a trial if that lever had been presented in the prior sample phase of that trial. When delays of 0-20 sec were imposed between sample and choice, choice accuracy declined with increasing delay. With short intertrial intervals (ITIs), choice accuracy decreased more at long delays than at short delays, showing that interference from previous trials impaired memory but not discrimination. Rats emitted overt mediating responses during delay by pressing the levers in the retracted position. However, the frequency of delay presses was low (less than 2/trial in all rats) and neither their frequency nor accuracy was related to choice accuracy. Resetting the delay interval for each delay press did not significantly alter choice response accuracy. Trimethyltin (TMT), 7 mg/kg IV, reduced the choice accuracy of one rat to chance levels at all delays; two other rats were affected transiently. TMT reduced choice accuracy during weeks 1 and 4 postinjection, with significant effects on the linear slope and intercept of the mean retention gradient during week 4. TMT did not affect responses to the retracted levers during delays. TMT treatment also elevated levels of glial fibrillary acidic protein (GFAP) in the CNS, measured 4 weeks after treatment. Hippocampal GFAP correlated highly with the reduction in choice accuracy during week 1 (r = -.903) and week 4 (r = -.797) postTMT.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of pimozide on the establishment of conditioned reinforcement as a function of the amount of conditioning

In an attempt to understand some inconsistent findings, the present experiment investigated the effects of pimozide, a dopamine (DA) receptor blocker, on the establishment of conditioned reinforcement as a function of the amount of conditioning. In Experiment 1, rats received three phases of training in a two-lever box. The pre-exposure phase measured the operant rates of pressing the levers; one produced a 3-s tone and the other turned the lights off for 3 s. In the conditioning phase, with the levers absent, the light-off stimulus was paired with food for two or four sessions. The test phase again measured the rate of pressing the levers. Conditioned reinforcement was shown by a relative increase in responding on the light lever during the test. Of the groups receiving four conditioning sessions, pimozide (0.5, 1.0, 2.0 and 4.0 mg/kg) produced a dose-dependent attenuation of conditioned reinforcement, those rats treated with 4.0 mg/kg failing to demonstrate a significant effect. When 2 conditioning days were employed, pimozide treatment also produced a dose-dependent attenuation; however, in these less conditioned animals 2.0 mg/kg blocked the effect. The possibility that pimozide produced a conditioned taste aversion to the food was ruled out in Experiment 2. These data suggest that DA transmission may be necessary for the establishment of conditioned reinforcement and that the effects of receptor blockade may be related to the amount of conditioning.     

Cocaine self-administration in pigeons.

Pigeons with chronic indwelling intravenous catheters responded under a multiple schedule of food and cocaine presentation. In one component, responding was maintained by food presentation under a fixed-ratio (FR 50) schedule, whereas in the other component, responding was maintained under the same schedule by IV infusions of cocaine (0.03 or 0.1 mg/kg/injection). A 30-s timeout followed each cocaine infusion. Components alternated after 3 presentations of either food or cocaine, and each session was terminated after 18 cocaine infusions or 2 h, whichever occurred first. In general, under baseline conditions, the response rate was higher in the food component than in the drug component. Under control conditions where saline was substituted for cocaine, the response rate gradually decreased across sessions, while food-maintained responding was generally unaffected. Substituting doses lower or higher than the training dose decreased the rate of cocaine-maintained responding. Food-maintained responding only decreased at higher doses of cocaine. When blackout periods were substituted for the food component (Experiment 2), the response rate in the cocaine component decreased and then stabilized at levels well above zero. Saline substitution on this baseline produced a further decrease in the rate of FR responding. In Experiment 3, the effects of pretreatment with haloperidol (0.056 or 0.1 mg/kg) on both food- and cocaine-maintained responding were examined using a multiple schedule similar to that used in Experiment 1. Each dose was given for a period of 7-10 days. In general, haloperidol dose-dependently decreased both the overall rate of cocaine-maintained responding and the percent of available reinforcers obtained, while having little or no effect on food-maintained responding. This research indicates that cocaine can serve as a reinforcing stimulus for maintaining self-administration behavior in pigeons, and that this behavior is sensitive to antagonism by haloperidol.