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Biomedical subjects

B J Everitt

Publications and source records attributed to B J Everitt.

At least 37 records · Page 2Linked to original sources
PubMed2001

Functional disconnection of a prefrontal cortical-dorsal striatal system disrupts choice reaction time performance: implications for attentional function.

This series of experiments investigated the role of a prefrontal cortical-dorsal striatal circuit in attention, using a continuous performance task of sustained and spatially divided visual attention. A unilateral excitotoxic lesion of the medial prefrontal cortex and a contralateral lesion of the medial caudate-putamen were used to "disconnect" the circuit. Control groups of rats with unilateral lesions of either structure were tested in the same task. Behavioral controls included testing the effects of the disconnection lesion on Pavlovian discriminated approach behavior. The disconnection lesion produced a significant reduction in the accuracy of performance in the attentional task but did not impair Pavlovian approach behavior or affect locomotor or motivational variables, providing evidence for the involvement of this medial prefrontal corticostriatal system in aspects of visual attentional function.

Animals↗
PubMed2001

Behavioral effects of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: locomotion, cocaine self-administration, and prepulse inhibition of startle.

Compelling evidence suggests a primary role for the mesoaccumbens dopaminergic pathway in the behavioral effects of amphetamine and cocaine, but the roles of other projections to the accumbens, including those arising in the hippocampal formation, are less clear. The authors evaluated the effects of discrete excitotoxic lesions of either the dorsal or ventral subiculum on the locomotor activating, reinforcing, and sensorimotor gating-disruptive effects of psychomotor stimulant drugs. Whereas dorsal subiculum-lesioned rats were hyperactive in tests of exploratory locomotion and startle reactivity, ventral subiculum-lesioned rats exhibited an attenuated locomotor response to amphetamine, moderately impaired acquisition of cocaine self-administration, and reduced levels of prepulse inhibition of startle. These 2 behavioral profiles overlap considerably with those previously observed in rats with lesions of the rostrodorsal and caudomedial accumbens, respectively, and suggest that projections from dorsal subiculum to accumbens core and ventral subiculum to accumbens shell exert distinct influences on behavioral responses that are amplified by psychomotor stimulant drugs.

Amphetamine↗
PubMed2001

The role of withdrawal in heroin addiction: enhances reward or promotes avoidance?

The compulsive nature of heroin abuse has been attributed to the fact that drug self-administration enables an addict to escape from and avoid the severe withdrawal symptoms resulting from opiate dependence. However, studies of incentive learning under natural motivational states suggest an alternative hypothesis, that withdrawal from heroin functions as a motivational state that enhances the incentive value of the drug, thereby enabling it to function as a much more effective reward for self-administration. In support of this hypothesis, we show here that previous experience with heroin in withdrawal is necessary for subsequent heroin-seeking behavior to be enhanced when dependent rats once again experience withdrawal.

Animals↗
PubMed2001

Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala.

Fear memory retrieval has been shown to induce a protein-synthesis dependent re-consolidation of memories within the amygdala. Here, using immunocytochemistry, we investigated the molecular basis of this process in the rat and show that retrieval of a cued fear memory induces the activation, by phosphorylation, of the transcription factor CREB within the basal and lateral nuclei of the amygdala, as well as expression of the CREB-regulated immediate-early gene, c-fos, in the basal amygdala. We also show an increase in CREB phosphorylation within the central nucleus of the amygdala following behavioural testing, with an accompanying increase in Fos-immunoreactive nuclei in animals retrieving the cued association. There were no changes in either phosphorylated CREB or Fos in the hippocampus following exposure to discrete fear stimuli. These results show that activation of CREB, which has been shown to be involved in the formation of long-term fear memories, also accompanies memory retrieval, and also suggest a role for CREB phosphorylation in memory re-consolidation following retrieval.

Amygdala↗
PubMed2001

Involvement of the central nucleus of the amygdala and nucleus accumbens core in mediating Pavlovian influences on instrumental behaviour.

Pavlovian conditioned cues exert a powerful influence on instrumental actions directed towards a common reward, this is known as Pavlovian-to-instrumental transfer (PIT). The nucleus accumbens (NAcc) has been hypothesized to function as an interface between limbic cortical structures required for associative conditioning, like the amygdala, and response mechanisms through which instrumental behaviour can be selected and performed. Here we have used selective excitotoxic lesions to investigate the involvement of subnuclei of the amygdala as well as the core and shell regions of the nucleus accumbens on PIT in rats. Within the amygdala, selective lesions of the central nucleus (CeN), but not of the basolateral nucleus (BLA), abolished the PIT effect. In addition, selective lesions of the NAcc core, but not the NAcc shell, also abolished PIT. None of the lesions impaired the acquisition of Pavlovian food cup approaches or instrumental responding itself. These data demonstrate that the CeN and NAcc core are central components of the neural system mediating the impact of Pavlovian cues on instrumental responding. We suggest that this effect may depend upon the regulation of the dopaminergic innervation of the NAcc core by projections from the CeN to the ventral tegmental area.

Amygdala↗
PubMed2001

Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set.

Evidence from both human and animal studies indicates that catecholamine (dopamine and noradrenaline) imbalances in the fronto-striatal circuitry are associated with deficits in higher- order cognitive functions. The present study examined how catecholamines within this circuitry modulate attentional function, specifically the ability to develop, maintain, and shift an attentional set. Catecholamine depletions within the frontal cortex of the common marmoset impaired the ability to acquire an attentional set, and increased susceptibility to distraction from task-irrelevant stimuli. Analysis of set-shifting performance with stimulus dimensions of varying salience suggested that frontal catecholamine depletion selectively disrupts "top-down", but not "bottom-up" attentional processing. In contrast, the ability to acquire and shift an attentional set remained intact following dopaminergic depletion from the caudate nucleus. However, the reduced susceptibility to distraction from task-irrelevant stimuli displayed by monkeys with dopaminergic depletions of the caudate nucleus suggests that responding was under more rigid control by the currently rewarded stimulus. The results demonstrate opposite behavioural effects of 6-hydroxydopamine (6-OHDA) lesions in the frontal cortex and caudate nucleus in tasks requiring selective attention. Frontal catecholamine depletion caused an increase in distractibility while caudate dopamine loss induced greater focusing of responding.

Adrenergic Agents↗
PubMed2001

Cocaine seeking by rats is a goal-directed action.

In two experiments rats were trained to self-administer intravenous cocaine on chained schedules using different responses in the initial (drug-seeking) and terminal (drug-taking) links. In both between- (Experiment 1) and within-subject designs (Experiment 2), the drug-taking response was then either extinguished or reinforced in the absence of the opportunity to perform the seeking response. In a subsequent extinction test with the seeking manipulanda alone, the rate of drug seeking was reduced after the prior extinction of the associated taking response. An additional group trained with a sucrose reinforcer showed a comparable devaluation effect. These findings demonstrate that seeking responses for cocaine and food rewards are mediated by a representation of the contingency between seeking responses and the opportunity to take the reward.

Animals↗
PubMed2000

Cocaine self-administration in rats differentially alters mRNA levels of the monoamine transporters and striatal neuropeptides.

The potential neuroadaptations to cocaine self-administration (SA) were evaluated using quantitative in situ hybridisation histochemistry. Levels of mRNAs of the monoamine transporters, i.e. the primary molecular targets of cocaine, and the striatal neuropeptides substance P and enkephalin, which predominantly exist in different populations of dopaminoceptive striatal neurons, were quantified in rats which had reached different stages of acquisition of cocaine SA. Thus, animals were killed 1 h after completing a self-administration session (i) early in or after acquisition of cocaine SA (ii) after various regimes of chronic cocaine SA, and (iii) a 10-day period of withdrawal from chronic cocaine intake. Control mRNA levels of all molecules under study were those quantified in animals receiving i.v. saline yoked to rats self-administering cocaine (1.5 or 0.75 mg/kg per infusion, depending on the experiment). Monoamine transporter expression was differentially altered by cocaine; dopamine transporter mRNA levels in the ventral tegmental area, but not in the substantia nigra, were increased following withdrawal from cocaine, suggesting a role for the upregulated mesolimbic dopamine transporter in the mechanisms underlying relapse to cocaine taking. By contrast, serotonin transporter mRNA in the dorsal raphé and noradrenaline transporter mRNA in the locus coeruleus remained unaltered under all experimental conditions. In addition, the expression of the striatal neuropeptides was also differentially altered; substance P mRNA levels were transiently increased in the shell of the nucleus accumbens by prolonged cocaine self-administration, but enkephalin mRNA levels in the dorsal and ventral striatum remained unaltered under all conditions.

Animals↗
PubMed2000

Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats.

The dopaminergic innervation of the nucleus accumbens is generally agreed to mediate the primary reinforcing and locomotor effects of psychostimulants, but there is less consensus on conditioned dopamine (DA) release during drug-seeking behavior. We investigated the neurochemical correlates of drug-seeking behavior under the control of a drug-associated cue [a light conditioned stimulus (CS+)] and to noncontingent presentations of the CS+ in the core and shell subregions of the nucleus accumbens. Rats self-administered cocaine under a continuous reinforcement schedule in which a response on one of two identical levers led to an intravenous cocaine infusion (0.25 mg/infusion) and a 20 sec light CS+. Response requirements for cocaine and the CS+ were then progressively increased until stable responding was established under a second-order schedule of reinforcement. During microdialysis, rats were presented noncontingently with a set of 10 sec CS+ and neutral tone stimuli (CS-) before and after a 90 min period during which they responded for cocaine under a second-order schedule. Results showed the following: (1) nucleus accumbens DA increased in both the core and shell during intravenous cocaine self-administration; (2) noncontingent presentations of a cocaine-associated CS+ led to increased DA release selectively in the nucleus accumbens core; and (3) extracellular DA levels were unaltered in both core and shell during a protracted period of drug-seeking behavior under the control of the same cocaine-associated cue. These results indicate that the mesolimbic dopamine system is activated after exposure to drug-associated stimuli under specific conditions.

Acoustic Stimulation↗
PubMed2000

Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex.

The role in spatial divided and sustained attention of D1 and D2-like dopamine (DA) receptors in the rat prelimbic medial prefrontal cortex (mPFC) was investigated in a five-choice serial reaction time task. Rats were trained to detect brief flashes of light (0.5-0.25 sec) presented randomly in a spatial array of five apertures. When performance stabilized, animals received bilateral microinfusions of either the D1 DA receptor antagonist SCH 23390, the D1 DA receptor agonist SKF 38393, or the D2 DA antagonist sulpiride into the mPFC. Rats were divided into two groups, with low (<75% correct) and high (>75%) baseline levels of accuracy. Infusions of the D2 receptor antagonist sulpiride had no significant effect on any task variable. SCH 23390 (0.3 microg) selectively impaired the accuracy of attentional performance in rats in the high baseline condition. By contrast, SKF 38393 (0.06 microg) enhanced the accuracy of attentional performance in the low baseline condition, a lower dose (0.03 microg) also increasing the speed of making correct responses. Finally, the beneficial effects of SKF-383893 on choice accuracy were antagonized by SCH 23390 (1.0 microg). The results provide apparently the first demonstration of enhanced cognitive function after local administration of a D1 receptor agonist to the mPFC and suggest dissociable roles of D1 and D2 DA receptors of the mPFC in modulating attentional function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Heroin self-administration under a second-order schedule of reinforcement: acquisition and maintenance of heroin-seeking behaviour in rats.

RATIONALE: Second-order schedules of heroin self-administration provide a method of measuring heroin-seeking behaviour independently of the effects of the drug on motor behaviour and of investigating the role of heroin-associated stimuli in such heroin-seeking behaviour. OBJECTIVES: These experiments aimed to establish a second-order schedule of heroin self-administration in rats, similar to that already established in this laboratory for cocaine self-administration and to investigate the role of discrete heroin-associated stimuli in the maintenance of heroin-seeking behaviour under a second-order schedule of reinforcement. METHODS: Heroin i.v. self-administration (0.04 mg/infusion) was initially contingent upon a lever press, and each infusion was paired with presentation of a 20-s light-conditioned stimulus (CS). Following acquisition of heroin self-administration, the response requirement was progressively increased so that, ultimately, responding was maintained under a fixed interval (FI) 15 min [fixed ratio (FR)5:S] second-order schedule. The effects of varying the dose of heroin (0.01 mg and 0.08 mg/infusion) and pre-treatment with the mu-opiate receptor antagonist, naloxone, on responding under a FI15(FR5:S) schedule were investigated. In addition, the role of the heroin-associated CS on responding was assessed by measuring the effects of omitting the CS during heroin-seeking behaviour and during extinction of responding, as well as the effect of CS presentation on the reinstatement of heroin-seeking behaviour following extinction. RESULTS: A second-order schedule of heroin self-administration was established. There were no clear effects on heroin-seeking behaviour of increasing or decreasing the dose of heroin. Although no effect of naloxone pre-treatment was seen on heroin-seeking behaviour during the first, drug-free interval of responding, an extinction-like pattern of responding was seen in that interval during subsequent sessions. Omission of the light CS resulted in a reduction in levels of responding for i.v. heroin, indicating its role in maintaining heroin-seeking behaviour. However, under extinction conditions, response-contingent CS presentations did not affect the rate of extinction, nor did non-contingent presentations of the CS following extinction reinstate heroin-seeking behaviour. CONCLUSIONS: These experiments have established a method of measuring heroin-seeking behaviour in rats by adopting a second-order schedule of i.v. heroin self-administration. The results indicate a relatively weak impact of discrete, heroin-associated cues on heroin-seeking behaviour relative to cocaine-seeking behaviour studied under similar conditions.

Animals↗
PubMed2000

Leftward shift in the acquisition of cocaine self-administration in isolation-reared rats: relationship to extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and amygdala-striatal FOS expression.

RATIONALE: Dopamine dysfunction in the nucleus accumbens is thought to underlie the altered propensity of isolation-reared rats to self-administer psychomotor stimulants. OBJECTIVE: To identify specific changes in monoamine and glutamate function in the nucleus accumbens and c-fos induction in the amygdala and striatum which may be correlated with altered cocaine self-administration in isolates. METHODS: In three separate studies, group-reared and isolation-reared rats were trained to self-administer cocaine (0.083. 0.25 or 1.5 mg/kg per IV infusion; FR1), intracerebral microdialysis was used to measure cocaine-induced changes in extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and the expression of the immediate-early gene c-fos was quantified using quantitative immunocytochemistry of its protein product Fos in several amygdala and striatal brain regions following cocaine administration. RESULTS: Isolation-reared rats showed an enhanced sensitivity to self-administer the lowest dose of cocaine but showed retarded acquisition at the highest dose. Isolation rearing produced no effect on basal levels of dopamine, serotonin or glutamate in the nucleus accumbens but potentiated the increase in dopamine efflux, though not serotonin efflux, induced by cocaine. Cocaine increased FOS expression in most amygdala and striatal brain regions examined that were relatively greater in isolation-reared rats in core and shell regions of the nucleus accumbens, medial and lateral regions of the dorsal striatum as well as the central nucleus of the amygdala. CONCLUSION: These data are consistent with the hypothesis that isolation rearing produces enduring changes in the sensitivity of dopamine-mediated functions in amygdala-striatal circuitry that may be directly related to the altered reinforcing properties of cocaine and other psychomotor stimulants.

Amygdala↗
PubMed2000

Cocaine-seeking by rats: regulation, reinforcement and activation.

RATIONALE: In animal models of drug self-administration, response rates often decrease with dose suggesting that a regulative process may mask the reinforcing effects of the drug. OBJECTIVE: The purpose of the present experiments was to dissociate the role of regulative and reinforcement processes in intravenous cocaine self-administration by rats using a paradigm that explicitly distinguishes between drug-seeking and drug-taking. METHODS: Rats were trained to respond for intravenous cocaine (0.25 mg/infusion) under a heterogeneous chain (tandem FR1 RI 30 s) FR1 schedule of reinforcement using different levers in the first (seeking) and second (taking) links of the chain. After 10 days of training, rats were switched to one of three doses of cocaine (0.08, 0.25, or 0.5 mg/infusion) and self-administration patterns were recorded for a further ten sessions in experiment 1. In experiment 2, a time-out (TO) period (0, 4, or 12 min) was imposed between successive cycles of the chain schedule. Finally, the effect of allowing animals to perform a drug-taking response on subsequent drug-seeking was assessed in experiment 3. RESULTS: Having verified that seeking responses for a conventional reinforcer (sucrose) were sensitive to changes in reward magnitude, experiment 1 demonstrated that the number of self-administered infusions was inversely related to dose whereas the latency to initiate drug-seeking increased with dose. Variations in the cocaine dose had no reliable effect on the number of drug seeking response per cycle of the chain schedule. The effect of dose on the latency to initiate drug-seeking was reversed in experiment 2 with increasing TO periods. Moreover, at the longest TO period, drug-seeking responses per cycle increased and the latency to initiate drug seeking decreased with dose. Experiment 3 showed that the latency to drug-seek for the low dose was reduced dramatically when the first drug-seeking response was preceded by a drug-taking response, even when this response did not produce a drug infusion. CONCLUSIONS: The overall pattern of results suggests that drug-seeking and drug-taking are controlled by three interacting processes: a regulative process depresses drug-seeking in the short-term; behavioral activation enhances drug-seeking and is sustained over longer intervals by higher drug doses; the reinforcing effect of cocaine increases with dose once the satiety producing effects of the drug dissipate.

Animals↗
PubMed2000

The effects of excitotoxic lesions of the basolateral amygdala on the acquisition of heroin-seeking behaviour in rats.

RATIONALE: Second-order schedules of drug-self-administration provide a method of examining drug-seeking behaviour, which is maintained in part by the presentation of a discrete, drug-associated light CS. Previous results have found that lesions of the basolateral amygdala (BLA) impair the acquisition of i.v. cocaine self-administration under this type of schedule. OBJECTIVES: The present experiments examined the effects of excitotoxic lesions of the BLA on the acquisition of i.v. heroin self-administration under both continuous reinforcement and second-order schedules, in order to investigate possible commonalties in the neural basis of heroin- and cocaine-seeking behaviour. METHODS: Rats received quinolinic acid or sham vehicle lesions of the BLA prior to i.v. self-administration training. Initially, heroin self-administration under a continuous reinforcement schedule was acquired. Each active lever-press resulted in a 0.04 mg i.v. heroin infusion, paired with presentation of a 20-s light conditioned stimulus. Following acquisition of responding under this schedule, the response requirement was gradually increased to a second-order schedule of FI15(FR5:S). RESULTS: There was no effect of lesions of the BLA on the acquisition of heroin self-administration under a continuous reinforcement schedule. The acquisition of heroin-seeking behaviour under a second-order schedule of self-administration was not affected by lesions of the BLA, but lesioned rats showed a significantly higher baseline level of responding. CONCLUSIONS: These results indicate that the rewarding effects of heroin do not depend on the integrity of the BLA. The BLA is also not critically involved in mediating heroin-seeking behaviour under a second-order schedule of reinforcement, and this stands in marked contrast to the effects of BLA lesions on the acquisition of cocaine-seeking behaviour. These findings suggest that discrete heroin cues were not critical in maintaining heroin-seeking behaviour under the second-order schedule used here and that other learning systems are engaged in the control of this behaviour.

Amygdala↗
PubMed2000

The effects of d-amphetamine, chlordiazepoxide, alpha-flupenthixol and behavioural manipulations on choice of signalled and unsignalled delayed reinforcement in rats.

RATIONALE: Inability to tolerate delays to reward is an important component of impulsive behaviour, and has been suggested to reflect dysfunction of dopamine systems. OBJECTIVES: The present experiments examined the effects of signalling a delayed, large reward on rats' ability to choose it over a small, immediate reward, and on the response to amphetamine, a dopamine receptor antagonist, and a benzodiazepine. METHODS: Three groups of Lister hooded rats were tested on a two-lever discrete-trial delayed reinforcement task in which they chose one pellet delivered immediately or four pellets delivered after a delay. This delay increased from 0 to 60 s during each session. Trials began with illumination of a houselight: in the Houselight group, this remained on during the delay and feeding period. In the No Cue group, the houselight was extinguished at the moment of choice. In the Cue group, a stimulus light was illuminated during the delay. Once trained, the rats were challenged with d-amphetamine (0.3, 1.0, 1.6 mg/kg), chlordiazepoxide (1.0, 3.2, 5.6, 10 mg/kg), alpha-flupenthixol (0.125, 0.25, 0.5 mg/kg), and various behavioural manipulations. RESULTS: Subjects' choice became and remained sensitive to the delay; the cue speeded learning. Amphetamine decreased choice of the large reinforcer in the No Cue group and increased it in the Cue group. alpha-Flupenthixol and chlordiazepoxide generally decreased preference for the delayed reinforcer; flupenthixol reduced the cue's effects, but chlordiazepoxide did not interact with the cue condition. CONCLUSIONS: Signals present during a delay can enhance the ability of amphetamine to promote choice of delayed rewards.

Animals↗
PubMed2000

Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour.

RATIONALE AND OBJECTIVES: To review the literature on the use of second-order schedules of drug reinforcement in the context of experimental investigations of the neural and pharmacological mechanisms underlying addictive behaviour in general and drug-seeking behaviour in particular. METHODS: Second-order schedules of drug reinforcement are described in which responding is maintained not only by the self-administered drug, but also by contingent presentation of drug-paired stimuli that serve as conditioned reinforcers of instrumental behaviour. RESULTS: The behaviour of rats and monkeys responding under second-order schedules is discussed in relation to self-administered drug dose and the importance of drug-associated cues in maintaining responding for cocaine, morphine or heroin. Drug-seeking behaviour during the period before drug is self-administered is described and compared with drug-seeking behaviour derived from other procedures. In addition, results are summarised that demonstrate the differential involvement of the amygdala and prefrontal cortex in the acquisition of cue-controlled cocaine- and heroin-seeking behaviour, as well as the effects of drugs interacting with D3 dopamine, NMDA and AMPA receptors on drug-seeking behaviour and dopaminergic correlates of drug-paired stimuli presented non-contingently and during responding for cocaine under a second-order schedule. CONCLUSIONS: We argue that the first, drug-free interval (or other period) of responding under a second-order schedule of reinforcement has particular utility in that it provides a measure of drug-seeking behaviour and reinforcing efficacy that are not affected by the pharmacological effects of recently administered drug. It also provides a means of investigating the role of drug-paired stimuli in drug-seeking behaviour, including its behavioural, neural and neurochemical basis.

Animals↗
PubMed2000

Age-dependence of malonate-induced striatal toxicity.

Malonate is an inhibitor of cellular metabolism, which, following intrastriatal injection, induces a striatal pathology similar to that seen in Huntington's disease. In two parallel studies, we have investigated the suggested relationship between the neuronal vulnerability to metabolic toxicity and the decline in metabolic function with increasing age. The first experiment investigated malonate-induced neuronal loss in animals aged from 6 weeks up to 27 months, and the second assessed the activities of two mitochondrial enzymes, succinate dehydrogenase and cytochrome oxidase (CYTOX) in animals aged 6 weeks, 3, 8 and 18 months. In the first study, male Lister-Hooded rats received intrastriatal stereotaxic injections of malonate (0.5 or 1.0 M). Animals were killed 10 days after surgery, and the brains were stained with cresyl violet and processed for NADPH-diaphorase activity and glial fibrillary-acidic-protein (GFAP) immunohistochemistry. Animals aged 6 months and older exhibited over 60% striatal neuronal loss. However, the degree of neuronal loss did not show any age-related increase in rats between 6 and 27 months of age, indicating that the extent of malonate-induced toxicity does not increase with age in animals older than 6 months. Infusion of 0.5 M malonate produced smaller lesions, which also demonstrated a consistent extent of neuronal loss from 6 months onwards. Metabolic enzyme activities were decreased in the striatum with increasing age, although this effect was only significant for CYTOX activity. Thus, the pattern of malonate-induced neuronal loss in aged animals partially reflects the changes in metabolic activity during ageing.

Aging↗