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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.

The hippocampus is required for many forms of long-term memory in both humans and animals, and formation of long-lasting memories requires the synthesis of new proteins. Furthermore, the long-term potentiation (LTP) of hippocampal synapses, a widely studied model of memory, also depends on both de novo gene transcription and protein synthesis and results in the activation of transcription from promotors containing the cAMP response element (CRE). Expression of several genes is induced during the establishment of LTP; these include the immediate-early genes (IEGs) BDNF (brain-derived neurotrophic factor), zif268 and C/EBPbeta (CCAAT-enhancer binding protein beta), all of which contain CRE sites within their promotor regions. However, these genes induced by LTP are not known to be rapidly induced following learning in a natural setting. Here we demonstrate rapid and selective induction of BDNF expression during hippocampus-dependent contextual learning.

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.

The nucleus accumbens (NAcc) has been implicated in a variety of forms of reward-related learning, reflecting its anatomical connections with limbic cortical structures. After confirming that excitotoxic lesions of the anterior cingulate cortex (Ant Cing) impaired the acquisition of appetitive Pavlovian conditioning in an autoshaping procedure, the effects of excitotoxic lesions to the NAcc core or shell on autoshaping were also assessed. Only selective core lesions impaired Pavlovian approach. A subsequent experiment studied the effects of a disconnection of the Ant Cing and NAcc core, using an asymmetric lesion procedure, to determine whether these structures interact sequentially as part of a limbic corticostriatal system. Such lesioned rats were also significantly impaired relative to controls at autoshaping. These results demonstrate that the NAcc core and Ant Cing are "nodes" of a corticostriatal circuit involved in stimulus-reward learning.

The amygdala is considered to be a core component of the brain's fear system. Data from neuroimaging studies of normal volunteers and brain-damaged patients perceiving emotional facial expressions, and studies of conditioned freezing in rats, all suggest a specific role for the amygdala in aversive motivation. However, the amygdala may also be critical for emotional processing in positive or appetitive settings. Using an appetitive Pavlovian approach procedure we show a theoretically important dissociation in the effects of excitotoxic lesions of the central nucleus and basolateral area of the amygdala, in the rat. Whilst central nucleus lesions impair appetitive Pavlovian conditioning, basolateral lesions do not. Together with other data, these results not only support the hypothesis that the amygdala is critical for appetitive as well as aversive learning, but are also consistent with amygdala subsystems subserving distinct aspects of emotional learning. Lesions of the dorsal or ventral subiculum were without effect on autoshaping, indicating the lack of involvement of hippocampal processing in this form of emotional behaviour and emphasizing further the neural specificity of the effects seen following central amygdala lesions.

Systemic administration of 3-nitropropionic acid (3NPA) in experimental animals produces bilateral striatal lesions similar to those seen in Huntington's disease (HD) caudate and putamen. 3H[-CP55,940 binding to cannabinoid receptors in human basal ganglia nuclei has been shown to be highly susceptible to the earliest pathological changes in the HD brain. In this study, to assess further the suitability of 3NPA-induced striatal lesions as a model for HD neuropathology, we examined the effects of striatal lesions induced by the systemic administration of 3NPA on the binding of 3H[-CP55,940 to pre- and postsynaptic cannabinoid receptors in striatum, globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata and also the effect of 3NPA-induced striatal lesions on the binding of 3H[-DAMGO to mu-opioid receptors in striatal striosomes. Systemic administration of 3NPA induced bilateral and symmetrical lesions in dorsolateral striatum. Within the lesion core, 3H[-CP55,940 and 3H[-DAMGO binding density was reduced to background levels. Beyond the immediate borders of the central core of the 3NPA-induced lesion, striatal binding density was not significantly different from that measured in unlesioned rats. 3H[-CP55,940 binding in globus pallidus, entopeduncular nucleus and substantia nigra in 3NPA-lesioned rats was significantly reduced compared to controls, and the individual decreases were similar for each site. However, these reductions were statistically marginal. These data suggest that, while producing striatal lesions which bear some similarity to those seen in HD, the consequences of 3NPA for striatopallidal and striatonigral efferent projections do not reflect the reported neurodegenerative changes seen in the HD brain.

Pedunculopontine tegmental nucleus (PPTg) lesions block place preferences to drugs or food only when animals are nondeprived. PPTg lesions also disrupt operant responding, but lesioned rats cannot discriminate active from inactive levers. It is not clear, therefore, whether PPTg lesions block reward or disrupt the ability to differentiate changes in reward magnitude. These hypotheses were tested by measuring sucrose consumption, choice, and contrast effects after PPTg lesions. Both sham and lesioned rats consumed greater amounts of a sucrose solution as the concentration and level of deprivation were increased. Given a choice between 2 solutions, all rats consumed more of the higher concentration. Both groups exhibited contrast effects when the concentration was shifted from 32% to 4% within a session. Somewhat surprisingly, lesions increased sucrose intake when rats were food-restricted. These results suggest that PPTg lesions do not disrupt primary motivation or the ability to evaluate and respond to changes in reward strength.

Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving and relapse in abstinent human substance abusers. In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction. Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction. Converging pharmacological, human post-mortem and genetic studies implicate the dopamine D3 receptor in drug addiction. Here we have designed BP 897, the first D3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D3-receptor genes. BP 897 is a partial agonist in vitro and acts in vivo as either an agonist or an antagonist. We show that BP 897 inhibits cocaine-seeking behaviour that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects. Our data indicate that compounds like BP 897 could be used for reducing the drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli.

Only recently have the functional implications of the organization of the ventral striatum, amygdala, and related limbic-cortical structures, and their neuroanatomical interactions begun to be clarified. Processes of activation and reward have long been associated with the NAcc and its dopamine innervation, but the precise relationships between these constructs have remained elusive. We have sought to enrich our understanding of the special role of the ventral striatum in coordinating the contribution of different functional subsystems to confer flexibility, as well as coherence and vigor, to goal-directed behavior, through different forms of associative learning. Such appetitive behavior comprises many subcomponents, some of which we have isolated in these experiments to reveal that, not surprisingly, the mechanisms by which an animal sequences responding to reach a goal are complex. The data reveal how the different components, pavlovian approach (or sign-tracking), conditioned reinforcement (whereby pavlovian stimuli control goal-directed action), and also more general response-invigorating processes (often called "activation," "stress," or "drive") may be integrated within the ventral striatum through convergent interactions of the amygdala, other limbic cortical structures, and the mesolimbic dopamine system to produce coherent behavior. The position is probably not far different when considering aversively motivated behavior. Although it may be necessary to employ simplified, even abstract, paradigms for isolating these mechanisms, their concerted action can readily be appreciated in an adaptive, functional setting, such as the responding by rats for intravenous cocaine under a second-order schedule of reinforcement. Here, the interactions of primary reinforcement, psychomotor activation, pavlovian conditioning, and the control that drug cues exert over the integrated drug-seeking response can be seen to operate both serially and concurrently. The power of our analytic techniques for understanding complex motivated behavior has been evident for some time. However, the crucial point is that we are now able to map these components with increasing certainty onto discrete amygdaloid, and other limbic cortical-ventral striatal subsystems. The neural dissection of these mechanisms also serves an important theoretical purpose in helping to validate the various hypothetical constructs and further developing theory. Major challenges remain, not the least of which is an understanding of the operation of the ventral striatum together with its dopaminergic innervation and its interactions with the basolateral amygdala, hippocampal formation, and prefrontal cortex at a more mechanistic, neuronal level.

Rats were trained to respond with intravenous cocaine as the reinforcer under a fixed interval 15-min schedule, during which conditioned stimuli paired with cocaine were presented contingent on completion of a fixed ratio of 10 responses (i.e., second-order schedule of reinforcement). The effects of contingent and noncontingent cocaine were investigated. The results show that pretreatment with noncontingent (i.e., experimenter-administered) cocaine led to a satiation-like effect that was reflected in decreased numbers of responses and a tendency for an increased latency to initiate responding when the doses of cocaine administered were similar to or higher than the training/maintenance dose of cocaine. By contrast, noncontingent administration of cocaine doses lower than the training/maintenance dose, and response-contingent cocaine administration, led to increased drug-seeking behavior, as reflected in increased numbers of responses. The present data indicate that at least two factors determine whether administration of cocaine would lead to drug-seeking behavior: whether the cocaine administration is contingent or noncontingent, and the relative magnitude of the cocaine dose administered in relation to the training/maintenance dose of cocaine.

Dopamine release within the nucleus accumbens (NAcc) has been associated with both the rewarding and locomotor-stimulant effects of abused drugs. The functions of the NAcc core and shell were investigated in mediating amphetamine-potentiated conditioned reinforcement and locomotion. Rats were initially trained to associate a neutral stimulus (Pavlovian CS) with food reinforcement (US). After excitotoxic lesions that selectively destroyed either the NAcc core or shell, animals underwent additional CS-US training sessions and then were tested for the acquisition of a new instrumental response that produced the CS acting as a conditioned reinforcer (CR). Animals were infused intra-NAcc with D-amphetamine (0, 1, 3, 10, or 20 microg) before each session. Shell lesions affected neither Pavlovian nor instrumental conditioning but completely abolished the potentiative effect of intra-NAcc amphetamine on responding with CR. Core-lesioned animals were impaired during the Pavlovian retraining sessions but showed no deficit in the acquisition of responding with CR. However, the selectivity in stimulant-induced potentiation of the CR lever was reduced, as intra-NAcc amphetamine infusions dose-dependently increased responding on both the CR lever and a nonreinforced (control) lever. Shell lesions produced hypoactivity and attenuated amphetamine-induced activity. In contrast, core lesions resulted in hyperactivity and enhanced the locomotor-stimulating effect of amphetamine. These results indicate a functional dissociation of subregions of the NAcc; the shell is a critical site for stimulant effects underlying the enhancement of responding with CR and locomotion after intra-NAcc injections of amphetamine, whereas the core is implicated in mechanisms underlying the expression of CS-US associations.

Behavioural responses to psychostimulant drugs can be profoundly affected by early environmental influences. The aim of this study was to describe the effects of repeated brief separations of rat pups from their dams during the early neonatal period on cocaine self-administration behaviour as adults. Lister hooded rats exposed to a repeated maternal separation procedure (REMS) showed altered acquisition and maintenance of cocaine self-administration as adults, the effects being dose and gender-dependent. Overall, the patterns of acquisition of self-administration across three doses of cocaine (0.05, 0.08 and 0.5 mg/injection) suggested a rightward shift in the acquisition dose-effect functions for the REMS animals relative to control animals. At 0.05 mg/injection, there was a retarded acquisition of cocaine self-administration in male and female neonatally separated rats. At 0.08 mg/injection there was a facilitated acquisition in female neonatally separated subjects. After establishment of stable self-administration of the training dose, in the same cohort of subjects, rightward and downward shifts in the cocaine self-administration dose-effect functions were determined for female and male REMS subjects, respectively, relative to their controls. The dose-effect function for both female groups was shifted to the left of that of the respective male groups, although the lighter body weights of the females meant that they administered a higher unit dose per unit body weight than the males. Whereas male REMS subjects tended to self-administer less cocaine than the controls at the dose eliciting maximal responding (0.03 mg/injection) and to make fewer lever responses overall at each dose tested, female REMS subjects self-administered significantly more cocaine than their respective controls at a dose of 0.03 mg/injection. There was no differential sensitivity to the rate-altering effects of the selective dopamine D2 receptor antagonist, eticlopride, or to the selective dopamine D1 receptor antagonist, SCH 23390. These data provide further evidence that altered early environment affects drug-taking behaviour in a developmentally specific and gender-specific manner, with the effects of neonatal separation contrasting with previously published data on the effects of post-weaning isolation rearing.

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.

The present experiments investigated the effects of excitotoxic, axon-sparing lesions of the mediodorsal nucleus of the thalamus (MD) on locomotor activity and i.v. cocaine self-administration. Infusion of quinolinic acid into the MD using a glass micropipette produced well-defined neuronal loss restricted to medial and lateral portions of the MD, sparing adjacent areas such as the lateral habenula and paraventricular thalamic nucleus. MD lesions resulted in delayed habituation to activity cages. In addition, lesioned rats self-administered significantly smaller amounts of cocaine than controls during a 14-day acquisition period, and showed attenuated responding for cocaine doses on the descending limb of the dose-effect function. Since typical titrating patterns of responding were maintained in lesioned rats, and responding on the inactive lever did not differ from sham-operated animals, these present results indicate an enhanced sensitivity to the reinforcing effects of response-contingent cocaine in rats with excitotoxic lesions of the MD.

Systemic administration of 3-nitropropionic acid (3NPA) in rats produces bilateral striatal lesions which are similar to those seen in Huntington's disease (HD). We examined the effects of systemic 3NPA on the expression of cytochrome oxidase (COX-II and COX-IV), succinate dehydrogenase (SDH) and astrocytic glial fibrillary acidic protein (GFAP) mRNAs and on the activity of COX and SDH as assessed by the density of histochemical staining. COX-II and COX-IV mRNA was reduced in rats with 3NPA-induced lesions, but not in those without, whereas SDH, but not COX, staining was significantly and dose-dependently reduced in both 3NPA treated groups. GFAP mRNA expression was increased in both intact striatum and cortex but was absent from the lesion core.

The monoaminergic and cholinergic systems are implicated in different forms of behavioral arousal that can be dissected in terms of their forebrain targets and the nature of the behavioral processes they modulate in distinct regions. Thus, evidence in rats with selective neurochemical manipulations tested behaviorally using an analog of an attentional task developed for human subjects indicates that the coeruleo-cortical noradrenergic system is implicated in divided and selective attention, the basal forebrain cholinergic system in stimulus detection, the mesostriatal and mesolimbic dopaminergic systems in response speed and vigor, and the mesencephalic serotoninergic or 5-HT systems in response inhibition. Our recent studies have focused on fractionating, in the same task, the differential contributions of the dorsal and median raphé 5-HT systems as well as elucidating the functions of the mesocortical dopaminergic system, each of which may be relevant to understanding the behavioral and cognitive sequelae of cocaine administration in human subjects as well as in experimental animals.

This study examined the effects of lesions to different neuronal populations within the basal forebrain on reward-related learning. Rats received bilateral alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or quinolinate lesions that preferentially destroy the cholinergic nucleus basalis magnocellularis (NBM) or noncholinergic ventral pallidal neurons, respectively. Both lesions enhanced conditioned approach responses to stimuli predictive of food but did not increase the locomotor stimulating effect of d-amphetamine. Although both lesions disrupted the discriminative control over behavior by a conditioned stimulus, they did not impair the subsequent acquisition of instrumental responding with conditioned reinforcement (CR). Indeed, both lesions were associated with an increased responding with CR following intra-accumbens infusions of d-amphetamine (0, 1, 3, 10, and 20 microg). Quinolinate lesions also increased responses on an inactive control lever. Neither lesion altered consummatory responses to food or sucrose. Results suggest that NBM lesions may disrupt the balance between cortical and subcortical dopamine levels, and/or produce a deficit in attentional mechanisms that is manifested as increased responding to specific stimuli.

The nucleus basalis magnocellularis (NBM) is one element in the limbic cortical-ventral striatal circuitry that has been implicated in reinforcement processes. The present study examined the involvement of the cholinergic neurons of the NBM in mediating aspects of cocaine reinforcement. Lesions of the NBM were made by injecting 0.01 M AMPA into the subpallidal basal forebrain. Following 4 days' recovery, rats were implanted chronically with catheters in the jugular vein. In three separate experiments, rats were trained to acquire cocaine self-administration under a FR1 schedule of reinforcement at doses of 0.25, 0.083 and 0.028 mg/injection. A dose-effect function was also determined at the end of the acquisition experiments using five different doses of cocaine (0.009, 0.028, 0.083, 0.25, 0.50 mg/injection) and saline which were presented once daily in a Latin square design. There were no significant differences between groups in the acquisition of cocaine self-administration at any of the three doses studied (0.028, 0.083 and 0.25 mg/injection), although at the lowest dose, lesioned animals responded at greater levels on both active and inactive levers. However, a shift to the left in the cocaine dose-response function was observed revealing that the lesioned group self-administered significantly higher amounts of low doses of cocaine than control rats. These data suggest that the integrity of the NBM is not a critical determinant of the reinforcing effects of cocaine during the acquisition of self-administration of the drug, but that NBM-dependent cholinergic mechanisms may nevertheless interact with the neural substrates mediating the reinforcing properties of cocaine. The data are relevant to recent hypotheses of functional interactions between the dopaminergic system and the cholinergic NBM.

Using radioactive in situ hybridization, we have mapped the expression of Huntingtin-associated protein (HAP1) mRNA in rat brain at developmental stages (E12-E19, PO-P21), in adult rats (3 months) and in 'aged' (19-21 months) rats. Using two pairs of 45mer oligonucleotide probes specific for HAP1A and a probe which recognizes regions of both the HAP1A and HAP1B mRNA sequences (panHAP1), we find that the expression of HAP1 mRNA is specific to the CNS and restricted predominantly to anatomically connected limbic structures, particularly the amygdala (medial and corticomedial nuclei), the hypothalamus (arcuate, preoptic, paraventricular and lateral hypothalamic area), bed nucleus of the stria terminalis (BNST) and the lateral septal nuclei. HAP1 mRNA was detected in embryos at E12 and displayed a prevalent distribution in the developing limbic structures by E15. In aged, 19-21-months-old, rats there is a downregulation of HAP1 mRNA expression across all CNS loci where HAP1 was previously abundant. The lowest levels of HAP1 mRNA expression corresponded with the areas of greatest pathological cell loss in Huntington's disease (HD); the caudate putamen, globus pallidus and neocortex. These observations support the suggestion that HAP1 plays an important role in the neuropathology of HD.

Dual perfusion in vivo brain microdialysis was used to monitor extracellular levels of dopamine in the medial prefrontal cortex and ventral striatum during the acquisition and extinction of a classical aversive conditioning paradigm in rats. The main finding was a dissociation in the pattern of release in the two brain areas. The first stimulus-footshock pairing elicited large increases in cortical dopamine over baseline levels that were much greater than the increases elicited by different stimuli of equivalent salience that were unpaired with footshock. In contrast, dopamine levels in ventral striatum were unchanged under these conditions. Over the next two pairings, there was a decline in the cortical response and an increase in the response in ventral striatum. The first presentation of the aversive conditioned stimulus in a separate context elicited the largest response in ventral striatum. Post-conditioning, the cortical response to the conditioned stimulus was smaller than that elicited by the initial stimulus-footshock pairing and was equivalent in magnitude to that elicited by stimuli unpaired with footshock. Over the final two conditioned stimuli presentations, in the absence of the footshock reinforcer (extinction), responses declined in both brain areas. Simultaneous monitoring of behaviour indicated that the neurochemical events were accompanied by effective aversive learning, as indexed by conditioned freezing responses. The data are discussed in terms of the hypothesis that medial prefrontal cortex is especially engaged during novel circumstances which may, potentially, require new learning, whilst ventral striatal dopamine more closely follows the expression of conditioned responding during learning and extinction.

N-methyl-D-aspartate (NMDA) and non-NMDA receptor-mediated manipulations of the cortical cholinergic input arising from the basal forebrain differentially affect cognitive function. We used [14C]-2-deoxyglucose autoradiography in conscious rats to map the effects of excitatory amino acid agonist infusions into the nucleus basalis magnocellularis (NBM) on cerebral functional activity, as reflected by local rates of glucose utilization. Acute stimulation of NBM neurones by local infusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 15 min before glucose use measurement, resulted in glucose use reductions in nine cortical regions innervated by NBM efferents including prefrontal, frontal, sensorimotor and cingulate cortices. NMDA infusions altered glucose use in two cortical areas. Both AMPA and NMDA markedly increased glucose use in the striatum and globus pallidus, with concomitant perturbations in striato-pallidal projection targets including the substantia nigra, entopeduncular nucleus, subthalamic nucleus and lateral habenular nucleus. In contrast, the GABAA agonist muscimol did not affect glucose use in the NBM or neocortical regions, but induced glucose use increases in several subcortical nuclei including the substantia nigra and entopeduncular nucleus. The delayed effects of excitotoxic lesions were assessed 3 weeks after basal forebrain infusions of AMPA, NMDA, ibotenate or quisqualate. Statistically significant glucose use changes only occurred in the hypothalamus after NMDA, and the NBM after ibotenate infusions, although reduced cortical metabolism was apparent following AMPA-induced lesions of the NBM. Results support a dissociation between the functional sequelae of NMDA and non-NMDA receptor-mediated events in the basal forebrain, and long-term compensatory functional adaptation following cortical denervation.

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.

Four experiments examined effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on tests of visual discrimination learning, using a new "touchscreen" testing method for rats. Anterior cingulate cortex lesions impaired acquisition of an 8-pair concurrent discrimination task, whereas posterior cingulate cortex lesions facilitated learning but selectively impaired the late stages of acquisition of a visuospatial conditional discrimination. Medial frontal cortex lesions selectively impaired reversal learning when stimuli were difficult to discriminate; lesions of anterior and posterior cingulate cortex had no effect. These results suggest roles for the anterior cingulate, posterior cingulate, and medial frontal cortex in stimulus-reward learning, stimulus-response learning or response generation, and attention during learning, respectively.

The effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on stimulus-reward learning were investigated with a novel Pavlovian autoshaping procedure in an apparatus allowing the automated presentation of computer-graphic stimuli to rats (T. J. Bussey, J. L. Muir, & T. W. Robbins, 1994). White vertical rectangles were presented on the left or the right of a computer screen. One of these conditioned stimuli (the CS+) was always followed by the presentation of a sucrose pellet; the other, the CS-, was never followed by reward. With training, rats came to approach the CS+ more often than the CS-. Anterior cingulate cortex-lesioned rats failed to demonstrate normal discriminated approach, making significantly more approaches to the CS- than did sham-operated controls. Medial frontal cortex-lesioned rats acquired the task normally but had longer overall approach latencies. Posterior cingulate cortex lesions did not affect acquisition.

A series of ten experiments examined the effects of profound central 5-HT depletion on attentional performance in the rat in the five-choice serial reaction time task, and also determined the effects of such depletion on responding affected by d-amphetamine and by selective dopamine receptor antagonists. Rats were trained to detect and locate brief visual stimuli randomly presented in one of five spatial locations. When performance had stabilised (> 80% correct, < 20% omissions), selective central 5-HT depletion was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. The lesioned animals performed the five-choice serial reaction time task with the same degree of accuracy as the sham-operated controls. However, 5-HT depletion reduced the percentage of omitted trials and increased the number of premature/anticipatory responses. This pattern of behaviour following 5-HT depletion could not be attributed to enhanced primary motivation as demonstrated by measures of food intake and latencies to collect food reinforcement. The lesion attenuated the increase of premature responding induced by high doses of systemically administered d-amphetamine. 5-HT depletion also attenuated the dose-dependent decrease in accuracy induced by (-)-sulpiride, a D2 receptor antagonist, although the effects of this drug on response latencies and premature responding were similar in both groups. However, the systemic administration of the D1 receptor antagonist, SCH 23390, blocked the impulsive responding produced by the lesion as indicated by a lack of lesion effects on the percentage of omitted trials and premature responding. The results suggest that central 5-HT depletion results in impulsive, fast responding, which nevertheless does not impair accuracy of visual discrimination performance. The increased impulsivity may be mediated by altered 5-HT-dopamine interactions, with the lesion removing an inhibitory influence over dopamine neurotransmission.

The amygdala has long been thought to be involved in emotional behaviour, and its role in anxiety and conditioned fear has been highlighted. Individual amygdaloid nuclei have been shown to project to various cortical and subcortical regions implicated in affective processing. Here we show that some of these nuclei have separate roles in distinct mechanisms underlying conditioned fear responses. Rats with lesions of the central nucleus exhibited reduction in the suppression of behaviour elicited by a conditioned fear stimulus, but were simultaneously able to direct their actions to avoid further presentations of this aversive stimulus. In contrast, animals with lesions of the basolateral amygdala were unable to avoid the conditioned aversive stimulus by their choice behaviour, but exhibited normal conditioned suppression to this stimulus. This double dissociation demonstrates that distinct neural systems involving separate amygdaloid nuclei mediate different types of conditioned fear behaviour. We suggest that theories of amygdala function should take into account the roles of discrete amygdala subsystems in controlling different components of integrated emotional responses.

The three dopamine agonists with highest reported D3 receptor selectivity in vitro, pramipexole, quinelorane and PD128,907, decreased self-administration of a high dose of cocaine in rats as a result of a leftward shift in the cocaine dose-effect function. In contrast the D3 preferring antagonist nafadotride increased cocaine self-administration. Moreover the relative potencies of these and other D2-like dopamine agonists (lisuride, 7-OH-DPAT, quinpirole, apomorphine, bromocriptine) to modulate cocaine self-administration were highly correlated with their relative potencies for increasing mitogenesis in vitro in cell lines expressing D3 but not D2 receptors. These results support the hypothesis that the D3 receptor may be an important target for pharmacotherapies for cocaine abuse and dependence.

The current status of the cholinergic hypothesis of cognitive dysfunction in Alzheimer's disease is reviewed in the context of recent attempts to alleviate specific cognitive impairments produced in rats by excitotoxic lesions of basal forebrain neurons by treatment with cholinergic agents. AMPA-induced lesions of the nucleus basalis region in rats produce profound and relatively specific reductions in neocortical markers of cholinergic function but fail to affect performance in many tests of memory and learning in rats. However, such lesions produce specific deficits in responding accurately in a test of visual attentional performance, which are reversed dose-dependently by treatment with systemic physostigmine or nicotine. Analogous improvements have been reported in a clinical trial of the anticholinesterase tacrine in patients with Alzheimer's disease. By contrast, AMPA-induced lesions of the medial septum produce profound reductions in hippocampal acetylcholine and accompanying delay-dependent deficits in a delayed non-matching-to-position procedure which measures spatial working memory in rats. This impairment is shown to be reversed to some extent by treatment with low doses of physostigmine. The results are discussed in terms of the multivariate nature of the neurochemical pathology of Alzheimer's disease and attendant limitations in the use of the cholinergic strategy. The cognitive costs, as well as benefits, of cognitive enhancers are discussed, as well as the need to broaden our therapeutic approach to other neurotransmitter systems and other neurodegenerative disorders.

The organization and possible functions of basal forebrain and pontine cholinergic systems are reviewed. Whereas the basal forebrain cholinergic neuronal projections likely subserve a common electrophysiological function, e.g. to boost signal-to-noise ratios in cortical target areas, this function has different effects on psychological processes dependent upon the neural network operations within these various cortical domains. Evidence is presented that (a) the nucleus basalis-neocortical cholinergic system contributes greatly to visual attentional function, but not to mnemonic processes per se; (b) the septohippocampal projection is involved in the modulation of short-term spatial (working) memory processes, perhaps by prolonging the neural representation of external stimuli within the hippocampus; and (c) the diagonal band-cingulate cortex cholinergic projection impacts on the ability to utilize response rules through conditional discrimination. We also suggest that nucleus basalis-amygdala cholinergic projections have a role in the retention of affective conditioning while brainstem cholinergic projections to the thalamus and midbrain dopamine neurons affect basic arousal processes (e.g. sleep-wake cycle) and behavioral activation, respectively. The possibilities and limitations of therapeutic interventions with procholinergic drugs in patients with Alzheimer's disease and other neurodegenerative disorders in which basal forebrain cholinergic neurons degenerate are also discussed.

The present study examined the effects of lesions of the central nucleus of the amygdala (CeA) on the acquisition of a new response with conditioned reinforcement (CR) and its potentiation by intra-accumbens infusions of d-amphetamine (1, 3, 10, and 20 microg/microl). Rats were trained to associate a light-plus-noise compound stimulus with the availability of a sucrose solution before receiving both bilateral ibotenic acid lesions of the CeA and cannulas implanted above the nucleus accumbens. Lesions of the central nucleus did not impair the performance of positively reinforced discriminated approach, nor did they impair the acquisition of a new response with conditioned reinforcement. However, the potentiation of responding with CR following intra-accumbens amphetamine was blocked in lesioned animals. These results are discussed in terms of the possible interactions between associative mechanisms in the amygdala and the mesolimbic dopamine projection.

In these experiments we sought to establish the intravenous (i.v.) 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 i.v. 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 i.v. 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 mechanisms 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.

The experiments examined the release of 5-hydroxytryptamine using in vivo microdialysis methods in the hippocampus of freely moving rats following Pavlovian aversive conditioning to discrete and contextual stimuli. Differential conditioning was achieved by manipulating the interval between the offset of a discrete auditory 'clicker' stimulus and the onset of a mild foot-shock reinforcer (0.5 mA, 0.5 s). Foot-shock occurred either simultaneously with the last second of the discrete auditory stimulus (in short-trace subjects) or 60 s later (long-trace subjects). In this way, subjects were preferentially conditioned to the discrete stimulus and background 'contextual' stimuli respectively. During conditioning subjects also received two identical unpaired visual stimuli. At test, dialysates were collected and behavioural measures taken as all animals experienced (i) the aversive and two other 'neutral' environments, and (ii) the discrete unconditioned and conditioned stimuli presented in both aversive and neutral environments. Exposure to the aversive environment, but not to either of the two neutral environments, was associated with significantly increased hippocampal 5-hydroxytryptamine release in long-trace subjects. There was also a small but non-significant increase in 5-hydroxytryptamine release in short-trace animals. In contrast, hippocampal 5-hydroxytryptamine release was unaffected by presentation of either of the discrete stimuli under all conditions. The last result was obtained despite robust behavioural responses (freezing) to the discrete conditioned stimulus. These data do not agree with the hypothesis that aversive cues generally activate 5-hydroxytryptamine function in the hippocampus. Rather, they suggest a degree of specificity whereby 5-hydroxytryptamine release in the hippocampus was determined primarily by other qualitative properties of the conditioned aversive stimulus, namely whether the aversive cue was discrete or contextual, as well as by the magnitude of conditioning.

The analysis of the behavioural and neural mechanisms of reinforcement and motivation has benefited from the recent application of learning theory and better anatomical knowledge of the connectivity of certain key neural structures, such as the nucleus accumbens. This progress has enabled the dissection of motivational processes into components that can begin to be related to the functioning of specific limbic cortical structures that project to different compartments of the ventral striatum.

The effects of bilateral excitotoxic lesions of 3 major sources of afferents to the ventral striatum (nucleus accumbens) were compared on an open field test of food neophobia allowing the choice between familiar and novel food. Whereas lesions of the basolateral amygdala and ventral subiculum had qualitatively similar effects to reduce food neophobia (although not affecting the latency to eat), amygdala lesions increased and the ventral subiculum decreased locomotor activity. In contrast, damage to the ventromedial prelimbic prefrontal cortex only affected initial food choice and latency measures. By comparison, excitotoxic lesions of the nucleus accumbens itself and intra-accumbens infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 increased activity and attenuated food neophobia. Results are discussed in terms of the role of limbic and prefrontal neuronal networks converging in the nucleus accumbens to control different aspects of the behavioral response to novelty.

The experiments examined the effects of depleting forebrain 5-hydroxytryptamine (5HT) on Pavlovian aversive conditioning to discrete and contextual stimuli. Rats were lesioned with intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine and then conditioned in a distinctive environment (termed the context) to a 30 s auditory stimulus. In 50% of animals the interval between the offset of the discrete auditory stimulus and the reinforcer, a mild foot-shock (0.5 mA, 0.5 s), was 5 s (the short-trace group) and in the other 50%, 30 s (the long-trace group). Theory predicts that animals in the short-trace condition will learn more about the discrete stimulus as a predictor of shock and become strongly conditioned, while those in the long-trace condition learn relatively more about the context. The extent of conditioning to the discrete and contextual stimuli was assessed separately, in extinction, using lick-suppression and place-preference measures respectively. Under these conditions sham subjects exhibited the expected dissociation with respect to trace interval. However, lesioned animals exhibited a specific impairment in contextual conditioning. The results are discussed in terms of the behavioural, neurochemical and neuroanatomical specificity of 5HT function in aversive conditioning and the implications for general theories of the role of 5HT in aversive processes.

The most extensive development during primate brain evolution involves the cortex of the frontal lobe, especially its prefrontal region. The distribution of neurotransmitter receptors is unknown in this part of the cortex of New World monkeys. The respective distributions of eight different receptors for the transmitters L-glutamate (L-glu and NMDA), gamma-amino-butyric acid (GABAA), noradrenaline (alpha 1), acetylcholine (M1 and M2) and serotonin (5-HT1 and 5-HT2) were therefore studied in cortical areas of the frontal lobe of the lissencephalic New World monkey, Callithrix jacchus. The results are compared to earlier data on Old World monkeys in order to obtain insight into evolutionary trends at the level of chemical neuroanatomy. Our results indicate that the density and laminar pattern of some receptors change precisely at the cytoarchitectonic boundaries between different cortical areas, while some other receptors do not exhibit measurable changes. For example, the premotor area 6 can be distinguished from prefrontal areas by its high concentration of adrenergic alpha 1 receptors as labelled with [3H] prazosin, with only the cingulate area 24 showing higher values. In other cases, the receptor distribution changes within a cytoarchitectonically homogeneous area. Thus, area 8 can be subdivided into dorsal and ventral regions on the basis of the distribution of GABAA, muscarinic and serotonin receptors. Comparison of these results in a New World monkey with receptor distributions in other primate species reveals much larger interspecies differences in the areas of the frontal lobe than e.g. in the primary visual cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

These experiments investigated in the rat the impact on spatial delayed non-matching to sample and on acquisition of the Morris water maze of (i) AMPA-induced lesions of the medial septal nucleus, which produced a marked reduction of hippocampal choline acetyltransferase activity and acetylcholine levels (measured using in vivo dialysis) together with lesser reductions in cholinergic markers in the cingulate cortex and (ii) similar AMPA-induced lesions of the vertical limb nucleus of the diagonal band of Broca (vDB), which produced more marked reductions in cholinergic markers in the cingulate cortex than in the hippocampus. Medial septal lesions produced a delay-dependent deficit in spatial working memory, while lesions of the vDB resulted in a delay-independent performance deficit. In addition, rats with vDB lesions adopted biased response strategies during the imposition of long delays. Neither lesion significantly affected the acquisition of a spatial reference memory task, the Morris water maze. The results are discussed in terms of cholinergic- and GABAergic-dependent functions of the hippocampal formation and cingulate cortex in spatial short-term and reference memory.

The regional distribution of neurons containing alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor (GluR1-4) subunit immunoreactivity, relative to the distribution of cholinergic neurons within the basal forebrain of rats, was assessed using single- and dual-antigen immunocytochemistry. Analysis of serial sections stained with antibodies to nerve growth factor receptor (NGFr) and antibodies against each of the AMPA receptor subunits, GluR1-4, revealed a regional codistribution between NGFr- and GluR1- and GluR4-immunoreactive neurons in the medial septum, diagonal band nuclei and nucleus basalis magnocellularis. Quantitative dual-labelling immunocytochemistry using NGFr in combination with each of the GluR antibodies revealed > 65% colocalization between NGFr and GluR4 in each of the major cholinergic nuclei in the basal forebrain and 10-15% colocalization between NGFr, GluR1 and GluR2-3. The reticular nucleus of the thalamus, a structure known to be highly susceptible to AMPA-induced neurotoxicity, expressed GluR4 immunoreactivity exclusively. The observation that cholinergic neurons of the basal forebrain are also highly sensitive to AMPA and express the GluR4 subunit suggests that GluR4 may be important in AMPA receptor-mediated excitotoxicity.

The direct and transynaptic effects of lesions of the basal forebrain induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and ibotenic acid were investigated using quantitative in situ hybridization histochemistry. Probes complementary to the sequences of choline acetyltransferase mRNA, glutamate decarboxylase mRNA and preproenkephalin mRNA were used to assess direct lesion effects within the basal forebrain and probes for postsynaptic M-1 and M-3 muscarinic receptors were used to assess long-term changes in neocortical muscarinic receptor mRNA expression following cholinergic deafferentation. AMPA-induced basal forebrain lesions destroyed significantly more neurons that expressed choline acetyltransferase mRNA than ibotenic acid-induced lesions (90 versus 60%), but significantly fewer neurons which expressed either glutamate decarboxylase or preproenkephalin mRNA (61 versus 83% reduction in glutamate decarboxylase mRNA and 56 versus 79% reduction in preproenkephalin mRNA). AMPA-induced lesions did, however, destroy a significant proportion of the neurons which expressed glutamate decarboxylase and preproenkephalin mRNA (approximately 60%). The neurons spared following AMPA-induced lesions were typically situated dorsolaterally within the dorsal pallidum, although neurons expressing glutamate decarboxylase or preproenkephalin mRNA were frequently observed within the areas of greatest cholinergic neuronal loss, i.e. the region of the nucleus basalis magnocellularis. These findings suggest that there is a population of non-cholinergic pallidal neurons which are insensitive to AMPA but not to ibotenic acid, reflecting a possibly heterogeneous distribution of NMDA and non-NMDA subtypes of glutamate receptors within the rat basal forebrain. AMPA-induced lesions of the basal forebrain were, however, without significant effect on the levels of expression of M-1 and M-3 muscarinic receptor mRNAs in the cerebral neocortex.

The regional and laminar distributions of eight different transmitter-binding sites were measured in the marmoset hippocampus by means of quantitative in vitro receptor autoradiography. Receptors for 5-HT1, L-glutamate, N-methyl-D-aspartate (NMDA) and GABAA were similarly distributed. The highest concentrations of these receptors were found in the pyramidal layer of CA1 and the molecular layer of the dentate gyrus. The 5-HT2 receptors showed the highest concentrations in the oriens layer of CA2. The highest concentrations of muscarinic M1 receptors were seen in the pyramidal layer of CA1. Muscarinic M2 receptors were most densely concentrated in the pyramidal layers of CA1, CA2 and CA3. The noradrenergic alpha 1 receptors were most densely packed in the radiatum-lacunosum-molecular layer of CA2 and the molecular layer of the dentate gyrus. Statistically significant co-distributions of serotoninergic, glutamatergic and GABAergic receptors point to possible interactions between these receptor systems in the same hippocampal regions and layers. Comparisons of marmoset distribution patterns for GABAA, NMDA, L-glutamate and 5-HT1 receptors with those in human hippocampi and those of other primates showed similarities between them. Clear differences in the patterns of alpha 1, M1, M2 and 5-HT2 receptors could be seen between marmoset and human hippocampi, indicating a high degree of species specificity in a presumably "conservative" brain region. More similarities, however, could be found between marmoset and human hippocampi than between those of rat and human brains, especially in relation to 5-HT1 and GABAA receptors and L-glutamate-binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate further the cholinergic specificity of the effects of basal forebrain lesion-induced disruption of attentional performance, the present study examined the efficacy of various pharmacological agents in improving performance of a five-choice serial reaction time task in rats that had received lesions of the cholinergic basal forebrain. Specifically, the effects of the novel 5-HT3 receptor antagonist, ondansetron (0.3, 1, 10 ng/kg), and of nicotine (0.03, 0.06, 0.1, 0.3 mg/kg) and the anticholinesterase, physostigmine (0.05, 0.1 mg/kg), on attentional function were examined in animals which had received AMPA-induced lesions of the nucleus basalis magnocellularis (nbM). The behavioural impairments observed immediately following the lesion were a reduction were choice accuracy and an increase in correct response latency. Although these impairments showed recovery over the course of the following weeks, the deficit in choice accuracy could be reinstated by reducing the duration of the visual stimulus and thus increasing the attentional load placed on the animals. This reduction in choice accuracy could be dose dependently improved by systemic administration of either physostigmine or nicotine, suggesting that this impairment in attentional function may be attributed to disruption of cholinergic function. The pharmacological specificity of these improvements was supported by the inability of d-amphetamine to improve task performance (0.2, 0.4, 0.8 mg/kg). Ondansetron was also unable to improve accuracy of performance in lesioned animals, but was effective in reducing the anticipatory or premature responding observed in both control and lesioned animals, even when elevated (in the case of controls) by treatment with systemic d-amphetamine. The results of the present study therefore suggest that cholinergic dysfunction can lead to attentional impairments which can be ameliorated by cholinergic treatments such as physostigmine and nicotine, but that ondansetron, despite its proposed ability to release cortical acetylcholine, was unable to restore choice accuracy at the doses employed. The results further suggest a double dissociation of effects on accuracy and the disinhibition of responding.

The environmental context of an animal both subsumes and is associated with the explicit cues that guide its behavioural responses. Recent work in this laboratory suggests that learning about the relationship between the cues which comprise a context depends on the hippocampus. In the present study the role of the cholinergic input to the hippocampus in contextual learning was assessed in rats using a conditioned stimulus/context conditioning paradigm and spatial learning in the Morris water maze. In the former, a place preference apparatus provided the context. The subject was confined in the black chamber and a 'clicker' conditioned stimulus was presented five times in a 20 min period. A trace interval of 5 or 30 s, depending on the group, was interposed between the end of the clicker and a footshock. Theory predicts that animals in the 5 s condition will learn more about the clicker as a predictor of shock and become strongly conditioned, while those in the 30 s condition learn relatively more about the context. Conditioning to the clicker (conditioned stimulus) was measured in a separate lick suppression chamber--presentation of the clicker suppresses drinking, and contextual learning was determined by recording the time spent on the black side of the place preference apparatus when both the black and a familiar white chamber were accessible. Lesions of the medial septum/diagonal band induced by RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) enhanced contextual learning in this paradigm but disrupted conditioned stimulus conditioning in the 30 s condition. Acquisition of the Morris water maze was largely unimpaired. The results are suggested to reflect a shift towards the use of hippocampal-dependent contextual learning strategies in lesioned animals.

The outcome of intra-accumbens infusions of the dopamine D1 receptor family agonist SKF-38393 and the D2 receptor family agonist LY-171555 upon measures taken during the behavioural satiety sequence was assessed (0.01 micrograms, 0.1 micrograms, 1.0 micrograms in each case). Each drug was infused either separately, or together as a co-infusion in order to examine the functional relationship between these dopamine receptor subtypes within the nucleus accumbens. Measures of feeding did not change following infusions of SKF-38393 or LY-171555, whether infused separately or together. However, following separate infusion of the lowest dose tested of each drug (0.01 micrograms), the onset of resting was advanced. Moderate to high doses of SKF-38393 and LY-171555 (0.1 micrograms, 1.0 micrograms) infused separately resulted in a marked increase in activity at the expense of resting. Co-infusion of 0.01 micrograms of each drug also resulted in a dramatic increase in activity. Thus, measures of feeding behaviour were unchanged following excitation of D1 and D2 dopamine receptor families within the nucleus accumbens. In marked contrast, locomotor behaviour appeared to be under the potent synergistic control of these receptor families.

Previous evidence suggests that glutamatergic limbic afferents participate in the potentiation of responding with conditioned reinforcement produced by intra-accumbens d-amphetamine. The present experiments were designed to investigate glutamate-dopamine interactions in the ventral striatum in both conditioned reinforcement and locomotor activity. Glutamate receptor agonists and antagonists were infused into the nucleus accumbens both alone and in combination with 3 micrograms d-amphetamine, and the effects of these interactions on responding with conditioned reinforcement and locomotor activity were measured. The glutamate receptor agonists NMDA, AMPA and quisqualate (agonists at the NMDA, AMPA and metabotropic glutamate receptor subtypes, respectively) and the antagonists AP5 and CNQX, (antagonists at the NMDA and AMPA receptor subtypes, respectively) were used in these investigations. These compounds were used in a dose range of 0.3 to 3 nmol, except CNQX, which was used in 0.2 to 2 nmol doses. While all agonists and antagonists increased locomotor activity when administered alone, the antagonists attenuated the locomotor response to d-amphetamine. In contrast, the agonists AMPA and quisqualate enhanced d-amphetamine-induced locomotor activity, although NMDA interfered with the effects of d-amphetamine. In the conditioned reinforcement paradigm, both the agonists and the antagonists abolished amphetamine's potentiation of responding with conditioned reinforcement, suggesting that the glutamatergic transmission of information about the conditioned reinforcer could be blocked by glutamate receptor antagonists and disrupted by administration of the agonists. The dissociation between the effects of these excitatory amino acids on amphetamine-induced locomotor activity versus their effects on amphetamine's potentiation of responding with conditioned reinforcement provides insight into the nature of the reward enhancement by accumbens dopamine versus its locomotor stimulant effects.

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, experiments began. Experiment 1 examined the effect of isolation rearing upon the locomotor response to a novel environment, and the locomotor stimulant effect of an injection of cocaine (10 mg/kg). Isolation reared animals were more active in a novel environment, and were more responsive to the locomotor stimulant action of cocaine. In succeeding experiments, the effects of isolation rearing on the reinforcing efficacy of intravenous cocaine were assessed. Animals were never "primed" with noncontingent infusions of cocaine at any time during these experiments. In experiment 2, the effect of isolation rearing upon the acquisition of the intravenous self-administration of cocaine was examined. Two levers were present in the operant chambers. Depression of one lever resulted in the intravenous delivery of a 1.5 mg/kg infusion of cocaine, responses on the second, control lever were recorded but had no programmed consequences. Isolation reared animals acquired a selective response on the drug lever at a slower rate than socially reared controls. In experiment 3, a full cocaine dose-response function was examined. Isolation rearing shifted the cocaine dose-response function to the right. In addition, isolation rearing impaired the selectivity of the response on the drug lever at lower doses of cocaine. In experiment 4, the effect of isolation rearing upon the response to a conditioned reinforcer associated previously with cocaine delivery was observed. In the absence of cocaine, the contingent presentation of the conditioned reinforcer enhanced selectively the rate of response by socially reared controls. However, isolation reared animals were unresponsive to this manipulation. These data are discussed with reference to dysfunctional cortico-limbic-striatal systems, and their interactions with the mesoaccumbens dopamine projection.

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration of d-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2: d-amphetamine, 0.25 micrograms/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not "primed" with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration of d-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a full d-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses of d-amphetamine. In experiment 2c, the infusate (1 microgram d-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbic-striatal systems, with particular reference to the mesoaccumbens dopamine projection.