Schizophrenia copy number variants and associative learning.

Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder.

Transgenic expression of the FTDP-17 tauV337M mutation in brain dissociates components of executive function in mice.

Frontotemporal lobe dementia (FTD) is a heterogeneous range of disorders, a subset of which arise from fully penetrant, autosomal dominant point mutations in the gene coding for the microtubule associated protein tau. These genetic tauopathies are associated with complex behavioural/cognitive disturbances, including compromised executive function. In the present study, we modelled the effects of the FTD with Parkinsonism linked to chromosome 17 (FTDP-17) tauV337M mutation (known as the Seattle Family A mutation) expressed in mice on executive processes using a novel murine analogue of the Stroop task. Employing biconditional discrimination procedures, Experiment 1 showed that normal mice, but not mice with excitotoxic lesions of the medial prefrontal cortex, were able to use context cues to resolve response conflict generated by incongruent stimulus compounds. In contrast to predictions, response conflict resolution was not disrupted by the tauV337M mutation (Experiment 2). However, while context appropriate actions were goal-directed in wild-type mice, performance of tauV337M mice was not goal-directed (Experiment 3). The results indicate that the tauV337M mutation in mice disrupts, selectively, a subset of processes related to executive function.

Effects of anesthetic agents on socially transmitted olfactory memories in mice.

Mice can learn a food preference from odor cues transmitted on the breath of a conspecific, even if the "demonstrator" is anesthetized. To our knowledge there are no studies examining the effect of anesthetizing the "observer" on development of memory for socially transmitted food preferences (STFP). In Experiment 1 we found that 2-4 month-old F2 C57Bl/6x129sv male and female mice demonstrated a STFP after a 5min exposure to an anesthetized demonstrator mouse when tested 24h later. In Experiment 2, observer mice anesthetized with Sagatal (60 mg/kg) prior to the "social interaction" preferentially avoided the cued food when tested 24h later. This aversion was not due to any overt aversive effects of this dose of Sagatal because mice that ate the food and were then anesthetized, or could only smell the food for 5 min while anesthetized, showed no preference or aversion. In a third experiment we found that the Sagatal-induced aversion was not a general property of anesthesia because there were varied results produced by observer mice treated with anesthetic drugs with different mechanisms of action. Vetalar (200mg/kg) and Rompun (10 mg/kg) treated animals ate similar amounts of cued and non-cued food at test, indicating an absence of learning. Hypnorm (0.5 ml/kg) treated animals showed a preference for the cued food whereas those treated with Hypnovel (2.5 ml/kg) showed an aversion to the cued food. These results show that the food aversion observed with Sagatal is not a general property of anesthetic agents, but appears to be restricted to those acting primarily on the GABAergic system. Thus, we have shown that under certain conditions it is possible for an anesthetized observer mouse to learn a preference or aversion of a socially-linked olfactory cue.

Preparing healthcare facilities to operate safely and effectively during the COVID-19 pandemic: The missing piece in the puzzle.

The stated objective of the COVID-19 lockdown was to allow time to prepare healthcare facilities. Preparation must include administrative and environmental measures, which when combined with personal protective equipment, minimise the risk of the spread of infection to patients and healthcare workers (HCWs) in facilities, allowing HCWs to safely provide essential services during the pandemic and limit the indirect effects of COVID-19 caused by healthcare disruption. We present our model for facility preparation based on colour-coded zones, social distancing, hand hygiene, rapid triage and separate management of symptomatic patients, and attention to infection transmission prevention between HCWs in communal staff areas. This model specifically addresses the challenges in preparing a facility for COVID-19 in a low-resource setting and in rural areas. In addition, we include links to resources to allow workers in low-resource settings to prepare their facilities adequately.

Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: potential mouse model for parkinsonism.

We have created a transgenic mouse with a hypomorphic allele of the vesicular monoamine transporter 2 (Vmat2) gene by gene targeting. These mice (KA1) have profound changes in monoamine metabolism and function and survive into adulthood. Specifically, these animals express very low levels of VMAT2, an endogenous protein which sequesters monoamines intracellularly into vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of the monoamine neurotransmitters below potentially toxic thresholds. Homozygous mice show large reductions in brain tissue monoamines, motor impairments, enhanced sensitivity to dopamine agonism, and changes in the chemical neuroanatomy of the striatum that are consistent with alterations in the balance of the striatonigral (direct) and striatopallidal (indirect) pathways. The VMAT2-deficient KA1 mice are also more vulnerable to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in terms of nigral dopamine cell death. We suggest that the mice may be of value in examining, long term, the insidious damaging consequences of abnormal intracellular handling of monoamines. On the basis of our current findings, the mice are likely to prove of immediate interest to aspects of the symptomatology of parkinsonism. They may also, however, be of use in probing other aspects of monoaminergic function and dysfunction in the brain, the latter making important contributions to the pathogenesis of schizophrenia and addiction.

Impulsive choices in mice lacking imprinted Nesp55.

Genomic imprinting is the process whereby germline epigenetic events lead to parent-of-origin specific monallelic expression of a number of key mammalian genes. The imprinted gene Nesp is expressed from the maternal allele only and encodes for Nesp55 protein. In the brain, Nesp55 is found predominately in discrete areas of the hypothalamus and midbrain. Previously, we have shown that loss of Nesp55 gives rise to alterations in novelty-related behaviour. Here, we extend these findings and demonstrate, using the Nespm/+ mouse model, that loss of Nesp55 leads to impulsive choices as measured by a delayed-reinforcement task, whereby Nespm/+ mice were less willing to wait for a delayed, larger reward, preferring instead to choose an immediate, smaller reward. These effects were highly specific as performance in another component of impulsive behaviour, the ability to stop a response once started as assayed in the stop-signal reaction time task, was equivalent to controls. We also showed changes in the serotonin system, a key neurotransmitter pathway mediating impulsive behaviour. First, we demonstrated that Nesp55 is co-localized with serotonin and then went on to show that in midbrain regions there were reductions in mRNA expression of the serotonin-specific genes Tph2 and Slc6a4, but not the dopamine-specific gene Th in Nespm/+ mice; suggesting an altered serotonergic system could contribute, in part, to the changes in impulsive behaviour. These data provide a novel mode of action for genomic imprinting in the brain and may have implications for pathological conditions characterized by maladaptive response control.

Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia.

Schizophrenic patients exhibit deficits in the prepulse inhibition of startle, an operational measure of the sensorimotor gating deficits that are theorized to contribute to cognitive disorganization. In rats, the activation of mesolimbic dopamine (DA) disrupts prepulse inhibition, providing a useful model of the similar deficits in sensorimotor gating in schizophrenic patients. Rats reared in isolation exhibit neurochemical and behavioral abnormalities suggestive of hyperactivity in mesolimbic DA systems. In the present studies, rats reared in social groups or in isolation were tested in startle response paradigms using 120 or 105 dB acoustic pulses, some of which were preceded (100 msec) by prepulses that were 2, 4, 8, or 16 dB above the 65 dB background. Isolation-reared animals were hyperreactive only in response to the initial few startle stimuli. The amount of prepulse inhibition was decreased significantly in isolation-reared animals, particularly when midrange 8 dB prepulses were used. A subsequent study replicated the effect of isolation rearing on prepulse inhibition and suggested that the deficit in sensorimotor gating exhibited by isolation-reared animals may be normalized by the administration of the DA antagonist raclopride (0.05 mg/kg). Hence, isolation rearing provides a nonpharmacological way to induce in rats a deficit in sensorimotor gating that is exhibited by schizophrenic patients.

Social isolation in the rat produces developmentally specific deficits in prepulse inhibition of the acoustic startle response without disrupting latent inhibition.

A series of experiments examined the effects of 8 weeks of social isolation on spontaneous locomotor activity, prepulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI) in a conditioned suppression paradigm, and basal and d-amphetamine stimulated dopamine (DA) release in the ventral striatum, as measured by in vivo microdialysis. Both isolation-reared animals (those isolated from the weaning age) and isolation-housed animals (those isolated as adults) were hyperactive when placed in a novel environment. Social isolation also led to deficits in PPI of the acoustic startle response that were specific to isolation-reared animals. Isolation rearing was without effect on the expression of LI but did lead to an enhanced response to systemic d-amphetamine in terms of striatal DA release. The data are discussed with respect to the involvement of ventral striatal DA mechanisms in the expression of PPI and LI, differences in the impact of social isolation in young and adult animals, and the utility of social isolation model as a nonlesion, nonpharmacologic means of perturbing ventral striatal DA function.

Marked lymphocytosis suggesting chronic lymphocytic leukemia in three patients with hyposplenism.

Three patients with hyposplenism of diverse cause are described, in whom marked persistent lymphocytosis suggested the diagnosis of an early phase of chronic lymphocytic leukemia. Absolute lymphocyte counts ranged from 4,900/mm3 to 10,500/mm3. Patient follow-up ranged from 120 months to 294 months. The clinical course and additional test results, including results of lymphocyte surface marker analysis in all three patients and bone marrow biopsy in two, excluded the diagnosis of chronic lymphocytic leukemia. The finding of marked lymphocytosis in the hyposplenic state is emphasized, extending the degree of absolute lymphocytosis previously reported and thereby expanding the differential diagnosis of sustained lymphocytosis. In addition, the normal findings on both bone marrow and surface marker studies, along with the prolonged clinical course, support the contention that this is a benign entity.

Acquired immune deficiency syndrome in homosexual men with Hodgkin's disease. Three case reports.

Fatal opportunistic infections developed in three homosexual men with Hodgkin's disease. Widely disseminated Kaposi's sarcoma developed in one, and another had persistent lymphadenopathy with a biopsy specimen showing benign follicular hyperplasia two years before the diagnosis of Hodgkin's disease. Physicians are alerted to the possible association of Hodgkin's disease and the acquired immune deficiency syndrome (AIDS). They are cautioned to consider the diagnosis of Hodgkin's disease in homosexual men with lymphadenopathy and warned of the risk of serious infections in homosexual men receiving therapy for Hodgkin's disease.

Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA- and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: differential dependence on cholinergic neuronal loss.

Excitotoxic lesions of the basal forebrain were made by infusing either alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or ibotenic acid. Acquisition and performance of spatial learning in the Morris water maze, over a ten day, two trials per day, training regimen were unaffected by the AMPA-induced lesions which reduced cortical choline acetyltransferase activity by 70%. However, acquisition was significantly impaired in rats with ibotenic acid-induced lesions that reduced cortical choline acetyltransferase by 50%. Additionally, ibotenic acid-lesioned rats swam further than either sham or AMPA-lesioned rats, in the "training" quadrant during a probe trial, in which the escape platform was removed, suggesting a perseverative search strategy. Lesions induced with AMPA, but not ibotenate, significantly impaired the acquisition of "step-through" passive avoidance. Both AMPA- and ibotenate-induced lesions significantly impaired the 96 h retention of passive avoidance, but the effect of AMPA was greater on latency measures. Histological analysis revealed that AMPA infusions destroyed more choline acetyltransferase-immunoreactive neurons than did ibotenate infusions but, unlike ibotenate, spared the overlying dorsal pallidum and also parvocellular, non-choline acetyltransferase-immunoreactive neurons in the ventral pallidal/substantia innominata region of the basal forebrain. The impairment in acquisition of the water maze following ibotenate-induced basal forebrain lesions therefore appears unrelated to damage to cholinergic neurons of the nucleus basalis of Meynert and to depend instead on damage to pallidal and other neurons in this area. The AMPA- and perhaps also the ibotenate-induced impairment in the retention of passive avoidance appears to be more directly related to destruction of cholinergic neurons of the nucleus basalis. These data are discussed in the context of cortical cholinergic involvement in mnemonic processes.

Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system.

The effectiveness of a recently developed immunotoxin, 192 IgG-saporin, was evaluated for making selective lesions of subgroups of basal forebrain cholinergic neurons. Following a pilot series of injections into the nucleus basalis magnocellularis to establish the effective dose for intraparenchymal lesions, separate groups of rats received injections of the immunotoxin into the septum, into the diagonal band of Broca or into the nucleus basalis magnocellularis. The lesions produced extensive and effective loss of cholinergic neurons in the discrete areas of the basal forebrain, as identified by loss of cells staining for acetylcholinesterase and p75NGFr, with a parallel loss of acetylcholinesterase staining and choline acetyltransferase activity in the target areas associated with each injection site in the dorsolateral neocortex, cingulate cortex and hippocampus. The selectivity of the lesion for cholinergic neurons was supported by the lack of gliosis and sparing of small to medium-sized cells at the site of injection of the toxin, including the glutamate decarboxylase immunoreactive cells that contribute to the septohippocampal projection. In spite of the extensive disturbance in the cholinergic innervation of the neocortex and hippocampus, immunotoxin lesions produced no detectable deficit in the Morris water maze task in any of the lesion sites within the basal forebrain. By contrast small but significant deficits were seen on tests of nocturnal activity (septal and nucleus basalis magnocellularis lesions), open field activity (septal and diagonal band lesions), passive avoidance (nucleus basalis magnocellularis lesions) and delayed non-matching to position (septal lesions). The results indicate that the 192 IgG-saporin provides a powerful tool for making effective lesions of the basal forebrain cholinergic neurons, and that the behavioural sequelae of such lesions warrant further detailed investigation.

Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioural response to D-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function in monkeys.

The effects of excitotoxic lesions of the prefrontal cortex on behavioural, neurochemical and molecular indices of dopamine function in the caudate nucleus were studied in the marmoset. The lesion, which encompassed both the lateral and orbital regions of prefrontal cortex, made the animals more sensitive to the performance disrupting effects of the dopamine releasing drug, D-amphetamine, in a variation of the object retrieval task. Specifically, following drug administration, the lesioned marmosets were less able to gain access to food reward in the minimum number of responses. Analysis of the nature of the errors suggested that the deficit was not due to inhibition of a prepotent response as the lesioned monkeys were just as likely to make a detour reach to the unopened side of the box as a direct "line-of-sight" reach into the unopened front of the box. Rather, the data indicated a general disorganization of behaviour. The enhanced behavioural responsiveness to manipulations increasing presynaptic dopamine function was accompanied by neurochemical changes indicating a reduced responsiveness, as revealed by in vivo microdialysis. Thus, in lesioned animals, whilst there were no effects on baseline levels of extracellular dopamine in dorsolateral caudate, evoked release, both to systemic D-amphetamine and to a local depolarizing pulse of potassium ions, was attenuated. These opposite effects of the prefrontal cortex lesion on behavioural and neurochemical indices of striatal dopamine function occurred in the absence of any changes in striatal dopamine receptors of the D1 and D2 subtype, as determined both by radioligand binding assays and measurements of messenger RNA using in situ hydridization techniques. These data provide further insight into the interactions between prefrontal cortex and striatal dopamine function in the non-human primate. In particular, when taken in the light of our previous studies they indicate that following prefrontal manipulations, concurrence between behavioural and neurochemical indices of striatal dopamine function depends, critically, on the behavioural task. These findings are discussed with respect to the growing body of evidence implicating abnormalities in frontostriatal neurotransmission in complex disorders such as schizophrenia.

Synaptosomal tryptophan uptake and efflux following lesion of central 5-hydroxytryptaminergic neurones.

1. This study attempted to determine whether the activation of the tryptophan carrier in rat forebrain synaptosomes caused by depolarization or by extracellular sodium depletion occurred exclusively in 5-hydroxytryptaminergic nerve endings. 2. Ascending 5-hydroxytryptaminergic neurones were lesioned either electrolytically or by intraventricular administration of 5,7-dihydroxytryptamine. The extent of the lesion was assessed by comparing the uptake of [3H]-5-hydroxytryptamine (5-HT) in lesioned animals and in sham-operated controls. [3H]-5-HT uptake was reduced by 85.9 +/- 1.63% (mean +/- s.e. mean) in animals receiving electrolytic lesions, and by 87.4 +/- 4.51% in those receiving 5,7-dihydroxytryptamine. 3. The uptake of [3H]-tryptophan by synaptosomes from lesioned animals incubated in standard Na(+)-rich media was slightly lower (278.8 +/- 27.3 pmol mg-1 protein min-1) than that observed in sham-operated controls (360.6 +/- 30.3 pmol mg-1 protein min-1). However, uptake in the absence of extracellular Na+ was increased to a similar extent in both the sham-operated (539 +/- 54.5 pmol mg-1 protein min-1) and lesioned animals (507.2 +/- 42.4 pmol mg-1 protein min-1). 4. The efflux of [3H]-tryptophan in response to extracellular Na+ depletion was similar in sham-operated and lesioned animals. Release expressed as a percentage of tissue [3H]-tryptophan released in response to the pulse of Na(+)-free medium was 6.691 +/- 0.585 (n = 4) in sham-operated controls and 8.195 +/- 0.906 in lesioned animals. 5. The efflux of [3H]-tryptophan in response to K+ depolarization was also unchanged in lesioned animals when compared with sham-operated controls. Release, expressed as described above was, in sham-operated controls 3.76 +/- 0.41 (n = 4) and 4.09 +/- 0.30 in lesioned animals. 6. The results of this study show that the tryptophan carrier which is activated by depolarization or by extracellular Na+ depletion is not located exclusively on 5-hydroxytryptaminergic nerve endings. Moreover the contribution made by 5-hydroxytryptaminergic neurones appears to be only minor.

Evidence for excitatory 5-HT2-receptors on rat brainstem neurones.

1. The technique of microiontophoresis was used to investigate the identity of the receptor mediating the excitatory effects of 5-hydroxytryptamine (5-HT) upon neurones in the midline of the medullary brainstem of the rat in vivo. 2. The 5-HT1-like receptor agonists 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) failed to excite the majority of neurones excited by 5-HT. The mobilities of 5-CT and 8-OH-DPAT when tested in vitro were found not to differ significantly from that of 5-HT, suggesting that the lack of effect of these agonists was not due to a lower rate of release from the microelectrodes. 3. The excitatory responses to 5-HT were attenuated by the 5-HT 2-receptor antagonists ketanserin and methysergide when applied microiontophoretically or administered intravenously (0.3 and 1 mg kg-1 respectively). Excitatory responses to glutamate and noradrenaline were not reduced. 4. The 5-HT3-receptor antagonist MDL 72222 failed to attenuate selectively the excitatory response to 5-HT when applied either by microiontophoresis or administered intravenously (1 mg kg-1). 5. Microiontophoretic application of the alpha 1-adrenoceptor antagonist prazosin did not attenuate excitatory responses to either 5-HT or noradrenaline. Intravenously administered prazosin (0.8 mg kg-1) also failed to attenuate excitatory responses to 5-HT, but did block excitatory responses to noradrenaline. 6. These results suggest that 5-HT2-receptors, but not 5-HT1-like receptors, 5-HT3-receptors or alpha 1-adrenoceptors, are involved in the excitatory response of midline medullary neurones to 5-HT.

Evidence for depressant 5-HT1-like receptors on rat brainstem neurones.

1. The technique of microiontophoresis was used to evaluate the contribution of 5-HT1-like, 5-HT2- and 5-HT3-receptors to the depressant effects of 5-hydroxytryptamine (5-HT) on neurones in the midline of the medullary brainstem of the rat in vivo. 2. Depressant responses to 5-HT were resistant to antagonism by the 5-HT2-receptor antagonist ketanserin and the 5-HT3-receptor antagonist MDL 72222 applied either microiontophoretically or administered systemically. 3. Microiontophoretic or systemic administration of the 5-HT antagonist metergoline, which shows nanomolar affinity for the 5-HT1-binding site, also failed to attenuate the depressant responses to 5-HT. 4. Systemic administration of high doses of methysergide (30-40 mg kg-1) attenuated the depressant responses to 5-HT but did not block depressant responses to GABA or excitatory responses to glutamate. 5. The depressant effects of 5-HT were potently mimicked by the 5-HT1-like receptor agonists 5-carboxamidotryptamine and 8-OH-DPAT. 6. These results indicate that neither 5-HT2-receptors nor 5-HT3-receptors are involved in the depressant effects of 5-HT on midline brainstem neurones. The depressant effects of 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and blockade of the response to 5-HT by high doses of methysergide suggests the involvement of 5-HT1-like receptors. The lack of effect of metergoline, however, indicates that this receptor may be different from any of the 5-HT1 binding sites yet described.

Studies on the mechanism by which tryptophan efflux from isolated synaptosomes is stimulated by depolarization.

1. The efflux and influx of tryptophan across the synaptosomal plasma membrane has been studied under a variety of experimental conditions, in order to examine the mechanism by which depolarization enhances the efflux of tryptophan from superfused synaptosomes. 2. Efflux of [3H]-tryptophan from preloaded superfused synaptosomes was found to be enhanced by K+ depolarization in a Ca2+ and dose-dependent manner. In contrast, [3H]-phenylalanine efflux was only poorly stimulated by depolarization and only by very high concentrations of K+. 3. Tryptophan efflux was also enhanced by decreasing the extracellular Na+ concentration, but this effect was not dependent on extracellular Ca2+. 4. Influx of [3H]-tryptophan into synaptosomes was stimulated by extracellular Na+ removal, but the uptake of [3H]-phenylalanine was unaffected by this procedure. 5. Both the induced influx and efflux of tryptophan observed under these experimental conditions was inhibited by immobilizing the plasma membrane carrier with parachlorophenylalanine. This implied that both the enhanced influx and efflux arose as a consequence of the activation of the membrane tryptophan carrier, the direction of the observed effect being dependent upon the manner in which the experiments were conducted. 6. The relationship between depolarization, the activation of the membrane tryptophan carrier and the significance of this to the in vivo situation is discussed.

The effect of dopamine depletion from the caudate nucleus of the common marmoset (Callithrix jacchus) on tests of prefrontal cognitive function.

This study examined the effects of depletion of dopamine from the caudate nucleus of the common marmoset (Callithrix jacchus), on tasks sensitive to prefrontal damage (attentional set-shifting and spatial delayed response). There was a marked impairment in performance on the spatial delayed response task, but performance on the attentional set-shifting task was relatively preserved except for an impairment in re-engagement of a previously relevant perceptual dimension. This pattern of impairment is distinct from that seen after excitotoxic lesions of the prefrontal cortex and in patients with Parkinson's disease. Though it is not possible to identify specific cognitive functions that are independent of dopaminergic modulation of the caudate nucleus, due to the partial nature of the lesion, the results do provide insight into those cognitive processes that appear most dependent on caudate dopamine.

Retarded acquisition and reduced expression of conditioned locomotor activity in adult rats following repeated early maternal separation: effects of prefeeding, d-amphetamine, dopamine antagonists and clonidine.

Adult hooded rats exposed to a repeated maternal separation procedure during the neonatal period showed a blunted expression of locomotor hyperactivity conditioned to the presentation of the daily food ration. We have demonstrated that the expression of food-conditioned anticipatory hyperactivity is sensitive to the response-enhancing effects of systemic d-amphetamine (0.5; 1.0 mg/kg) and to the response-attenuating effects of the selective dopamine D2 antagonist sulpiride (8; 20 mg/kg), the selective dopamine D1 antagonist SCH 23390 (0.01; 0.022 mg/kg) and the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (5; 15 micrograms/kg) in a dose dependent manner. Animals from the early separation groups showed a reduced enhancement of activity in response to 0.5 mg/kg d-amphetamine and a greater attenuation of activity in response to 8 mg/kg sulpiride and 5 micrograms/kg clonidine. Female separated rats also exhibited an attenuated locomotor response to the unconditioned stimulant effects of 0.5 mg/kg systemic d-amphetamine. The experiments confirm that early maternal separation attenuates the response to conditioned appetitive cues in adult rats and implicate altered dopaminergic and noradrenergic function in the changes. It is possible that early maternal separation in the rat may offer a useful preparation for investigation of the neural substrates mediating affective development and affective psychopathology.

Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex.

RATIONALE: Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT(1A) agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats. OBJECTIVES: Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT(1A) antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats. METHODS: In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex. RESULTS: Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT(1A) receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition. CONCLUSIONS: These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT(1A) receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.