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Evidence from experimental animal studies convincingly argues for a role of pro-inflammatory cytokines due to surgical trauma in causing postoperative cognitive dysfunction. However, other studies have shown exposure to 2–4 h of isoflurane anesthetic without surgical trauma can also impair cognitive function. We aimed to determine cytokine changes over time following isoflurane exposure in the presence and absence of surgery and examine subsequent cognitive function. Male rats were exposed to isoflurane (1.8%, 4 h) with or without laparotomy or control conditions and tested in a contextual fear conditioning paradigm 8 days later. On day 9 rats were perfused, serum and hippocampal samples were collected and 24 cytokines were analysed. Groups of rats exposed as above were killed 6 or 48 h after isoflurane exposure to examine early cytokine changes. Isoflurane exposure resulted in significantly less freezing in the contextual fear conditioning test ( F (2,31) = 6.11, P = 0.006) and addition of laparotomy caused no further deficits ( P > 0.05). At 6 h post isoflurane exposure an immunosuppressive response was observed in the serum while hippocampal cytokines were largely unchanged. These finding suggest isoflurane alone causes inflammatory changes and cognitive deficits. The addition of a laparotomy had a negligible effect. Early after isoflurane exposure changes in serum and hippocampal cytokines were divergent but by 9 days were aligned. At this time cytokines associated with memory deficits and brain injury processes were significantly elevated in serum and brain.

INTRODUCTION: In schizophrenia early treatment may prevent disorder onset, or at least minimize its impact, suggesting possible neuroprotective properties of antipsychotics. The present study investigates the effects of chronic treatment with the atypical antipsychotic, risperidone, on locomotor sensitization in the subchronic phencyclidine-treated rat. METHODS: Rats were treated with phencyclidine sub-chronically (2 mg/kg bi-daily for one week followed by a one-week wash-out period) or vehicle. Half of the phencyclidine group was concurrently treated with risperidone (0.5 mg/kg IP) twice daily for 15 days, beginning 3 days before the start of phencyclidine administration. 6 weeks after treatment all rats were injected with a phencyclidine-challenge (3.2 mg/kg) and immediately after their locomotor activity measured for 20 min. RESULTS: Co-administration of risperidone at the time of phencyclidine administration significantly reduced the phencyclidine-challenge locomotor effect administered 6 weeks later. DISCUSSION: These results demonstrate that concurrent risperidone is neuroprotective, and clearly suggests its functionality can be translated to a clinical setting for treating the so-called prodrome.

The early life period is one of significant vulnerability to programming effects from the environment. Given the sensitivity of microglial cells to early life programming and to adult diet, we hypothesized overfeeding during the neonatal period would acutely alter microglial profiles within the developing brain, predisposing the individual to a lasting central pro-inflammatory profile that contributes to overactive immune responses long-term. We tested this idea by manipulating litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of 4 (neonatally overfed) or 12 (control). This manipulation induces obesity and susceptibility to lipopolysaccharide (LPS) long-term. We then examined microglial and central pro-inflammatory profiles during development and in adulthood as well as susceptibility to neuroimmune challenge with LPS. Neonatally overfed rats have evidence of microgliosis in the paraventricular nucleus of the hypothalamus (PVN) as early as postnatal day 14. They also show changes in hypothalamic gene expression at this time, with suppressed hypothalamic interleukin 1β mRNA. These effects persist into adulthood, with basal PVN microgliosis and increased hypothalamic toll-like receptor 4, nuclear factor κB, and interleukin 6 gene expression. These neonatally overfed rats also have dramatically exacerbated microglial activation in the PVN 24h after an adult LPS challenge, coupled with changes in inflammatory gene expression. Thus, it appears neonatal overfeeding sensitizes PVN microglia, contributing to a basal pro-inflammatory profile and an altered response to a neuroimmune challenge throughout life. It remains to be seen if these effects can be reversed with early interventions.

Exercise has been demonstrated to have positive effects on both the body and brain. The present study aimed to determine the behavioural and morphological consequence of low-intensity running. Rats were exercised on a treadmill for a total of 30 days, 30 min/day. Social interaction, locomotor activity and behaviour on an elevated plus maze were assessed post-treatment. Exercised animals demonstrated more passive interaction and less time not interacting than control animals that were not exercised. Conversely, locomotor and anxiety measures showed no effect of exercise. Analysis of brains demonstrated an increase in expression of parvalbumin immunoreactive neurons in the hippocampus localised to the CA1 and CA2/3 regions. These results demonstrate that low-intensity exercise leads to changes in social behaviour as well as neuroplastic morphological changes within the hippocampus.

Obesity-induced lipid oversupply promotes skeletal muscle mitochondrial biogenesis. Previous investigations have utilized extreme high-fat diets (HFD) to induce such mitochondrial perturbations despite their disparity from human obesogenic diets. Here, we evaluate the effects of Western diet (WD)-induced obesity on skeletal muscle mitochondrial function. Long-Evans rats were given ad libitum access to either a WD [40% energy (E) from fat, 17% protein, and 43% carbohydrate (30% sucrose); n = 12] or a control diet (CON; 16% of E from fat, 21% protein, and 63% carbohydrate; n = 12) for 12 wk. Rats fed the WD consumed 23% more E than CON ( P = 0.0001), which was associated with greater increases in body mass (23%, P = 0.0002) and adiposity (17%, P = 0.03). There were no differences in fasting blood glucose concentration or glucose tolerance between diets, although fasting insulin was increased by 40% ( P = 0.007). Fasting serum triglycerides were also elevated in WD (86%, P = 0.001). The maximal capacity of the electron transfer system was greater following WD (37%, P = 0.02), as were the maximal activities of several mitochondrial enzymes (citrate synthase, β-hydroxyacyl-CoA dehydrogenase, carnitine palmitoyltransferase). Protein expression of citrate synthase, UCP3, and individual respiratory complexes was greater after WD ( P < 0.05) despite no differences in the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARδ, or PPARγ coactivator-1 mRNA or protein abundance. We conclude that the respiratory capacity of skeletal muscle is enhanced in response to the excess energy supplied by a WD. This is likely due to an increase in mitochondrial density, which at least in the short term, and in the absence of increased energy demand, may protect the tissue from lipid-induced impairments in glycemic control.

Sequence learning and spatial alternation were examined in rats with anterior thalamic lesions or sham surgeries. There was a lesion-induced deficit in spatial alternation but not in sequence learning. During sequence learning, rats discriminated between six different sequentially presented compounds (e.g., reinforce A before B, but not B before A), composed of audio-visual elements. The solution required rats to learn both specific stimulus sequences and the reward contingencies associated with these specific temporal relationships. The failure of anterior thalamic lesions to affect the acquisition of this sequential configural task complements the recent finding that anterior thalamic lesions also spare the acquisition of a configural task involving specific stimulus pairings and their spatial relationships. These findings suggest that such “structural” learning is more reliant on cortico-hippocampal than thalamo-hippocampal interactions.

Tryptophan depletion techniques are effective in reducing central serotonergic function and have been used to investigate its role in mood and cognition. In the present study a tryptophan-free diet was fed to Lister-hooded male rats chronically for 21 days to investigate the effect of lowering central serotonin concentration on cognition using the novel object-recognition paradigm. Chronically tryptophan-depleted rats had impaired object-recognition memory; this was accompanied by a reduction in central serotonin of 40-50% in the hippocampus, frontal cortex and striatum. In a subsequent experiment, the atypical antipsychotic, risperidone (0.2 mg/kg), but not the typical antipsychotic, haloperidol (0.1 mg/kg), administered i.p. 30 min prior to the retention test, significantly attenuated the chronic tryptophan depletion impairment. These data show that chronic lowering of central serotonin is associated with impaired cognitive performance, and that this can be reversed by the atypical antipsychotic, risperidone.

Sub-chronic administration of phencyclidine to the rat induces enduring cognitive and pathophysiological changes that resemble some features of schizophrenia. The present study aimed to determine if concurrent administration of the atypical antipsychotic, risperidone, could attenuate the effect of phencyclidine on object recognition memory and parvalbumin-containing neurons in the prefrontal cortex. Rats were administered phencyclidine at a dose of 2mg/kg i.p. bi-daily for 1 week, or vehicle. Half of the phencyclidine group was concurrently treated with risperidone (0.5mg/kg i.p.) twice daily for 10 days, beginning 3 days before the start of phencyclidine administration. Novel object recognition memory and subsequent brain analysis were assessed 6 weeks post-phencyclidine treatment. Phencyclidine produced a deficit in object recognition memory as measured by the discrimination ratio. In addition, 6 weeks post-phencyclidine, analysis of brains showed a reduction in expression of parvalbumin-immunoreactive neurons in the prefrontal cortex, with specific deficits observed in the prelimbic region, but not infralimbic or cingulate cortices. Concurrent administration of risperidone showed no protective effects against these deficits. These results show the importance of the sub-chronic phencyclidine rat in modelling cognitive and prefrontal pathophysiology observed in schizophrenia, but suggest that concurrent risperidone is not neuroprotective in this model.

In 3 habituation experiments, rats with excitotoxic lesions of the perirhinal cortex were found to be indistinguishable from control rats. Two of the habituation experiments examined the habituation of suppression of responding on an appetitive, instrumental baseline. One of those experiments used stimuli selected from the visual modality (lights), the other used auditory stimuli. The third experiment examined habituation of suppression of novel-flavored water consumption. In contrast to the null results on the habituation experiments, the perirhinal lesions disrupted transfer performance on a configural, visual discrimination, indicating the behavioral effectiveness of the lesions. Implications for comparator theories of habituation are considered, and it is concluded that others' demonstrations of the sensitivity of object recognition to perirhinal cortex damage is not the result of standard habituation.

A sub-chronic administration of phencyclidine to the rat brings about enduring pathophysiological and cognitive changes that resemble some features of schizophrenia. The present study aimed to determine whether the behavioural consequence of this phencyclidine regime extends to a long-term disruption of social interaction that might provide a parallel with some negative symptoms of the disease. Rats were treated with phencyclidine (2 mg/kg bi-daily for 1 week) or vehicle followed by a drug-free period. Social interaction was assessed 24 h, 1 week, 3 weeks and 6 weeks post-treatment. A long-lasting disturbance of social behaviour was observed in the phencyclidine group, namely more contact and non-contact interaction with an unfamiliar target rat at all time points. Six weeks post-phencyclidine, analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus with significant reductions localised to the CA1 and dentate gyrus regions. These results show that sub-chronic phencyclidine produces long-lasting disruptions in social interaction that, however, do not model the social withdrawal seen in patients with schizophrenia. These disturbances of social behaviour may be associated with concurrent pathophysiological brain changes.

The extensive clinical experience of angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists as antihypertensive agents provide numerous examples of anecdotal evidence of improvements in cognition and mood. This study aimed to determine the effect of chronic treatment with the angiotensin converting enzyme inhibitor, perindopril, and the angiotensin AT(1) receptor antagonist, candesartan, on central neurotransmitter levels in the rat. Perindopril (1.0mg/kg/day) or candesartan (10mg/kg/day) was administered via the drinking water at for 1 week, while controls received water alone. At the end of treatment rats were sacrificed, brains removed and discrete regions dissected and analysed for noradrenaline, dopamine and its major metabolites, and serotonin content. As shown previously we found an increase in striatal dopamine levels after perindopril treatment, though this did not extend to the mesolimbic system with neurotransmitter levels unchanged in the hippocampus, nucleus accumbens and frontal cortex. Conversely, candesartan administration produced no change in dopamine, but significant decreases in both DOPAC and HVA in the striatum. In addition chronic candesartan infusion produced a significant increase in the levels of hippocampal noradrenaline and serotonin; and frontal cortex serotonin content. These results demonstrate that while angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists act as antihypertensives by affecting the renin-angiotensin system, they have divergent actions on brain neurochemistry.

Background Obesity can lead to cognitive dysfunction including poor performance in memory tasks. However, poor memory is not seen in all obese humans and takes several months to develop in animal models, indicating the adult brain is relatively resistant to obesity’s cognitive effects. We have seen that, in the rat, overfeeding for as little as 3 weeks in early life leads to lasting obesity and microglial priming in the hypothalamus. Here we hypothesized that microglial hyper-sensitivity in the neonatally overfed rats extends beyond the hypothalamus into memory-associated brain regions, resulting in cognitive deficits. Methods We tested this idea by manipulating Wistar rat litter sizes to suckle pups in litters of 4 (overfed) or 12 (control). Results Neonatally overfed rats had microgliosis in the hippocampus after only 14 days overfeeding, and this persisted into adulthood. These changes were coupled with poor performance in radial arm maze and novel object recognition tests relative to controls. In controls, the experience of the radial arm maze reduced cell proliferation in the dentate gyrus and neuron numbers in the CA3. The learning task also suppressed microglial number and density in hippocampus and retrosplenial cortex. Neonatally overfed brains had impaired sensitivity to learning, with no neuronal or cell proliferative effects and less effective microglial suppression. Conclusions Thus, early life overfeeding contributes to a long-term impairment in learning and memory with a likely role for microglia. These data may partially explain why some obese individuals display cognitive dysfunction and some do not, i.e. the early life dietary environment is likely to have a vital long-term contribution. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0578-7) contains supplementary material, which is available to authorized users.

Activity of the immediate early genes c-fos and zif268 was compared across hemispheres in rats with unilateral, excitotoxic lesions of the hippocampus (dentate gyrus and CA fields 1-4). Counts of the protein products of these genes were made shortly after rats performed a test of spatial working memory in the radial-arm maze, a task that is sensitive to bilateral lesions of the hippocampus. Unilateral hippocampal lesions produced evidence of widespread hypoactivity. Significant reductions in immediate early gene counts were observed within all three anterior thalamic nuclei, as well as the entorhinal, perirhinal, and postrhinal cortices, and much of the subicular complex. In contrast, no observable changes were detected in the anterior cingulate, infralimbic or prelimbic cortices, as well as several amygdala nuclei, even though many of these regions receive projections from the subiculum. Instead, the immediate early gene changes were closely linked to sites that are thought to be required for successful task performance, with both immediate early genes giving similar patterns of results. The findings support the notion that the anterior thalamic nuclei, hippocampus, and parahippocampal cortices form the key components of an interdependent neuronal network involved in spatial mnemonic processing.

Fos levels were measured in rats trained in one of two qualitatively different spatial memory tasks in a water maze. In one task, ( landmark condition) rats found a submerged platform that was always 25 cm south of a visible landmark, the absolute position of the platform and landmark changing after every trial. In the other task ( place condition), rats swam to a platform that remained in the same absolute position on every session, but changed session to session, with this task relying on the memory of allocentric cues. Despite matched swim times, the landmark condition resulted in higher levels of Fos in a wide range of cortical and subcortical sites, including the hippocampus and its connections. Structural equation modelling revealed two different patterns of hippocampal function. In the allocentric place task there was a significant association between Fos activity in the entorhinal cortices and the hippocampus proper, while in the non-allocentric landmark task this relationship was not present, but was replaced by a connection from the entorhinal cortices to the subiculum. Thus, the two different tasks engage two different modes of hippocampal activity as demonstrated by Fos expression.

Rats rapidly learned to find a submerged platform in a water maze at a constant distance and angle from the start point, which changed on every trial. The rats performed accurately in the light and dark, but prior rotation disrupted the latter condition. The rats were then retested after receiving cytotoxic hippocampal or retrosplenial cortex lesions. Retrosplenial lesions had no apparent effect in either the light or dark. Hippocampal lesions impaired performance in both conditions but spared the ability to locate a platform placed in the center of the pool. A hippocampal deficit emerged when this pool-center task was run in the dark. The spatial effects of hippocampal damage extend beyond allocentric tasks to include aspects of idiothetic guidance.

Activity of the immediate early gene c-fos was compared in rats with neurotoxic lesions of the anterior thalamic nuclei and in surgical controls. Fos levels were measured after rats had been placed in a novel room and allowed to run up and down preselected arms of a radial maze. An additional control group showed that in normal rats, this exposure to a novel room leads to a Fos increase in a number of structures, including the anterior thalamic nuclei and hippocampus. In contrast, rats with anterior thalamic lesions were found to have significantly less Fos-positive cells in an array of sites, including the hippocampus (dorsal and ventral), retrosplenial cortex, anterior cingulate cortex, and prelimbic cortex. These results show that anterior thalamic lesions disrupt multiple limbic brain regions, producing hypoactivity in sites associated in rats with spatial memory. Because many of the same sites are implicated in memory processes in humans (e.g., the hippocampus and retrosplenial cortex), this hypoactivity might contribute to diencephalic amnesia.

Both acute and sub-chronic phencyclidine administration produce behavioural and pathophysiological changes that resemble some features of schizophrenia. The present study aimed to determine if acute and sub-chronic phencyclidine treatment in male rats produces deficits in sociability and social novelty preference, which may reflect aspects of the negative symptomatology observed in schizophrenia. Rats were treated with phencyclidine acutely (2 or 5 mg/kg) or subchronically (2 or 5 mg/kg bi-daily for one week followed by a one week wash-out period) or vehicle. Social affiliative behaviour was assessed using the sociability and preference for social novelty paradigm where social interaction time was measured in (a) a chamber containing an unfamiliar conspecific vs an empty chamber (sociability), or (b) a chamber containing an unfamiliar conspecific vs a chamber containing a familiar conspecific (preference for social novelty). Results showed that acute administration of phencyclidine produced a reduction in measures of sociability but had no effect on preference for social novelty while sub-chronic administration of phencyclidine had no effect on sociability or social novelty. This study provides further evidence for the usefulness of phencyclidine models in modelling the symptomatology of schizophrenia.

Background The renin-angiotensin system (RAS) functions as both a circulating endocrine system and a tissue paracrine/autocrine system. As a circulating peptide, angiotensin II (Ang II) plays a prominent role in blood-pressure control and body fluid and electrolyte balance by acting on the AT, receptor in the brain and peripheral tissues. As a paracrine/autocrine peptide, locally formed Ang II also plays additional roles in tissues involving the regulation of regional haemodynamics, cell growth and remodelling, and neurotransmitter release. Evidence is emerging that Ang II is not the only active peptide of the RAS, and other Ang II fragments may also have important biological activities. Objectives To provide a morphological basis for understanding novel actions of angiotensin-converting enzyme (ACE), Ang II and related peptides in tissues, this article will review the localization of ACE and AT 1 , AT 2 and AT 4 receptors in the central nervous system, blood vessels and kidney. Results and conclusion Autoradiographic mapping of the major components of the RAS has proved a valuable strategy to reveal, or suggest, cellular sites of novel actions for Ang II and related peptides in tissues. First, colocalization of ACE and AT 1 receptors in the substantia nigra, the caudate nucleus and putamen of human and rat brain, which contain the dopamine-synthesizing neurons, suggests that the central RAS may be important in modulating central dopamine release. Secondly, the distribution of AT 4 receptors with a striking association with cholinergic neurons, motor and sensory nuclei in the brain reveals that Ang IV may modulate central motor and sensory activities and memory. Thirdly, the occurrence of high levels of ACE and AT 1 and/or AT 2 receptors in the adventitia of blood vessels suggests important paracrine roles of the vascular RAS. Finally, the identification of abundant AT 1 receptor and elucidation of its roles in the renomedullary interstitial cells of the kidney may provide a new impetus to study further the role of Ang II in the regulation of renal medullary function and blood pressure. Overall, circulating and locally produced Ang II and related peptides may exert a remarkable range of actions in the brain, kidney and cardiovascular system through multiple angiotensin receptors.

We have previously demonstrated that angiotensin II stimulates the release of dopamine from the normotensive rat striatum via the AT1 receptor. In this study, the effect of angiotensin II-stimulated striatal dopamine release in the spontaneous hypertensive rat was compared to normotensive controls. In the spontaneous hypertensive rat, angiotensin II stimulated dopamine release to 169 +/- 13% (P0.05) in the experimental period, with levels remaining high in the recovery phase, 158 +/- 16% (P0.05). This effect was not significantly different from the response in normotensive controls, in which angiotensin II stimulated dopamine release to 149 +/- 18% (P0.05) in the experimental period, with the effect also persisting through the recovery period, 244 +/- 62% (P0.05). Thus, despite reports of increased activity of the brain angiotensin II and dopamine systems in the spontaneous hypertensive rat, there is no evidence of abnormal regulation of the striatonigral dopamine system.

There is a large body of anatomical and functional evidence supporting an interaction between brain angiotensin and central catecholamine systems. Angiotensin II AT1 receptors have been identified on dopamine containing cells in the substantia nigra and striatum of human brain using receptor autoradiography. Using in vivo microdialysis we have demonstrated that locally administered angiotensin II stimulates dopamine release from the striatum of conscious rats. Since some angiotensin receptor antagonists and angiotensin converting enzyme inhibitors can cross the blood brain barrier it is possible that they interact with the brain catecholaminergic systems.

Recent evidence shows an association between obesity and cognitive decline. The present study aimed to determine whether a very high fat (60%) or western diet can affect working or spatial memory in rats and whether the diet-induced cognitive impairment is linked to the level of acetylcholine in the brain. Three groups of male Long Evans rats were fed either chow, western diet (21% fat, 0.15% cholesterol) or a high fat diet (60% fat) for 12 weeks (n=12 per group). Body weight, food intake and blood pressure were measured weekly. Behavioural testing, novel object recognition and Y-maze were carried out at 12 weeks. At the end of the study brain choline acetyltransferase and acetylcholinesterase levels were estimated. Results showed that consumption of a western diet for twelve weeks impaired a rat's spatial memory (p

There is converging evidence that the prefrontal and mesolimbic dopaminergic (DAergic) systems are involved in the performance of a variety of tasks that require the use of contextual, or task-setting, information to select an appropriate response from a number of candidate responses. Performance on tasks of this nature are impaired in schizophrenia and in rats exposed to psychotomimetics; impairments that are often attenuated by administration of dopamine (DA) antagonists. Rats were trained on either a complex instrumental discrimination task, that required the use of task-setting cues, or a simple discrimination task that did not. Following training, microdialysis probes were implanted unilaterally in either the medial prefrontal cortex (mPFC) or nucleus accumbens (NAc) and samples were collected in freely moving animals during a behavioural test session. In Experiment 1, we found no difference in levels of DA in the mPFC of rats while they were performing the two discrimination tasks. Rats that performed the complex task did, however, show significantly higher mPFC DA levels relative to rats in the simple discrimination condition following the end of the behavioural test session. In Experiment 2, rats performing the conditional discrimination showed lower levels of DA in the NAc compared to the simple discrimination group both during the test session and after it. These results provide direct evidence that conditional discrimination tasks engage frontal and mesolimbic DAergic systems and are consistent with the proposal that regulation of fronto-striatal DA is involved in aspects of cognitive control that are known to be impaired in individuals with schizophrenia.

Introduction Antipsychotic drug‐induced sexual dysfunction is a common and problematic side effect, which may diminish quality of life and lead to treatment noncompliance. Up to date, there is still a scarcity of basic research regarding the chronic effects of most antipsychotic agents on sexual behavior. Aim The present study investigated the effect of a range of doses of three antipsychotic drugs (haloperidol, risperidone, and quetiapine) on male rat sexual competence following chronic administration. Methods Twelve groups of Sprague‐Dawley rats (n = 7 each) received by gavage haloperidol (0.25, 0.5, or 1 mg/kg), risperidone (0.125, 0.25, or 0.5 mg/kg), quetiapine (10, 20, and 40 mg/kg) or vehicle (distilled water) in the corresponding control groups, respectively, once daily for 21 days. Sexual function was evaluated by the copulatory behavior test 10 hours after the last dose. Main Outcome Measure The male rat behavioral parameters of copulatory test. Results Sexual function was widely and significantly suppressed by high dose haloperidol (1 mg/kg) after 21 days administration compared with the control group, which included both frequency and latency of intromission and ejaculation. Only ejaculation latency was significantly impaired after administration with 0.5 mg/kg haloperidol. Compared with the control group, high dose risperidone (0.5 mg/kg) significantly decreased the frequency of mounting. There were no significant changes in sexual behavior with the lower doses of either haloperidol or risperidone. Sexual behavior was not influenced by any dose of quetiapine. Conclusions Haloperidol and risperidone, but not quetiapine, could impair sexual competence in a dose‐related manner in male rats. Zhang XR, Zhang ZJ, Jenkins TA, Cheng WR, and Reynolds GP. The dose‐dependent effect of chronic administration of haloperidol, risperidone, and quetiapine on sexual behavior in the male rat. J Sex Med **;**:**–**.

Persistent blockade of NMDA receptor function by repeated phencyclidine dosing produces pathophysiological changes that model deficits observed in schizophrenia. The present study investigates the effects of subchronic phencyclidine administration (PCP; 2 or 5mg/kg bi-daily for 7 days followed by a drug-free period) on sucrose choice, a measure of anhedonia. Sucrose preference in a two-bottle sucrose-water choice test was assessed 1 and 2 weeks after PCP. Results showed no differences in sucrose intake between PCP rats and controls, nor a difference in water intake or total volume of liquid consumed at either time-point. Six weeks post-PCP, analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus with significant reductions localised to the CA1 and CA2/3 regions. These results demonstrate that while subchronic PCP may not be a valid model for the negative symptom of anhedonia observed in schizophrenia, it induces pathology in the brain in hippocampal subregions that are reminiscent of changes observed in schizophrenia.

Antipsychotic drug treatment may be associated with common and problematic sexual dysfunction, especially impotence, which can diminish quality of life and lead to treatment noncompliance. Nitric oxide synthase (NOS) is an important cellular modulator of erectile function. We have therefore investigated the effect of antipsychotic drug on activity and gene expression of NOS in rat penile tissues. The activity of constitutive NOS was significantly suppressed below control by a 21 days administration of 1 mg/kg haloperidol, which also significantly decreased expression of endothelial NOS (eNOS) and neural NOS mRNA. Risperidone at 0.5 mg/kg also reduced eNOS mRNA expression. Haloperidol or risperidone did not change gene expression and activity of inducible NOS (iNOS). Quetiapine significantly increased activity and mRNA expression of iNOS with 20 and 40 mg/kg doses. These preliminary results have important implications for enhancing our understanding of mechanisms by which antipsychotic drugs induce sexual dysfunction.

Early exposure to infection is known to affect brain development and has been linked to an increased risk for schizophrenia. The present study aimed to determine whether neonatal infection produced long-term disruptions in behaviour and pathology that might provide a parallel with that observed in schizophrenia. Rats were administered lipopolysaccharide (LPS; 500 microg/kg i.p.) on postnatal day 7 and 9. Locomotor activity and object recognition memory were tested at day 35 and day 70. LPS animals were observed to be less active at adulthood as measured by locomotor activity. With regards to object recognition memory, LPS administration produced no early impairment in task performance, however, at day 70 LPS animals spent significantly less time exploring the novel object than control animals. Analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus of LPS animals with significant reductions selectively localised to the CA1-CA3 region, and not the dentate gyrus. No changes were observed in prefrontal cortex. These results show that neonatal LPS results in pathophysiological brain changes in hippocampal CA1-CA3 subregions.

Angiotensin converting enzyme inhibitors (ACEis) are widely used anti-hypertensive agents that are also reported to have positive effects on mood and cognition. The present study examined the influence of the ACEi, perindopril, on cognitive performance and anxiety measures in rats. Two groups of rats were treated orally for one week with the ACEi, perindopril, at doses of 0.1 and 1.0 mg/kg/day. Learning was assessed by the reference memory task in the water maze, comparing treated to control rats. Over five training days both perindopril-treated groups learnt the location of the submerged platform in the water maze task significantly faster than control rats. A 60 s probe trial on day 6 showed that the 1.0 mg/kg/day group spent significantly longer time in the training quadrant than control rats. This improved performance in the swim maze task was not due to the effect of perindopril on motor activity or the anxiety levels of the rats as perindopril-treated and control animals behaved similarly in activity boxes and on the elevated + maze. These results confirm the anecdotal human studies that ACEis have a positive influence on cognition and provide possibilities for ACEis to be developed into therapies for memory loss.

The pedunculopontine tegmental nucleus (PPTg) is a major source of cholinergic input to the thalamus. Tracing studies have established that the PPTg has projections to many thalamic nuclei and electrophysiological studies have shown acetylcholine (ACh) to have characteristic effects on thalamic neurons. Behavioural studies point to a role for the PPTg in attention and it is possible that a key substrate for this is the ability of the PPTg to modify sensorimotor gating through the thalamus. However, it is not clear how altered PPTg activity effects neuronal activity across the thalamus en masse. We have attempted to examine this by stimulating the PPTg in freely moving rats and measuring thalamic activation with c-fos immunohistochemistry. The PPTg was stimulated by unilateral microinjection of the L-glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) with the rationale that reuptake blockade increases locally the availability of endogenous neurotransmitter. It was shown that PDC microinjection into PPTg produced clear and consistent changes in Fos immunoreactivity in several thalamic nuclei, but most markedly in the centrolateral, ventrolateral and reticular nuclei. A second study was carried out to determine the gross behavioural effects of intra-PPTg L-glutamate blockade. No changes in locomotion or other general behaviours were observed, indicating that observed changes in thalamic Fos expression were not the result of increased behavioural output but rather a direct consequence of increased neuronal activity from PPTg input. The present data extend previous work establishing pedunculopontine-thalamic connections by specifying which particular nuclei are most affected by PPTg activation.

Lesions involving the anterior thalamic nuclei stopped immediate early gene (IEG) activity in specific regions of the rat retrosplenial cortex, even though there were no apparent cytoarchitectonic changes. Discrete anterior thalamic lesions were made either by excitotoxin (Experiment 1) or radiofrequency (Experiment 2) and, following recovery, the rats foraged in a radial-arm maze in a novel room. Measurements made 6-12 weeks postsurgery showed that, in comparison with surgical controls, the thalamic lesions produced the same, selective patterns of Fos changes irrespective of method. Granular (caudal granular cortex and rostral granular cortex), but not dysgranular (dysgranular cortex), retrosplenial cortex showed a striking loss of Fos-positive cells. While a loss of between 79 and 89% of Fos-positive cells was found in the superficial laminae, the deeper layers appeared normal. In Experiments 3 and 4, rats 9-10 months postsurgery were placed in an activity box for 30 min. Anterior thalamic lesions (Experiment 3) led to a pronounced IEG decrease of both Fos and zif268 throughout the retrosplenial cortex that now included the dysgranular area. These IEG losses were found even though the same regions appeared normal using standard histological techniques. Lesions of the postrhinal cortex (Experiment 4) did not bring about a loss of retrosplenial IEG activity even though this region is also reciprocally connected with the retrosplenial cortex. This selective effect of anterior thalamic damage upon retrosplenial activity may both amplify the disruptive effects of anterior thalamic lesions and help to explain the posterior cingulate hypoactivity found in Alzheimer's disease.

The novelty of a cue may arise from the presence of an element that has not previously been experienced or from familiar elements that have been rearranged. The present study mapped the anatomical basis of responding to this second form of novelty. For this, rats were trained on a working memory spatial task in a radial-arm maze in a cue-controlled environment. On the final test day the positions of the familiar, extra-maze cues were rearranged for half of the rats (group Novel). The spatial configuration of the cues now matched that of the control rats (group Familiar). Neuronal activation, as measured by the immediate early gene, c-fos, was then compared between the two groups. Rearrangement of visual stimuli led to significant increases in Fos-positive cells in various hippocampal subfields (rostral CA1, rostral CA3 and rostral dentate gyrus) as well as the parietal cortex and the postsubiculum. In contrast, no changes were observed in other sites including the perirhinal cortex, postrhinal cortex, lateral and medial entorhinal cortices, retrosplenial cortices, or anterior thalamic nuclei. These results highlight the selective involvement of the hippocampus for processing novel rearrangements of visual stimuli and suggest that this involvement is intrinsic as it is independent of the parahippocampal cortices. This pattern of Fos changes is the mirror image of that repeatedly found for novel individual stimuli (perirhinal increase, no hippocampal change), demonstrating that these two forms of novelty have qualitatively different neural attributes.

Activity of the immediate early gene c-fos was compared across hemispheres in rats with unilateral anterior thalamic lesions. Fos protein was quantified after rats performed a spatial working memory test in the radial-arm maze, a task that is sensitive to bilateral lesions of the anterior thalamic nuclei. Unilateral anterior thalamic lesions produced evidence of a widespread hippocampal hypoactivity, as there were significant reductions in Fos counts in a range of regions within the ipsilateral hippocampal formation (rostral CA1, rostral dentate gyrus, 'dorsal' hippocampus, presubiculum and postsubiculum). A decrease in Fos levels was also found in the rostral and caudal retrosplenial cortex but not in the parahippocampal cortices or anterior cingulate cortices. The Fos changes seem most closely linked to sites that are also required for successful task performance, supporting the notion that the anterior thalamus, retrosplenial cortex and hippocampus form key components of an interdependent neuronal network involved in spatial mnemonic processing.

The pedunculopontine tegmental nucleus (PPTg) contains cholinergic neurons whose principal ascending connections are with thalamic nuclei and structures associated with the striatum. It has been hypothesized that PPTg neurons are more closely associated with the substantia nigra (and therefore striatal motor systems) than with the ventral tegmental area (and therefore limbic striatal functions). In the present experiments we have examined the hypothesis that the PPTg is similarly associated with motor nuclei in the thalamus. Rats received unilateral ibotenate lesions of PPTg and were sacrificed 1, 2, 4 or 7 days later. Discrete thalamic nuclei, and samples of caudate-putamen and nucleus accumbens, were punched out and thalamic acetylcholine (ACh) and striatal ACh and dopamine (DA) content examined. Anteroventral nucleus had decreased ACh content after PPTg lesion, but a time dependent increase was found in mediodorsal nucleus; ACh concentration was unchanged in thalamic reticular nucleus or medial geniculate. No long-term lesion-dependent changes in striatal ACh or DA content were found. The effects of PPTg lesion on thalamic ACh content are consistent with the hypothesis that it has effects on motor nuclei, but also indicate that PPTg lesions have complex and dynamic effects on thalamic ACh content.

A number of studies have suggested that the pedunculopontine tegmental nucleus (PPTg) may play a role in reward-related behaviour. The present study was intended to investigate this further using conditioned place preference. In conditioned place preference paradigms the amount of time spent in a preferred environment is proportional to the value of the reinforcement present, until a maximum is reached. In the present experiments we aimed to determine whether this relationship was affected by lesions of the PPTg by examining the formation of a conditioned place preference to either 4%, 12% or 20% sucrose solutions in food-deprived PPTg lesioned rats. The conditioned place preference apparatus had two compartments different in colour, smell and floor texture. During conditioning, rats were restricted to one compartment or the other, one of which was paired with sucrose. This was carried out during 30 min sessions, alternating conditioned or nonconditioned trials for 14 days. On the test day, rats were given access to both compartments through a connecting chamber, and were scored for side preference over 15 min. Both PPTg and sham lesioned rats showed a conditioned place preference to 12% and 20% sucrose, but no place preference was formed by either group to 4% sucrose. There was no significant difference between the groups in the place preference shown. Consumption of 4% sucrose was not affected by excitotoxic lesions of the PPTg, but PPTg lesioned rats consumed significantly more 12% and 20% sucrose than sham controls. This suggests that perception of reward value, as judged by CPP formation, is unchanged by excitotoxic lesions of the PPTg. The increased consumption of 12% and 20% sucrose shown by rats bearing such lesions is therefore not likely to be a product of altered reward perception.

In rats with unilateral 6-hydroxydopamine lesions in the nigrostriatal pathway, injection of Angiotensin II (2 nmol) into the unlesioned striatum elicited dose-related tight rotations ipsilateral to the lesion. This rotation was suppressed by coadministration of the Angiotensin AT1 receptor antagonist, losartan (2 nmol), which had no significant effect when injected alone. Preadministration of the dopamine antagonist, haloperidol (2 mg/kg i.p.) completely blocked angiotensin II-induced turning at doses of 0.3–3 nmol, and partially at 10 nmol. These results further confirm the hypothesis that Ang II is intrinsically involved in modulating dopamine release in the striatum, an effect which is mediated predominantly by AT1 receptors.

This study was designed to evaluate the functional significance of angiotensin II (Ang II) receptors identified by previous receptor autoradiography studies to be located presynaptically on terminals of dopaminergic neurones projecting to the striatum. Microdialysis was performed in the striatum of conscious freely moving rats and dopamine and serotonin metabolites measured by HPLC with electrochemical detection. During perfusion with artificial CSF, the major extracellular dopamine metabolite identified was DOPAC with smaller concentrations of HVA. When Ang II (1 μM) was introduced into the dialysis perfusion medium, DOPAC output increased markedly, peaking at 219%, and returned to control with vehicle perfusion during the recovery period. This increase in DOPAC output with Ang II was completely blocked by co-administration of the AT1 selective antagonist, Losartan (1 μM). Administration of Losartan alone led to a significant (16%) depression of DOPAC output relative changes were seen with HVA outputs. During Ang II perfusion the output of HVA was elevated 34–79% of that in vehicle-treated rats and this effect was completely abolished by concomitant administration of Losartan. As was observed with DOPAC output, administration of Losartan alone led to a 13–24% depression of HVA output compared to vehicle perfusion. When nomifensine (10 μM) was included in the infusion fluid, dopamine was clearly measurable. Ang II perfusion increased the levels of dopamine to 225%. Values returned towards baseline during the recovery period. Ang II administration also increased (by 15% and 55%) the levels of the major serotonin metabolite, 5HIAA. This effect was also abolished by co-administration with Losartan, and Losartan alone depressed basal levels of 5HIAA. Although these results are less dramatic than those seen with the dopamine metabolites, they suggest that serotonin turnover may be under the influence of Ang II in the striatum. The findings of increased DOPAC and HVA output following Ang II infusion, which are blocked by Losartan, together with the decreased basal output of these dopamine metabolites following Losartan alone, is strong evidence for an in vivo role of Ang II in modulating dopaminergic transmission, probably via presynaptic Ang II receptors which facilitate dopamine release.