Haloperidol-induced within-session response decrement patterns and catalepsy in rats: behavioural dissociation.

The typical antipsychotic haloperidol is known to induce extra-pyramidal side-effects (EPS). Catalepsy in rats is generally regarded as a valid model for detecting the EPS liability of compounds in humans. Together with its antipsychotic and cataleptogenic actions, haloperidol causes an attenuation of instrumental responding which becomes larger in the course of a session: a within-session response decrement. The present study compared the time-course of haloperidol-induced catalepsy, measured by a bar test, to the haloperidol-induced within-session response decrements, measured by operant behaviour under a fixed ratio 10 schedule of reinforcement. Rats were trained to press a lever on a Fixed Ratio 10 schedule of food reinforcement during sessions of 15 min. When responding was stable, saline or haloperidol in 0.03 mg/kg, 0.1 mg/kg, or 0.3 mg/kg was administered intra-peritoneally either 30, 90 or 180 min prior to behavioural testing. The number of lever presses, food tray visits and latency to press the lever and to visit the food tray were analysed in five successive blocks of 3 min. Catalepsy was tested 30, 60, 90, 120, and 180 min. after injection, by placing a rat with its forepaws on a horizontal bar. The latency to remove both forepaws from the bar was scored. Within-session response decrements were present at 0.1 mg/kg and at 0.3 mg/kg, from 30 min after administration onward. At these doses, latency to press the lever was increased after 30 and 90 min, but not significantly after 180 min. Latency to visit the tray was affected only after 30 min, at 0.3 mg/kg. Haloperidol induced a dose-dependent increase in catalepsy from 60 min onwards, with maximal effect after 120 min. A dissociation between the time-course of occurrence of within-session response decrement and the cataleptogenic action of haloperidol, as well as between the latter and both latency measures, was found. Consequently, the present data suggest that within-session response decrements are not obviously caused by catalepsy-related impairments.

Satisfaction with practice in a rural state: perceptions of nurse practitioners and nurse midwives.

Data from nurse practitioners and certified nurse midwives are used to explore contributions to primary care in a rural state and how regulatory restrictiveness and other factors affect satisfaction with practice (N = 151). Satisfaction is high, especially with home communities and professional aspects of work, including collaboration with physicians. However, many feel limited by regulations and are less satisfied, especially those with a master's degree and those in organizational versus office practice sites. Reducing restrictive regulations, reevaluating practice structures, and providing for full scope of practice and other incentives consistent with rising educational levels can increase access to care.

Effect of aluminium on expression and processing of amyloid precursor protein.

The environmental agent aluminium has been extensively investigated for a potential role in the aetiology of Alzheimer's disease. Despite many investigations there is at present no definite proof for any involvement. If aluminium is involved it is possible that its action is mediated through interaction with the synthesis or processing of amyloid precursor protein (APP). The present study compared aluminium loaded IMR-32 neuroblastoma cells and rat brains with control cells and brains to determine if aluminium affected APP expression and/or processing. In the IMR-32 model system aluminium had no effect on steady-state APP mRNA levels or on the ratio of individual isoforms. It also had no quantitative or qualitative effect on APP-immunoreactive bands detected in protein extracts from conditioned medium of these cells. In total cell extracts, aluminium reduced the intensity of APP-immunoreactive bands between 120-105 kDa but had no effect on a 9 kDa band. In rat brains, aluminium had no effect on APP-immunoreactive bands from soluble or insoluble-membranous extracts. The results, in general, provide no evidence for any effect of aluminium on APP expression or processing.

Cholinergic lesions by 192 IgG-saporin and short-term recognition memory: role of the septohippocampal projection.

Two experiments examined the effects of cholinergic basal forebrain lesions by intraventricular and intrahippocampal infusions of the immunotoxin 192 IgG-saporin on recognition memory in an operant delayed-non-matching-to-position task in rats. Intraventricular infusions produced extensive reductions in cortical and hippocampal choline acetyltransferase activity in the first experiment. Behaviourally, a mixed delay-dependent/independent accuracy deficit and increased biased responding was observed post-lesioning. Thus, both mnemonic as well as non-mnemonic processes were affected by the lesion. This performance deficit was indistinguishable from the impairment induced by acute intraventricular injections of the choline uptake inhibitor hemicholinium-3, which suggests that cholinergic damage induced by 192 IgG-saporin disrupted performance. In the second experiment more discrete intrahippocampal 192 IgG-saporin lesions were made, which reduced hippocampal choline acetyltransferase activity about 57%, although this reduction was not as extensive as following intraventricular injections. Although intrahippocampal lesions also impaired non-matching accuracy, this effect failed to reach significance during most stages of the experiment. Scopolamine just failed to significantly impair (P = 0.053) performance in hippocampal lesioned rats more than in controls. The nicotinic antagonist mecamylamine did not affect the lesion-induced changes in performance. These results suggest that the cholinergic basal forebrain, including the septohippocampal system, is important for the mediation of recognition memory, and muscarinic receptor-mediated mechanisms may be of greater importance than alterations of nicotinic receptor-mediated processes in the septohippocampal system.

Lesions of the pedunculopontine tegmental nucleus do not alter delayed non-matching to position accuracy.

The cholinergic pedunculopontine tegmental nucleus, located in the brainstem, and part of the reticular formation, has traditionally been linked to motor function, sleep and arousal, but has recently been implicated in cognition. To investigate this possibility, rats with radiofrequency lesions were tested on a delayed non-matching to position task, a test for spatial recognition memory abilities. Data were analysed according to the methods of signal detection theory. Lesions of the pedunculopontine nucleus did not produce marked deficits in accuracy, although there was some evidence to suggest that motivational processes could have been affected.

Combined serotonergic-cholinergic lesions do not disrupt memory in rats.

Rats were trained on a delayed nonmatching to position task, divided into four groups and given the following lesions: (a) SHAM (vehicle injection into nucleus basalis magnocellularis (NBM) and raphé nuclei (RN), (b) RN (5,7-dihydroxytryptamine lesions of raphé, vehicle into NBM), (c) NBM (quisqualic acid lesion of NBM, vehicle into RN), and (d) COMB (lesions of both RN and NBM). RN lesions had no effect on performance measures including accuracy (percent correct), errors of omission, bias, latencies, and magazine response rate. NBM lesions produced delay-independent (nonmnemonic) disruptions, but performance improved over the 20 days' test. The effects of COMB lesions were no worse than NBM lesions alone. The results suggest that (a) the serotonergic system is not essential for performance in this task, (b) NBM lesions transiently impair nonmnemonic aspects of performance, and (c) serotonergic-cholinergic interactions may not be essential for some cognitive processes.

Iron uptake in the brain of the myelin-deficient rat.

The role of oligodendrocyte-derived transferrin in the transport and regional accumulation of iron has been studied in myelin-deficient (md) rats, which lack functional oligodendrocytes and have an almost complete depletion of transferrin in the brain, although they have normal peripheral levels of transferrin. The regional uptake of 59Fe into the brain has been studied autoradiographically in md and littermate control rats. Differences in uptake were found in only three of the 28 regions studied. These results suggest that the uptake and distribution of iron is not impaired in the md rat despite a markedly reduced level of brain transferrin. The choroid plexus contains high levels of transferrin mRNA and it is therefore likely that transferrin synthesized by choroid plexus epithelial cells can mediate the transport of iron within the brain.

Germanium-68 as a possible marker for silicon transport in rat brain.

Silicon (Si) is an essential trace element normally present in brain and cerebrospinal fluid, although the mechanism by which it enters and distributes in brain is largely unknown. Due to the short radioactive half-life of 31Si (156 min) we have investigated the use of 68Germanium (68-Ge, half-life 282 days) as a possible marker for Si transport in rat brain over longer periods than are possible with 31Si. Adult male anaesthetised rats were given a bolus of 68Ge I.V. and arterial blood samples taken during experiments that lasted between 5 min and 3 days. At termination, the brain was removed and analysed for radioactivity as were the plasma samples. Data were analyzed by Graphical Analysis which showed that the blood-brain barrier permeability to 68Ge (Kin approximately 10(-4) ml/min/g) is similar to that for many non protein-bound electrolytes in plasma and that 68Ge fluxes across cerebral capillaries are bidirectional. The autoradiographic distribution of 68Ge in brain was homogenous. Our results are in agreement with those of previous studies using 31Si or 68Ge, which suggest 68Ge may be a useful marker for Si when investigating the role of this element in conditions such as neurodegenerative diseases.

Removal of the hippocampus and transection of the fornix produce comparable deficits on delayed non-matching to position by rats.

Rats with radiofrequency lesions of the fimbria/fornix or with extensive aspiration lesions of the hippocampal region (the hippocampus proper, dentate gyrus, and subicular complex) were tested on their performance of a delayed non-matching to position task which had been learnt before surgery. On a given trial, one of two sample levers was presented in a random manner. Following a response on this lever and a subsequent delay, both levers were presented and reward was now contingent on a response on the lever that was not used as the sample. Both lesions produced equivalent performance deficits on this test of spatial working memory, the pattern of these deficits being consistent with a mnemonic impairment. The lack of difference between these two groups on a variety of performance measures indicates that hippocampal connections passing through the fornix are not only necessary for this test, but that non-fornical hippocampal connections appear unable on their own to maintain accurate responding.

Brain iron homeostasis.

The anatomical and cellular distribution of non-haem iron, ferritin, transferrin, and the transferrin receptor have been studied in postmortem human brain and these studies, together with data on the uptake and transport of labeled iron, by the rat brain, have been used to elucidate the role of iron and other metal ions in certain neurological disorders. High levels of non-haem iron, mainly in the form of ferritin, are found in the extrapyramidal system, associated predominantly with glial cells. In contrast to non-haem iron, the density of transferrin receptors is highest in cortical and brainstem structures and appears to relate to the iron requirement of neurones for mitochondrial respiratory activity. Transferrin is synthesized within the brain by oligodendrocytes and the choroid plexus, and is present in neurones, consistent with receptor mediated uptake. The uptake of iron into the brain appears to be by a two-stage process involving initial deposition of iron in the brain capillary endothelium by serum transferrin, and subsequent transfer of iron to brain-derived transferrin and transport within the brain to sites with a high transferrin receptor density. A second, as yet unidentified mechanism, may be involved in the transfer of iron from neurones possessing transferrin receptors to sites of storage in glial cells in the extrapyramidal system. The distribution of iron and the transferrin receptor may be of relevance to iron-induced free radical formation and selective neuronal vulnerability in neurodegenerative disorders.

Uptake and distribution of iron and transferrin in the adult rat brain.

Brain uptake of iron-59 and iodine-125-labelled transferrin from blood in the adult rat has been investigated using graphical analysis to determine the blood-brain barrier permeability to these tracers in experiments that lasted between 5 min and 8 days. The blood-brain barrier permeability (K(in)) to 59Fe was 89 x 10(-5) ml/min/g compared to the value of 7 x 10(-5) ml/min/g for 125I-transferrin, which is similar to that of albumin, a plasma marker. The autoradiographic distribution of these tracers in brain was also studied to determine any regional variation in brain uptake after the tracers had been administered either systemically or applied in vitro. No regional uptake was seen for 125I-transferrin even after 24 h of circulation. In contrast, 59Fe showed selective regional uptake by the choroid plexus and extra-blood-brain barrier structures 4 h after administration. After 24 h of circulation, 59Fe distribution in brain was similar to the transferrin receptor distribution, as determined in vitro, but was unlike the distribution of nonhaem iron determined histochemically. The data suggest that brain iron uptake does not involve any significant transcytotic pathway of transferrin-bound iron into brain. It is proposed that the uptake of iron into brain involves the entry of iron-loaded transferrin to the cerebral capillaries, deposition of iron within the endothelial cells, followed by recycling of apotransferrin to the circulation. The deposited iron is then delivered to brain-derived transferrin for extracellular transport within the brain, and subsequently taken up via transferrin receptors on neurones and glia for usage or storage.

Both fornix and anterior thalamic, but not mammillary, lesions disrupt delayed non-matching-to-position memory in rats.

Rats with radiofrequency lesions of the fimbria/fornix, or neurotoxic lesions of the mammillary bodies or the anterior thalamic nuclei were tested on their ability to perform a delayed non-matching-to-position task that had been learnt before surgery. In this task rats had to respond to a sample lever in an operant chamber and, after a variable delay (during which they were required to respond at the magazine tray), press the other lever when both were presented. Extensive mammillary body lesions had no effect on performance. In contrast, lesions in either the anterior thalamic nuclei or the fimbria/fornix produced marked deficits, the pattern of these deficits being consistent with a mnemonic impairment. It is argued that the anterior thalamic nuclei represent an important hippocampal output for spatial problems, but that the mammillary bodies are only necessary for certain types of mnemonic task.

Memory following cholinergic (NBM) and noradrenergic (DNAB) lesions made singly or in combination: potentiation of disruption by scopolamine.

Groups of rats were trained on either delayed matching or nonmatching to position tasks, then divided into four subgroups and given the following bilateral lesions: (a) SHAM [vehicle injection into the nucleus basalis magnocellularis (NBM) and dorsal noradrenergic bundle (DNAB)], (b) DNAB (6-hydroxydopamine lesion of the DNAB, vehicle into the NBM), (c) NBM (quisqualic acid lesion of the NBM, vehicle into the DNAB) and (d) DUAL (neurotoxin lesions of both DNAB and NBM). Following postoperative recovery, the DUAL lesion subjects were slightly impaired, but by the seventh day of testing all groups were performing at similar levels. This strongly suggests that quisqualate lesions of the NBM are not sufficient to produce severe and lasting mnemonic disorders resembling those seen in Alzheimer's disease (AD). These data also indicate that the noradrenergic system may not be of critical importance with respect to cognition. It was reasoned that an additional anticholinergic treatment might exacerbate an underlying deficiency. All groups were injected, peripherally, with the cholinergic antagonist scopolamine (0-0.5 mg/kg). This drug dose-dependently disrupted performance in all groups. Moreover, the highest dose had a marked effect in the DUAL group, impairing performance even when no mnemonic burden was present (at zero delay). The results suggest that cholinergic NBM and noradrenergic DNAB lesions produce only transient mnemonic deficiencies. A combination of the two can be disruptive, but longer term task (or reference) memory is the primary process affected, and only under certain conditions. The implication of these findings to research concerning animal models relating to Alzheimer's disease is discussed.

Fimbria-fornix lesions in aged rats cause increased carbachol-stimulated phosphoinositide hydrolysis in the hippocampus, but no change in muscarinic receptor binding.

Electrolytic lesions of the fimbria/fornix in 26-month-old rats led to an enhanced phosphoinositide (PI) hydrolysis in response to carbachol in hippocampal slices, 11-15 days after surgery. The lesions caused a 78% reduction of choline acetyltransferase but no change in muscarinic binding. The PI response to carbachol and the enhancement of this after lesioning were not as great as that previously reported in young adult rats.

Gallium-67 as a potential marker for aluminium transport in rat brain: implications for Alzheimer's disease.

Evidence of a link between aluminium and Alzheimer's disease, parkinsonism-dementia of Guam, and dialysis encephalopathy raises questions regarding the role of this element in the pathogenesis of these conditions. Therefore, we have investigated the use of gallium-67 (67Ga) as a marker for brain uptake of aluminium. The binding of 67Ga to plasma proteins has been studied, and the blood-brain barrier permeability and autoradiographic distribution of this isotope in rat brain determined in vivo. The autoradiographic distribution of 125I-Fe-transferrin receptors in rat brain has also been determined in vitro. Results show that 67Ga was bound to plasma transferrin, entered the brain with a blood-brain barrier permeability of 2.48 x 10(-6) ml/min/g, and showed a marked regional distribution that was very similar to that of 125I-Fe-transferrin receptors. Our data suggest that the vulnerability of the hippocampus, amygdala, and cerebral cortex in conditions such as those mentioned above may be partly due to an increased uptake and deposition of aluminium in these regions by the iron transport system.

Opposing effects of vasopressin on matching versus non-matching to position: further evidence for response, not memory, modulation.

Rats were trained on either of two related variants of an operant memory task. In the matching to position (MTP) task, one of two retractable response levers appeared, at random, as the sample. A response caused the lever to retract and this was followed by a delay (0-32 s) interval, during which the subjects had to approach and respond at the magazine tray. Both levers were then presented and the rat had to respond, for food reward, to the one which had appeared as the sample. A second group of rats learned non-matching to position (NMTP). This task was very similar to MTP, with one crucial difference: here, the subject had to respond to the lever which had not appeared as the sample. Both groups of rats learned their respective tasks rapidly, performance depending on the delay interval as expected. They were then injected, peripherally, with different doses of arginine-vasopressin (AVP: 0-25 micrograms/kg), a peptide which others have argued improves mnemonic performance. There was evidence to suggest that MTP performance was improved by AVP; on the other hand, NMTP performance appeared to be disrupted. It is suggested that AVP induces a bias towards responding on one side of the two lever test chamber. In other words, it affects motor or motivational, not mnemonic mechanisms.

Effects of nicotine, oxotremorine and 9-amino 1,2,3,4- tetrahydroacridine (tacrine) on matching and non matching to position in rats: no evidence for mnemonic enhancement.

Groups of rats were trained on one of two variants of an operant memory task which allows strength of memory (accuracy), bias and response rates to be measured directly. In matching to position (MTP), one of two retractable response levers appeared at random as the sample. A response caused the lever to retract and this was followed by a delay (0-64 s) interval, during which the rat had to approach, and respond at, the magazine tray. Both levers were then presented and the rat had to respond to the lever which had most recently appeared as the sample, for food reward. A second group of rats learned non-matching to position (NMTP). In this task, rats had to respond to the lever which had not appeared as the sample.The subjects were then divided into subgroups and injected, peripherally and prior to test, with one of three cholinergic drugs. These were nicotine (NIC: 0-0.3 mg/kg), oxotremorine (OXO: 0-0.3 mg/kg) and 9-amino 1,2,3,4-tetrahydroacridine (tacrine, THA: 0-3.0 mg/kg). NIC had a delay-independent disruptive effect on accuracy, but only in the non-matching version, and it did not affect rate of responding. OXO and THA had no effect on accuracy, but adversely affected response latencies and rates.The results suggest that these drugs do not affect memory mechanisms; instead, and at the doses used, certain types of bias may be induced (NIC) and general responsiveness altered (OXO and THA).

Increases in muscarinic stimulated hydrolysis of inositol phospholipids in rat hippocampus following cholinergic deafferentation are not parallelled by alterations in cholinergic receptor density.

The effect of electrolytic fimbria/fornix lesions on muscarinic receptor subtypes and putative nicotinic binding sites in the hippocampus has been studied using [3H]N-methylscopolamine, [3H]pirenzepine and [3H]L-nicotine, respectively. In parallel experiments the carbachol-stimulated hydrolysis of inositol phospholipids was measured after incorporation of [3H]inositol into hippocampal slice preparations. Ten days after lesioning there were no apparent changes in either receptor density or affinities despite extensive reductions in choline acetyltransferase. In contrast a significant increase in carbachol stimulated turnover of inositol phospholipids was measured. These observations suggest that whilst loss of cholinergic afferents may not affect receptor density per se, the efficacy of the post synaptic muscarinic receptors can be up-regulated at least in the short term.

[D-TRP11]-neurotensin, unlike alpha-flupenthixol, may not block amphetamine-induced hyperactivity in rats.

Recent reports have suggested that neurotensin (NT) and some of its analogues resemble neuroleptics, for example alpha-flupenthixol (FLU), in their ability to suppress locomotor activity. The results obtained support this conclusion, but only if total photocell counts (the "traditional" index) are considered. An improved method of measuring activity--where subjects have to interrupt photocell beams in sequence before a ("conditional") count is registered--suggested, in direct contrast to the total counts index, that the stable analogue of neurotensin [D-Trp11]-neurotensin (DTNT) increased activity slightly (Sahgal and Keith, 1986). The present report is on the effects of DTNT (0-8 microgram/rat, i.c.v.) and FLU (0-1 mg/kg, i.p.) on hyperactivity induced by D-amphetamine (1.5 mg/kg, i.p.). The usual total counts index of activity suggested that FLU and DTNT blocked the increase. On the other hand, conditional count data suggested that only FLU was effective. Both measures indicated that FLU and amphetamine, administered separately, suppressed and enhanced activity, respectively. In contrast, DTNT at these doses had no significant effect on the conditional counts but markedly suppressed total counts. Subsequent observation of DTNT-treated rats placed in small open fields, suggested that the peptide induced marked circling (ambulatory) behaviour, at the cost of other behavioural categories, especially rearing and grooming. It is argued that (a) DTNT may not resemble neuroleptics in its effects on motor behaviour and (b) conditional activity counts, and also measures relating to brief interruptions of photocell beams, can provide useful additional information concerning motor activity.