Biomedical subjects

R U Hasenöhrl

Publications and source records attributed to R U Hasenöhrl.

At least 19 recordsLinked to original sources

PubMed2007

Impaired maze performance in aged rats is accompanied by increased density of NMDA, 5-HT1A, and alpha-adrenoceptor binding in hippocampus.

Using quantitative receptor autoradiography, we assessed binding site densities and distribution patterns of glutamate, GABA(A), acetylcholine (ACh), and monoamine receptors in the hippocampus of 32-month-old Fischer 344/Brown Norway rats. Prior to autoradiography, the rats were divided into two groups according to their retention performance in a water maze reference memory task, which was assessed 1 week after 8 days of daily maze training. The animals of the inferior group showed less long-term retention of the hidden-platform task but did not differ from superior rats in their navigation performance during place training and cued trials. The decreased retention performance in the group of inferior learners was primarily accompanied by increased alpha(1)-adrenoceptors in all hippocampal subregions under inspection (CA1-CA4 and dentate gyrus), while elevated alpha(2)-adrenoceptor binding was observed in the CA1 region and DG. Furthermore, inferior learners had higher NMDA binding in the CA2 and CA4 and increased 5-HT(1A) binding sites in the CA2, CA3, and CA4 region. No significant differences between inferior and superior learners were evident with regard to AMPA, kainate, GABA(A), muscarinergic M(1), dopamine D(1), and 5-HT(2) binding densities in any hippocampal region analyzed. These results show that increased NMDA, 5-HT(1A), and alpha-adrenoceptor binding in the hippocampus is associated with a decline in spatial memory. The increased receptor binding observed in the group of old rats with inferior maze performance might be the result of neural adaptation triggered by age-related changes in synaptic connectivity and/or synaptic activity.

Adrenergic Agents↗

PubMed2002

Learning deficits in aged rats related to decrease in extracellular volume and loss of diffusion anisotropy in hippocampus.

The extracellular space (ECS) is the microenvironment of the nerve cells and an important communication channel, allowing for long-distance extrasynaptic communication between cells. Changes in ECS size, geometry, and composition have been reported in diverse (patho)physiological states, including aging. In the present study, real-time tetramethylammonium (TMA+) iontophoresis was used to quantify ECS diffusion parameters in different brain regions of adult and behaviorally characterized aged rats. Prior to ECS diffusion measurement, superior and inferior learners were selected from a large group of aged rats, according to their performance in the open-field water maze. The main finding was that the degree of impaired maze performance of old rats correlates, firstly, with decrease in ECS volume, loss of diffusion anisotropy in hippocampus, and degree of astrogliosis, and secondly, with disorganization of the astrocytic processes and reduction of hippocampal ECS matrix molecules. Importantly, no significant differences were found in the density of neurons in any region of the hippocampus or dentate gyrus. The alterations in hippocampal diffusion parameters evident in aged animals with severe learning deficits could account for the learning impairment, due to their effects on extrasynaptic volume transmission and/or on the "cross-talk" between synapses, which has been suggested to be involved in neural processes associated with learning and memory formation.

Aging↗

PubMed2002

Enhanced conditioned inhibitory avoidance by a combined extract of Zingiber officinale and Ginkgo biloba.

Previous work has shown that intragastric administration of Zingicomb, a preparation consisting of Zingiber officinale and Ginkgo biloba extracts, has anxiolytic-like properties. The aim of the present study was to assess the effects of acute treatment with this preparation on inhibitory avoidance learning. The influence of pre-trial administered Zingicomb (ZC) on inhibitory avoidance conditioning was investigated in adult male Wistar rats, with a one-trial step-through avoidance task. The animals were treated intragastrically with either vehicle, 0.5, 1, 10 or 100 mg/kg ZC 60 min prior to the acquisition trial. When tested 24 h after training, rats which had received 10 mg/kg ZC exhibited significantly longer step-through latencies than vehicle treated animals. This result, thus, demonstrates the beneficial effects of Zingicomb on conditioned inhibitory avoidance. Unlike conventional anxiolytic drugs, such as the benzodiazepines, which tend to have amnesic properties, this phytopharmacon is a potent anxiolytic agent which, additionally, can facilitate performance on a learning task, indicating promising clinical applications.

Administration, Oral↗

PubMed2002

Facilitation of learning and modulation of frontal cortex acetylcholine by ventral pallidal injection of heparin glucosaminoglycan.

We examined the effects of heparin on learning and frontal cortex acetylcholine parameters following injection of the glucosaminoglycan into the ventral pallidum. In Experiment 1, possible mnemoactive effects of intrapallidal heparin injection were assessed. Rats with chronically implanted cannulae were administered heparin (0.1, 1.0, 10 ng) or vehicle (0.5 microl) and were tested on a one-trial step-through avoidance task. Two retention tests were carried out in each animal, one at 1.5 h after training to measure short-term memory and another at 24 h to measure long-term memory. Post-trial intrapallidal injection of 1.0 ng heparin improved both short- and long-term retention of the task, whereas the lower and the higher dose of the glucosaminoglycan had no effect. When the effective dose of heparin was injected 5 h, rather than immediately after training, it no longer facilitated long-term retention of the conditioned avoidance response. In Experiment 2, the effects of ventral pallidal heparin injection on frontal cortex acetylcholine and choline concentrations were investigated with in vivo microdialysis in anaesthetized rats. Heparin, administered in the dose of 1.0 ng, which was effective in facilitating avoidance performance, produced a delayed increase in cortical acetylcholine levels ipsi- and contralaterally to the side of intrabasalis injection, resembling the known neurochemical effects obtained for another glycosaminoglycan, chondroitin sulfate, which recently was shown to facilitate inhibitory avoidance learning and to increase frontal cortex acetylcholine. The present findings indicate that heparin, like other extracellular matrix proteoglycans, can exert beneficial effects on memory and strengthen the presumptive relationship between such promnestic effects of proteoglycans and basal forebrain cholinergic mechanisms. The data are discussed with respect to the presumed roles of matrix molecules in extrasynaptic volume transmission and in the 'cross-talk' between synapses.

Acetylcholine↗

PubMed2001

Comparison of intra-accumbens injection of histamine with histamine H1-receptor antagonist chlorpheniramine in effects on reinforcement and memory parameters.

Histaminergic neurons are located exclusively in the tuberomammillary nuclei (TM) of the hypothalamus from where they project to many regions of the brain including the basal ganglia. Earlier experiments led to the hypothesis that neuronal histamine (HA), particularly in relation to the H1 receptor, has an inhibitory role in learning and reward-related processes. Based on this premise, the objective of the present study was to compare HA with the H1-receptor antagonist d-chlorpheniramine (CPR) in effects on reinforcement and memory parameters after injection into different subregions of the rat nucleus accumbens (NAcc). In the first experiment, mnemoactive effects of CPR (0.1-10 microg) were assessed after injection into the caudal or rostral part of the NAcc with the one-trial uphill avoidance task as a measure of learning. The data show that intra-NAcc injection of CPR (10 microg) facilitated retention of the task, when the compound was administered immediately after training. This effect was evident only when CPR was administered into the caudal-shell but not into the rostral pole of the NAcc providing evidence for anatomical specificity of the intra-NAcc induced promotion of memory. In the second experiment, possible mnemonic and reinforcing effects of HA (0.001-1 microg) were gauged after injection of the amine into the caudal NAcc, using post-trial application in the uphill avoidance task to assess effects on learning and place preference as an index of reinforcing properties. The data show that caudal-NAcc injection of HA (0.1 microg) improved retention of the avoidance task and produced place preference indicative of a reinforcing action. The finding that intra-NAcc injection of HA can facilitate learning and has reinforcing effects is at variance with the proposed inhibitory nature of neuronal HA in reward-related processes. Thus, the disinhibition of reinforcement and facilitation of learning found earlier after partial destruction of TM-intrinsic neurons might not necessarily be related to a lesion-induced reduction of the HAergic tone. The observation that CPR has behavioral effects quite similar to HA suggests that the mnemoactive and reinforcing action of this compound might involve pharmacodynamic aspects beyond its antagonistic activity at H1-receptive sites.

Animals↗

PubMed2001

Hyperanxiety produced by periaqueductal gray injection of chondroitin sulphate glycosaminoglycan.

We examined the effects of chondroitin sulphate C (CSC) on fear and anxiety parameters following injection of the glycosaminoglycan into the dorsal periaqueductal gray. Rats with chronically implanted cannulae were administered CSC (0.4 or 4.0 nmol) or vehicle (saline, 0.2 microl) and exposed to the elevated plus-maze test of emotionality. Intra-periaqueductal gray injection of CSC produced a dose-dependent anxiogenic effect as indicated by reduced entries into and time spent on the open arms, fewer excursions into the end of the open arms and by increased stretched attend posture, flat back approach and closed arm peeping-out behaviour. The behavioural effects of CSC appeared to be anxioselective, since the glycosaminoglycan did not influence measures of general (exploratory) activity, such as number of entries into the enclosed arms and amount of scanning, rearing and grooming. The present results show that CSC can produce an anxiogenic-like profile after injection into the dorsal periaqueductal gray. This is the first such report implicating an endogenous matrix glycosaminoglycan in neural mechanisms governing fear and anxiety.

Animals↗

PubMed2001

Comparison of neurokinin SP with diazepam in effects on memory and fear parameters in the elevated T-maze free exploration paradigm.

The elevated T-maze was combined with a free exploration protocol, which, in contrast to the conventional procedure, dispenses with handling of the animals during the experimental sessions. This allows measurement of fear indexes derived from the elevated plus-maze as well as assessment of acquisition of open arm avoidance and open arm escape in one continuous session. Retention of the different fear-responses is measured 72 h later without drug treatment. In order to assess the effects of two known anxiolytics in this paradigm, rats received an IP injection of diazepam (1 to 4 mg/kg), substance P (5 to 500 microg/kg) or vehicle (1 ml/kg) and were tested on the T-maze for 5 min. Diazepam elevated open arm activity, indicative of an anxiolytic effect. The drug also increased the latency to escape from the open arms, but did not significantly affect acquisition of open arm avoidance. During the retention trial, diazepam in higher doses impaired the performance of both fear-responses, suggestive of an anterograde amnesic effect. Substance P did not influence acquisition and retention of open arm avoidance and escape. However, in high doses, the peptide increased the sojourn time in the central arena of the maze, indicating reduced fear and, hence, a dissociation between anxiolytic and amnesic effects. The present findings demonstrate that the elevated T-maze free exploration paradigm is sensitive to anxiolytic and memory-modulating effects of drugs.

Animals↗

PubMed2001

Repeated treatment with cholecystokinin octapeptide improves maze performance in aged Fischer 344 rats.

Previous studies have shown that sulfated cholecystokinin octapeptide (CCK-8S) can improve learning in adult rodents when administered systemically or into the central nucleus of amygdala. Here we analyzed the effect of repeated intraperitoneal (i.p.) injection of CCK-8S on the performance of 26-month-old Fischer 344 rats in different versions of the Morris water maze and in a rota-rod test of motor coordination. Old rats were injected daily with different doses of CCK-8S (0.32 to 8.0 microg/kg; IP) 10 min before the behavioral tests. Control groups included vehicle-injected old and adult (3-month-old) F 344 rats. To control for a possible development of tolerance to the behavioral effects of repeated CCK-8S administration, groups of aged rats were included which were subjected to an acute rather than a repeated CCK injection schedule. The repeated administration of CCK-8S did not influence the performance of the old rats in the hidden-platform version of the maze. In addition, the acute treatment with CCK-8S failed to modify navigation performance in this task, suggesting that drug-tolerance may not account for the lack of behavioral effects seen after repeated CCK-8S injection. During the "probe trial", the percentage of animals per group, which swam exactly across the former platform site, was markedly increased in aged rats treated repeatedly with 1.6 microg/kg CCK-8S. This might be indicative of improved retention of the prior platform location and/or a higher resistance of the learned escape response to extinction. The specificity of the effect of CCK-8S on processes related to spatial learning and memory is supported by the lack of effect on motor performance.

Age Factors↗

PubMed2000

Differential modulation of frontal cortex acetylcholine by injection of substance P into the nucleus basalis magnocellularis region in the freely-moving vs. the anesthetized preparation.

In vivo microdialysis was used to assess the effects of unilateral substance P (SP) injection into the nucleus basalis magnocellularis on extracellular levels of acetylcholine (ACh) in the frontal cortex, either in freely moving or urethane-anesthetized rats. The results show that the neurochemical effects of SP are critically dependent on the choice of the experimental preparation: In the freely-moving rat, the injection procedure led to behavioral and concurrent bilateral cholinergic activation in the frontal cortex. This cholinergic activation was ipsilaterally reduced by intrabasalis injection of SP (1 ng), indicating that the peptide exerted an inhibitory influence on the neurochemical effect exerted by handling, intracranial needle insertion, and vehicle injection. In the anesthetized preparation, SP had a biphasic dose-dependent action on cortical ACh: a short-lasting ipsilateral increase immediately after injection (especially with 1 ng), and a delayed bilateral increase after more than 2 h (10, 100 ng). The procedure of inserting the injection needle moderately increased cortical ACh levels. Methodologically, these data are discussed with respect to the importance of using anesthetized vs. freely moving rats and the effects of intraparenchymal injections.

Acetylcholine↗

PubMed2000

Anxiolytic-like effects in rats produced by ventral pallidal injection of both N- and C-terminal fragments of substance P.

Prior studies have shown that the neurokinin substance P (SP) has anxiolytic-like effects when administered into the nucleus basalis (NB) area of the rat ventral pallidum. The present work was performed to examine whether the anxiolytic effects of SP in the nucleus basalis can be assigned its amino (N)- or carboxy (C)-terminal moiety. Using the elevated plus-maze model of anxiety in combination with unilateral injection of N-terminal SP(1-7) or C-terminal SP(7-11) into the NB region, we found that the treatment with either SP-fragment increased the number of entries into and time spent on the open arms as well as excursions into the end of the open arms, indicative of an anxiolytic-like profile. Furthermore, the effective doses of SP(1-7) (0.67 ng) and SP(7-11) (0.45 ng) were equimolar to the dosage of the whole SP molecule (1 ng), which was effective to reduce anxiety. Thus, the results support earlier findings that ventral pallidal injection of SP has anxiolytic-like effects and provide new evidence that fragments of SP, representing the N- and C-terminal domain of the peptide can reduce fear-parameters at a concentration similar to that of the parent peptide.

Animals↗

PubMed2000

Facilitation of learning and long-term ventral pallidal-cortical cholinergic activation by proteoglycan biglycan and chondroitin sulfate C.

We have shown previously in the rat that biglycan, a recently discovered chondroitin sulfate proteoglycan, has neurotrophic effects which are mediated by its chondroitin/dermatan sulfate chains. Here we report that biglycan has neurochemical effects when injected into the nucleus basalis magnocellularis of the ventral pallidum, a site of dense cholinergic cell bodies. The effects on the cholinergic output in the frontal cortex are long lasting, indicating profound neuroactive function akin to that expected of a long-acting hormone. Injected into the same area of the brain, as well as into the ventricles in behaviorally impaired old animals, we found that biglycan can improve learning and memory in several behavioral paradigms. Furthermore, we show that both the neurochemical effectiveness as well as the promotion of learning is carried not by the proteoglycan per se, but rather by its chondroitin sulfate moiety, thus, demonstrating for the first time memory-promoting and neuroactive effects of a glycosaminoglycan, namely, chondroitin sulfate C. The results suggest that biglycan and other extracellular matrix molecules can have neurobehavioral and pharmacological functions for beyond those traditionally attributed to this class of molecules.

Acetylcholine↗

PubMed2000

Substance P and its role in neural mechanisms governing learning, anxiety and functional recovery.

The neurokinin Substance P (SP) is widely distributed in the central nervous system and has been extensively studied in various functional aspects. This review focuses on the behavioral relevance of SP. Here we show that SP can have memory-promoting, reinforcing and anxiolytic-like effects when administered systemically or into the nucleus basalis of the ventral pallidum. These effects seem to be mediated via the SP-preferring NK(1)receptor and differentially related to N- versus C-terminal fragments of the undecapeptide. Secondly, SP injection into the ventral pallidum can lead to increases of acetylcholine in frontal cortex and dopamine in nucleus accumbens, suggesting that the hypermnestic, positively reinforcing and anxiolytic effects observed upon basal forebrain injection of SP are mediated by activation of the nucleus accumbens-ventral pallidum circuitry. Furthermore, SP and certain SP-fragments may not only be considered to have beneficial behavioral effects in normal animals, but can also prevent lesion-induced functional deficits and improve the speed of recovery. This indicates that SP agonists might also have a neuroprotective capacity in parallel with recovery-promoting actions.

Animals↗

PubMed1999

The neurokinin-1 receptor antagonist WIN51,708 attenuates the anxiolytic-like effects of ventralpallidal substance P injection.

We reported previously that the neurokinin substance P has anxiolytic-like effects when administered into the nucleus basalis of the rat ventral pallidum. The present study aimed to determine the possible involvement of the neurokinin-1 receptor in the anxiolytic action of intrabasalis substance P injection. Behavioral testing was performed in the rat elevated plus-maze model of anxiety. Microinjection of substance P (1 ng) into the nucleus basalis increased sojourn times on the open arms, excursions into the end of the open arms and scanning over the edge of an open arm, indicative of an anxiolytic-like profile. The non-peptide neurokinin-1 receptor antagonist WIN51,708, administered i.p. 20 min prior to intrabasalis substance P injection, antagonized the anxiolytic effects of the neurokinin in a dose-dependent manner. WIN51,708 at 10 mg/kg diminished, while at the higher dose of 20 mg/kg the antagonist completely blocked, the effect of substance P on anxiety-related behaviors. These findings suggest that the anxiolytic-like effects of substance P in the nucleus basalis are mediated through neurokinin-1 receptive sites.

Androstanes↗

PubMed1999

Reinforcing effects of neurokinin substance P in the ventral pallidum: mediation by the tachykinin NK1 receptor.

The neurokinin substance P has reinforcing effects when administered into the nucleus basalis of the rat's ventral pallidum and these effects are encoded by its carboxy-terminal amino acid sequence. The present study examined the effect of prior treatment with the tachykinin NK1 receptor antagonist WIN51,708 on the conditioned place preference produced by intrabasalis injection of substance P and its carboxy-terminal heptapeptide analog dimethyl-C7. Pretreatment with WIN51,708 (10 and 20 mg/kg, i.p.) dose-dependently reversed the place preference produced by intrabasalis substance P (0.74 pmol). The carboxy-terminal analog dimethyl-C7 (0.74 pmol) was also found to act as a reinforcer following injection into the nucleus basalis region, but unlike for substance P, the behavioral effects of dimethyl-C7 could not be completely antagonized by joint administration of the NK1 antagonist. When injected alone, WIN51,708 did not influence the preference behavior. These findings suggest that the reinforcing effects of substance P in the nucleus basalis region might be mediated via NK receptive sites. The failure of WIN51,708 to completely antagonize the behavioral effects of dimethyl-C7 is interesting in the light of evidence, indicating that the carboxy-terminal substance P analog shows higher affinity for the tachykinin NK3 than for the NK1 receptor subtype.

Androstanes↗

PubMed1999

Enhanced learning by posttrial injection of H1-but not H2-histaminergic antagonists into the nucleus basalis magnocellularis region.

The aim of this study was to examine the effects of histaminergic antagonists on memory upon injection into the region of the nucleus basalis magnocellularis (NBM). In experiment 1, rats with chronically implanted cannulae were trained on the uphill avoidance task, which involves a punishment of a high-probability turning response on a tilted platform (negative geotaxis). Immediately after the training trial, that is, after a tail shock was administered upon performing the response, rats received one microinjection (0.5 microliter) of H1-receptor blocker chlorpheniramine (dose range 0.1 to 20 microgram) or the H2-receptor blocker ranitidine (same dose range) or saline into the NBM region. When tested 24 h later, rats treated with chlorpheniramine (20 micrograms) had significantly longer uphill latencies than vehicle controls and ranitidine-treated animals, indicative of superior learning of the avoidance response. In experiment 2, a test for possible proactive effects of posttrial chlorpheniramine on performance during the retention trial was performed. Animals were injected with either 20 micrograms chlorpheniramine or saline immediately after the training trial of the uphill task. One chlorpheniramine control group was treated with a delay of 5 h. Additional groups which received chlorpheniramine or vehicle after the training trial but no trail shock were included. When tested 24 h later, rats injected with 20 micrograms chlorpheniramine again exhibited significantly longer uphill latencies than did vehicle-injected rats. Retention latencies for the rats of the chlorpheniramine 5-h delayed group did not differ from those of the vehicle-injected rats, ruling out proactive effects of chlorpheniramine on performance. In summary, the histaminergic H1-blocker chlorpheniramine can enhance mnemonic functioning in addition to its reinforcing effects upon NBM injection as reported previously.

Animals↗

PubMed1999

Memory improvement by post-trial injection of lidocaine into the tuberomammillary nucleus, the source of neuronal histamine.

Brain histamine is exclusively contained within and released from neurons whose cell bodies are clustered in the tuberomammillary nucleus (TM) of the posterior hypothalamus. This experiment examined the effects of a transient inactivation of the TM on inhibitory avoidance learning. Rats with chronically implanted cannulae were tested on a 1-trial step-through avoidance task. Immediately following training, the rats received unilateral intra-TM infusions (0.5 microl) of lidocaine (5 or 20 microg). Control groups included vehicle-injected rats and a group given an injection of 20 microg lidocaine 5 h after training. When tested 24 h later, rats treated with 20 microg lidocaine exhibited longer step-through latencies than vehicle-treated controls, indicative of superior learning of the task. The failure of the delayed post-trial injection of lidocaine to significantly influence step-through latencies indicates that the compound influenced learning by modulating memory storage processes rather than by acting on performance variables during retrieval of the task. Thus, inactivation of the TM by lidocaine can exert facilitatory effects on mnemonic processing, which might be related to a temporary reduction of histaminergic activity during the early phase of memory consolidation.

Anesthetics, Local↗

PubMed1999

Intraventricular infusion of the histamine H(1) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats.

In the present study we analyzed the effect of continuous intraventricular infusion of the histamine H(1) receptor antagonist d-chlorpheniramine on the performance of 32-month-old Fischer 344/Brown Norway F1 hybrid rats in the place version of the Morris water maze and in two different tests of anxiety (open field and black-and-white exploration). Control groups included vehicle-infused old and adult (3-month-old) F1 hybrids. Chronic infusion of chlorpheniramine improved the maze performance of the old rats and reduced fear-related behaviors in the open field and black-and-white box. Furthermore, long-term administration of chlorpheniramine was found to diminish age-related deficits in motor capacities. The findings substantiate that histamine H(1)-receptive sites are involved in learning and fear-related processes and indicate that hypomnesia and hyperanxiety seen in the course of brain aging may be based, in part, on hyperactivation of the central histaminergic neuron system. Furthermore, the data contribute to the behavioral characterization of the Fischer 344/Brown Norway F1 hybrid rat in the context of behavioral gerontopharmacology.

Aging↗

PubMed1998

Anxiolytic-like action of neurokinin substance P administered systemically or into the nucleus basalis magnocellularis region.

There is evidence that the neurokinin substance P plays a role in neural mechanisms governing learning and reinforcement. Reinforcing and memory-promoting effects of substance P were found after it was injected into several parts of the brain and intraperitoneally. With regard to the close link between anxiety and memory processes for negative reinforcement learning, the aim of the present study was to gauge the effect of substance P on anxiety-related behaviors in the rat elevated plus-maze and social interaction test. Substance P was tested at injection sites where the neurokinin has been shown to promote learning and to serve as a reinforcer, namely in the periphery (after i.p. administration) and after injection into the nucleus basalis magnocellularis region. When administered i.p., substance P had a biphasic dose-response effect on behavior in the plus-maze with an anxiolytic-like action at 50 microg/kg and an anxiogenic-like one at 500 microg/kg. After unilateral microinjection into the nucleus basalis magnocellularis region, substance P (1 ng) was found to exert anxiolytic-like effects, because substance P-treated rats spent more time on the open arms of the plus-maze and showed an increase in time spent in social interaction. Furthermore, the anxiolytic effects of intrabasalis substance P were sequence-specific since injection of a compound with the inverse amino acid sequence of substance P (0.1 to 100 ng) did not influence anxiety parameters. These results show that substance P has anxiolytic-like properties in addition to its known promnestic and reinforcing effects, supporting the hypothesis of a close relationship between anxiety, memory and reinforcement processes.

Animals↗