Joseph P . Huston - Profile on Academia.edu (original) (raw)

Papers by Joseph P . Huston

Pharmacology Biochemistry and Behavior, 2019

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist,... more D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine D 2/3 R binding in the brain of adult rats in relation to motor behavior. D 2/3 R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [ 123 I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased D 2/3 R binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased D 2/3 R binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of D 2/3 R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D 2/3 R binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA. D-cycloserine (DCS; D-4-amino-isoaxazolidinon) and amantadine (AMA; 1-amino-adamantane) act as N-methyl-D-aspartate (NMDA) receptor (R) agonist and antagonist, respectively. DCS binds with high affinity to the glycine B NMDAR subunit 1 (inhibition constant [K i ] = 2.33 ± 0.29 μM 2), and has proven beneficial for the treatment of psychiatric conditions, including schizophrenia 3 , major depressive disorder 4 , anxiety disorder 5,6 and autism 7. AMA binds to the phencyclidine NMDAR (K i = 10 μM 8) and to the opiate σ 1 R (K i = 20 μM 9). It is mainly applied for the treatment of L-DOPA induced dyskinesia and psychiatric symptoms of Parkinson's disease 10 , but may also ameliorate major depressive disorder 11 , traumatic brain injury 12 , refractory electrical status epilepticus 13 and multiple sclerosis fatigue 14 .

Frontiers in Neuroscience, 2021

Purpose: The 5-HT2A receptor (R) is known to modulate dopamine (DA) release in the mammalian brai... more Purpose: The 5-HT2A receptor (R) is known to modulate dopamine (DA) release in the mammalian brain. Altanserin (ALT) and 2,5-dimethoxy-4-iodoamphetamine (DOI) act as 5-HT2AR antagonist and agonist, respectively. In the present study, we assessed the effects of ALT and DOI on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. Methods: D2/3R binding was determined after systemic application of ALT (10 mg/kg) or DOI (0.5 mg/kg) and the respective vehicles [dimethyl sulfoxide (DMSO) and 0.9% saline (SAL)] with [123I]IBZM as a single-photon emission computed tomography (SPECT) radioligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after 5-HT2AR antagonistic or agonistic treatment, motor/exploratory behaviors were assessed for 45 (ALT) or 30 min (DOI) in an open field. Additional rats underwent behavioral measurements after injection of DMSO or SAL. Results: AL...

Handbook of behavioural neuroscience

Elsevier eBooks, 2007

Pharmacological Reports, 2020

Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, ... more Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, and thus, involved in the pathogenesis of several psychiatric and neurodegenerative disorders. However, little is known about the role of particular enzymes of the ceramide metabolism in the mechanisms of normal behavioral plasticity. Here, we studied the contribution of neutral ceramidase (NC), one of the main enzymes mediating ceramide degradation, in the mechanisms of learning and memory in rats and non-human primates. Methods Naïve Wistar rats and black tufted-ear marmosets (Callithrix penicillata) were tested in several tests for short- and long-term memory and then divided into groups with various memory performance. The activities of NC and acid ceramidase (AC) were measured in these animals. Additionally, anxiety and depression-like behavior and brain levels of monoamines were assessed in the rats. Results We observed a predictive role of NC activity in the blood serum for superi...

Hippocampal high-frequency (200 Hz) network synchronization is modulated by reinforcement learning

Acta Neurobiologiae Experimentalis, 2003

Neuroscience, Oct 1, 2015

Parkinson's disease (PD) patients not only exhibit motor impairments, but also characteristic def... more Parkinson's disease (PD) patients not only exhibit motor impairments, but also characteristic deficits in cognitive and affective functions. Such functions have consistently been associated with the medial prefrontal cortex (mPFC). To determine whether there is an interaction between the midbrain dopamine system (MDS) and the mPFC underlying the cognitive and emotional deficits seen in rats, we administered a disconnection procedure of these structures by applying lesions to the mPFC (N-methyl-D-aspartic acid (NMDA)) and the medial forebrain bundle (6-hydroxydopamine (6-OHDA)) either in the same or opposite hemispheres. The results indicate a functional interaction of the MDS and the mPFC: Disconnection effects on behavior were observed with respect to memory-, anxiety-and depression-related behaviors. A disconnection of the mPFC and MDS had promnestic, antidepressant-and anxiolyticlike effects. In order to determine whether this circuit between the mPFC and MDS involves serotonergic mechanisms, we also utilized serotonin-specific disconnections of the mPFC by applying the 5-HT-specific agent 5,7-dihydroxytryptamine (5,7-DHT) into the mPFC and 6-OHDA into the medial forebrain bundle, again either in the same or opposite hemispheres. The behavioral effects observed here resembled those incurred by the unspecific disconnection of the mPFC, demonstrating a significant contribution of serotonergic mechanisms to the interplay between the MDS and the mPFC. Taken together, these experiments provide evidence for an interaction of the MDS and the mPFC in the control of cognitive and affective processes known to be impaired in PD and point toward a prominent involvement of the serotonergic system. A disconnection of the mPFC and the MDS had promnestic, antidepressant-and anxiolytic-like behavioral effects. These findings may impact therapeutic approaches in the treatment of cognitive and neuropsychiatric symptoms seen in PD.

Automated Video-Image Analysis of Behavioral Asymmetries

Humana Press eBooks, 1996

... As indicated in the previous example, this is the typical ipsiversive asymmetry of animals wi... more ... As indicated in the previous example, this is the typical ipsiversive asymmetry of animals with severe unilateral DA Page 181. Automated Video-Image Analysis 161 PRE APO I APO II APO III APO IV TEST 1234 1234 1234 1234 1234 MINUTES 1234 Fig. ...

Distance from source of reward as a marker for extinction-induced “despair”: Modulation by the antidepressants clomipramine and citalopram

Neuroscience, Oct 1, 2012

Despair-related withdrawal behaviors are common symptoms of major depression (MD) and can be ascr... more Despair-related withdrawal behaviors are common symptoms of major depression (MD) and can be ascribed to a loss or absence of former rewarding events. Extinction of negatively reinforced escape behavior in the Morris Water Maze has been shown to induce despair-like behavior. A new animal model of depressive-like behavior is based on the extinction of positively reinforced behavior, which was shown to induce spatial avoidance of the former source of reward and biting of the operandum. Treatment with antidepressants attenuated these extinction-induced behaviors, suggesting that they reflect a depressive-like state. Here we present a methodological variation of this depression model. We employed an elongated operant chamber rather than a two-compartment procedure with the intent to establish a flowing gradient of withdrawal from the source of reward, rather than an all-or-none binary measure. Furthermore, instead of employing extinction of lever-pressing behavior, we applied a cued fixed-time food-delivery schedule. Sixty adult male Wistar rats (n=12/group) were trained to receive a food reward after appearance of a cue-light (fixed interval 90s) in an elongated Skinner-box of 72 cm length. Prior to extinction, the animals were treated for 9 days with either 7.5 or 10mg/kg of the tricyclic antidepressant clomipramine, 7.5 or 10mg/kg of the selective serotonin reuptake inhibitor (SSRI) citalopram or vehicle. Subsequent testing in an open field was carried out to investigate potential effects of the antidepressants on locomotor- and anxiety-like behavior. An overall increase in distance from the feeder and biting behavior was found over the course of the extinction trials. Both, citalopram and clomipramine decreased the distance from the pellet feeder during the initial extinction trials compared to the vehicle-treated group. The attenuation of withdrawal behavior by the antidepressants supports the hypothesis that avoidance/withdrawal behavior during extinction trials can serve as a marker for extinction-induced depression and suggests the utility of this paradigm as a rodent model of depression.

Antidepressants reduce extinction-induced withdrawal and biting behaviors: a model for depressive-like behavior

Neuroscience, May 1, 2012

The withholding of expected rewards results in extinction of behavior and, hypothetically, to dep... more The withholding of expected rewards results in extinction of behavior and, hypothetically, to depression-like symptoms. In a test of this hypothesis, we examined the effects of extinction of food-reinforced lever-pressing on collateral behaviors that might be indices of depression. Operant extinction is known to be aversive to the organism and results in avoidance behavior. We hypothesized that avoidance of, or withdrawal from, the former source of reward may serve as a marker for "despair." Adult male Wistar rats (n=6-7 animals per group) were exposed to a Skinner box attached to a second compartment of the same size, providing opportunity for the animals to leave the operant chamber and to enter the "withdrawal" compartment. The animals spent a portion of the time during the extinction trials in this second chamber. To assess the predictive validity of this behavior as a potential marker of "despair," we tested the effects of chronic administration of two common antidepressant drugs on this measure. The tricyclic antidepressant imipramine (20 mg/kg) as well as the selective serotonin reuptake inhibitor citalopram (20 mg/kg) reduced the number of entries and time spent in the withdrawal compartment. We propose that entries into and time spent in the withdrawal compartment may operationalize "avoidance," a core symptom of major depression. Rearing as well as biting behaviors during the extinction trials were also attenuated by the antidepressant treatment. These results lend support to the hypothesis that extinction of positively reinforced operants evokes behaviors that reflect elements of "despair/depression" because these behaviors are modulated by antidepressant treatment. The avoidance of the operant chamber as a consequence of extinction, together with rearing and biting behaviors, may serve as useful measures for the testing of antidepressant treatments.

A Dynamical Analysis via the Extended-Return-Map

Sleep, Apr 16, 2015

Studies on the GABA pathway. I. The inhibition of y-aminobutyric acid-a-ketoglutaric acid transam... more Studies on the GABA pathway. I. The inhibition of y-aminobutyric acid-a-ketoglutaric acid transaminase in vitro and in vivo by U-7524 (aminooxyacetic acid). Biochem. PharmacoI. 5: 523-331 (1961).

Experimental Brain Research, Oct 4, 1999

In the present study we analyzed the effect of continuous intraventricular infusion of the histam... more 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.

Pharmacological Reports, Sep 16, 2020

Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, ... more Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, and thus, involved in the pathogenesis of several psychiatric and neurodegenerative disorders. However, little is known about the role of particular enzymes of the ceramide metabolism in the mechanisms of normal behavioral plasticity. Here, we studied the contribution of neutral ceramidase (NC), one of the main enzymes mediating ceramide degradation, in the mechanisms of learning and memory in rats and non-human primates. Methods Naïve Wistar rats and black tufted-ear marmosets (Callithrix penicillata) were tested in several tests for short-and long-term memory and then divided into groups with various memory performance. The activities of NC and acid ceramidase (AC) were measured in these animals. Additionally, anxiety and depression-like behavior and brain levels of monoamines were assessed in the rats. Results We observed a predictive role of NC activity in the blood serum for superior performance of long-term object memory tasks in both species. A brain area analysis suggested that high NC activity in the ventral mesencephalon (VM) predicts better short-term memory performance in rats. High NC activity in the VM was also associated with worse long-term object memory, which might be mediated by an enhanced depression-like state and a monoaminergic imbalance. Conclusions Altogether, these data suggest a role for NC in short-and long-term memory of various mammalian species. Serum activity of NC may possess a predictive role in the assessing the performance of certain types of memory.

PLOS ONE, Sep 19, 2013

Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. el... more Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the aged mammalian brain, and whether a particular signature of aberrant proteostasis is related to behavioral performance of learning and memory. Young (adult, n = 30) and aged (2 years, n = 50) Wistar rats were tested in the Morris Water Maze (MWM) to distinguish superior and inferior performers. For both young and old rats, the best and worst performers in the MWM were selected and the insoluble proteome, termed aggregome, was purified from the hippocampus as evidence for aberrant proteostasis. Quantitative proteomics (iTRAQ) was performed. The aged inferior performers were considered as a model for spontaneous, age-associated cognitive impairment. Whereas variability of the insoluble proteome increased with age, absolute changes in the levels of insoluble proteins were small compared to the findings in the whole C. elegans insoluble proteome. However, we identified proteins with aberrant proteostasis in aging. For the cognitively impaired rats, we identified a changed molecular circuitry of proteins selectively involved in F-actin remodeling, synapse building and long-term depression: actin related protein 3 (ARP3), neurabin II (NEB2) and IQ motif and SEC7 domain-containing protein 1 (BRAG2). We demonstrate that aberrant proteostasis is a specific phenotype of brain aging in mammals. We identify a distinct molecular circuitry where changes in proteostasis are characteristic for poor learning and memory performance in the wild type, aged rat. Our findings 1. establish the search for aberrant proteostasis as a successful strategy to identify neuronal dysfunction in deficient cognitive behavior, 2. reveal a previously unknown functional network of proteins (ARP3, NEB2, BRAG2) involved in age-associated cognitive dysfunction.

Neutral Sphingomyelinase is an Affective Valence-Dependent Regulator of Learning and Memory

Cerebral Cortex, Oct 12, 2020

Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signalin... more Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signaling in the brain, but sphingolipid contribution to normal behavioral plasticity is little understood. Here we asked how the sphingolipid rheostat contributes to learning and memory of various dimensions. We investigated the role of these lipids in the mechanisms of two different types of memory, such as appetitively and aversively motivated memory, which are considered to be mediated by different neural mechanisms. We found an association between superior performance in short- and long-term appetitively motivated learning and regionally enhanced neutral sphingomyelinase (NSM) activity. An opposite interaction was observed in an aversively motivated task. A valence-dissociating role of NSM in learning was confirmed in mice with genetically reduced NSM activity. This role may be mediated by the NSM control of N-methyl-d-aspartate receptor subunit expression. In a translational approach, we confirmed a positive association of serum NSM activity with long-term appetitively motivated memory in nonhuman primates and in healthy humans. Altogether, these data suggest a new sphingolipid mechanism of de-novo learning and memory, which is based on NSM activity.

Functional Convergence of Motor and Social Processes in Lobule IV/V of the Mouse Cerebellum

The Cerebellum, Mar 4, 2021

Topographic organization of the cerebellum is largely segregated into the anterior and posterior ... more Topographic organization of the cerebellum is largely segregated into the anterior and posterior lobes that represent its “motor” and “non-motor” functions, respectively. Although patients with damage to the anterior cerebellum often exhibit motor deficits, it remains unclear whether and how such an injury affects cognitive and social behaviors. To address this, we perturbed the activity of major anterior lobule IV/V in mice by either neurotoxic lesion or chemogenetic excitation of Purkinje cells in the cerebellar cortex. We found that both of the manipulations impaired motor coordination, but not general locomotion or anxiety-related behavior. The lesioned animals showed memory deficits in object recognition and social-associative recognition tests, which were confounded by a lack of exploration. Chemogenetic excitation of Purkinje cells disrupted the animals’ social approach in a less-preferred context and social memory, without affecting their overall exploration and object-based memory. In a free social interaction test, the two groups exhibited less interaction with a stranger conspecific. Subsequent c-Fos imaging indicated that decreased neuronal activities in the medial prefrontal cortex, hippocampal dentate gyrus, parahippocampal cortices and basolateral amygdala, as well as disorganized modular structures of the brain networks might underlie the reduced social interaction. These findings suggest that the anterior cerebellum plays an intricate role in processing motor, cognitive and social functions.

Art, Aesthetics, and the Brain

Oxford University Press eBooks, Jun 1, 2015

SECTION ONE: FOUNDATIONAL ISSUES SECTION TWO: COGNITIVE NEUROSCIENCE OF VISUAL AESTHETICS AND ART... more SECTION ONE: FOUNDATIONAL ISSUES SECTION TWO: COGNITIVE NEUROSCIENCE OF VISUAL AESTHETICS AND ART SECTION THREE: COGNITIVE NEUROSCIENCE OF DANCE SECTION FOUR: COGNITIVE NEUROSCIENCE OF MUSIC SECTION FIVE: NEUROPSYCHOLOGY OF ART AND AESTHETICS SECTION SIX: THE EVOLUTION OF ART, AESTHETICS, AND THE BRAIN SECTION SEVEN: INTEGRATIVE APPROACHES

Intranasal dopamine treatment reinstates object-place memory in aged rats

Neurobiology of Learning and Memory, Oct 1, 2014

Following oral or IV administration, dopamine (DA) cannot cross the blood-brain barrier to a sign... more Following oral or IV administration, dopamine (DA) cannot cross the blood-brain barrier to a significant extent, but can enter the brain when administered via the nasal passages. Intranasal administration of DA was shown to increase extracellular DA in the striatum, to have antidepressant action and to improve attention and working memory in rats. Here we show that aged (22-24 months old) rats are deficient in an object-place learning task, but that this learning/memory is intact and comparable with that of adult rats upon pre-trial administration of 0.3 mg/kg DA gel into the nasal passages. This result raises the possibility of the therapeutic application of intranasal DA treatment for age-related cognitive disorders.

NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL/6 mice

Behavioural Pharmacology, May 1, 2003

The majority of N-methyl-D-aspartate receptors (NMDA-R) in the adult forebrain are di- or trihete... more The majority of N-methyl-D-aspartate receptors (NMDA-R) in the adult forebrain are di- or triheteromers composed of NR1, NR2A and NR2B subunits. Subunit non-selective NMDA-R antagonists produce anxiolytic-like effects together with motor and sensory side-effects. The graded anxiety test (GAT), permits the within-task distinction of drug effects on anxiety from those on activity and perception. By testing NMDA-R subunit selective agents in the GAT it might be possible to determine whether their effects on anxiety, activity and perception are interrelated, and whether separate NMDA-R subtypes are involved. Dextromethorphan (weakly NR2A-selective) (10 and 30 mg/kg, i.p.) and ifenprodil (highly NR2B-selective) (1, 3 and 5 mg/kg, i.p.) were tested in the GAT. Both drugs failed to induce anxiolysis devoid of side-effects. However, the 10 mg/kg dose of dextromethorpan showed an anxiolytic, whereas the 30 mg/kg dose showed an anxiogenic, behavioral profile. Since the selective blockade of the NR2B subunit by ifenprodil had no clear anxiolytic effect, the anxiolytic potential of NMDA subunit non-selective agents might involve NR2A-containing receptors.

Journal of Neural Transmission, Feb 1, 1994

The in vivomicrodialysis technique was used to measure extracellular concentrations of acetylchol... more The in vivomicrodialysis technique was used to measure extracellular concentrations of acetylcholine (ACh) in the neostriatum (NS) and nucleus accumbens (NAc) of freely moving rats after intraperitoneal administration of the muscarinic receptor antagonist scopolamine (0.5 mg/kg) or vehicle. Simultaneously, behavior was monitored. The administration of scopolamine induced an increase in extracellular ACh levels in the NS, which reached a maximum of about 185% within one hour after injection and returned to baseline values about three hours after injection. In the NAc, an increase of similar time-course was observed; however, this increase reached a maximum of 250%, which was significantly higher than the one observed in NS. These changes in ACh levels were accompanied by enhanced locomotion, rearing and grooming; however, the behavioral changes were of shorter time-course than those of extracellular ACh. The injection of vehicle did not affect ACh levels in NS, but induced a significant increase (60%) in the NAc. The levels of behavioral activity after vehicle injection did not differ from pre-injection levels. These results suggest, that the cholinergic systems in the NAc and NS are differently affected by peripheral administration of both scopolamine and vehicle. The differential effects of scopolamine in NS and NAc could reflect pharmacodynamic differences between these two striatal brain areas, perhaps due to a higher density of cholinergic interneurons or muscarinic autoreceptors in the NAc in comparsion to the NS. However, the increase of extracellular ACh observed after vehicle injection suggests that factors such as aversive stimulation through the injection procedure can increase ACh release in the NAc and that such a mechanism can interact within the action of scopolamine. Thus, the stronger action of scopolamine on extracellular ACh in the NAc might be an additive effect of the drug with that of the injection procedure. 14 M. Pfister et al.

Pharmacology Biochemistry and Behavior, 2019

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist,... more D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine D 2/3 R binding in the brain of adult rats in relation to motor behavior. D 2/3 R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [ 123 I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased D 2/3 R binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased D 2/3 R binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of D 2/3 R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D 2/3 R binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA. D-cycloserine (DCS; D-4-amino-isoaxazolidinon) and amantadine (AMA; 1-amino-adamantane) act as N-methyl-D-aspartate (NMDA) receptor (R) agonist and antagonist, respectively. DCS binds with high affinity to the glycine B NMDAR subunit 1 (inhibition constant [K i ] = 2.33 ± 0.29 μM 2), and has proven beneficial for the treatment of psychiatric conditions, including schizophrenia 3 , major depressive disorder 4 , anxiety disorder 5,6 and autism 7. AMA binds to the phencyclidine NMDAR (K i = 10 μM 8) and to the opiate σ 1 R (K i = 20 μM 9). It is mainly applied for the treatment of L-DOPA induced dyskinesia and psychiatric symptoms of Parkinson's disease 10 , but may also ameliorate major depressive disorder 11 , traumatic brain injury 12 , refractory electrical status epilepticus 13 and multiple sclerosis fatigue 14 .

Frontiers in Neuroscience, 2021

Purpose: The 5-HT2A receptor (R) is known to modulate dopamine (DA) release in the mammalian brai... more Purpose: The 5-HT2A receptor (R) is known to modulate dopamine (DA) release in the mammalian brain. Altanserin (ALT) and 2,5-dimethoxy-4-iodoamphetamine (DOI) act as 5-HT2AR antagonist and agonist, respectively. In the present study, we assessed the effects of ALT and DOI on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. Methods: D2/3R binding was determined after systemic application of ALT (10 mg/kg) or DOI (0.5 mg/kg) and the respective vehicles [dimethyl sulfoxide (DMSO) and 0.9% saline (SAL)] with [123I]IBZM as a single-photon emission computed tomography (SPECT) radioligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after 5-HT2AR antagonistic or agonistic treatment, motor/exploratory behaviors were assessed for 45 (ALT) or 30 min (DOI) in an open field. Additional rats underwent behavioral measurements after injection of DMSO or SAL. Results: AL...

Handbook of behavioural neuroscience

Elsevier eBooks, 2007

Pharmacological Reports, 2020

Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, ... more Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, and thus, involved in the pathogenesis of several psychiatric and neurodegenerative disorders. However, little is known about the role of particular enzymes of the ceramide metabolism in the mechanisms of normal behavioral plasticity. Here, we studied the contribution of neutral ceramidase (NC), one of the main enzymes mediating ceramide degradation, in the mechanisms of learning and memory in rats and non-human primates. Methods Naïve Wistar rats and black tufted-ear marmosets (Callithrix penicillata) were tested in several tests for short- and long-term memory and then divided into groups with various memory performance. The activities of NC and acid ceramidase (AC) were measured in these animals. Additionally, anxiety and depression-like behavior and brain levels of monoamines were assessed in the rats. Results We observed a predictive role of NC activity in the blood serum for superi...

Hippocampal high-frequency (200 Hz) network synchronization is modulated by reinforcement learning

Acta Neurobiologiae Experimentalis, 2003

Neuroscience, Oct 1, 2015

Parkinson's disease (PD) patients not only exhibit motor impairments, but also characteristic def... more Parkinson's disease (PD) patients not only exhibit motor impairments, but also characteristic deficits in cognitive and affective functions. Such functions have consistently been associated with the medial prefrontal cortex (mPFC). To determine whether there is an interaction between the midbrain dopamine system (MDS) and the mPFC underlying the cognitive and emotional deficits seen in rats, we administered a disconnection procedure of these structures by applying lesions to the mPFC (N-methyl-D-aspartic acid (NMDA)) and the medial forebrain bundle (6-hydroxydopamine (6-OHDA)) either in the same or opposite hemispheres. The results indicate a functional interaction of the MDS and the mPFC: Disconnection effects on behavior were observed with respect to memory-, anxiety-and depression-related behaviors. A disconnection of the mPFC and MDS had promnestic, antidepressant-and anxiolyticlike effects. In order to determine whether this circuit between the mPFC and MDS involves serotonergic mechanisms, we also utilized serotonin-specific disconnections of the mPFC by applying the 5-HT-specific agent 5,7-dihydroxytryptamine (5,7-DHT) into the mPFC and 6-OHDA into the medial forebrain bundle, again either in the same or opposite hemispheres. The behavioral effects observed here resembled those incurred by the unspecific disconnection of the mPFC, demonstrating a significant contribution of serotonergic mechanisms to the interplay between the MDS and the mPFC. Taken together, these experiments provide evidence for an interaction of the MDS and the mPFC in the control of cognitive and affective processes known to be impaired in PD and point toward a prominent involvement of the serotonergic system. A disconnection of the mPFC and the MDS had promnestic, antidepressant-and anxiolytic-like behavioral effects. These findings may impact therapeutic approaches in the treatment of cognitive and neuropsychiatric symptoms seen in PD.

Automated Video-Image Analysis of Behavioral Asymmetries

Humana Press eBooks, 1996

... As indicated in the previous example, this is the typical ipsiversive asymmetry of animals wi... more ... As indicated in the previous example, this is the typical ipsiversive asymmetry of animals with severe unilateral DA Page 181. Automated Video-Image Analysis 161 PRE APO I APO II APO III APO IV TEST 1234 1234 1234 1234 1234 MINUTES 1234 Fig. ...

Distance from source of reward as a marker for extinction-induced “despair”: Modulation by the antidepressants clomipramine and citalopram

Neuroscience, Oct 1, 2012

Despair-related withdrawal behaviors are common symptoms of major depression (MD) and can be ascr... more Despair-related withdrawal behaviors are common symptoms of major depression (MD) and can be ascribed to a loss or absence of former rewarding events. Extinction of negatively reinforced escape behavior in the Morris Water Maze has been shown to induce despair-like behavior. A new animal model of depressive-like behavior is based on the extinction of positively reinforced behavior, which was shown to induce spatial avoidance of the former source of reward and biting of the operandum. Treatment with antidepressants attenuated these extinction-induced behaviors, suggesting that they reflect a depressive-like state. Here we present a methodological variation of this depression model. We employed an elongated operant chamber rather than a two-compartment procedure with the intent to establish a flowing gradient of withdrawal from the source of reward, rather than an all-or-none binary measure. Furthermore, instead of employing extinction of lever-pressing behavior, we applied a cued fixed-time food-delivery schedule. Sixty adult male Wistar rats (n=12/group) were trained to receive a food reward after appearance of a cue-light (fixed interval 90s) in an elongated Skinner-box of 72 cm length. Prior to extinction, the animals were treated for 9 days with either 7.5 or 10mg/kg of the tricyclic antidepressant clomipramine, 7.5 or 10mg/kg of the selective serotonin reuptake inhibitor (SSRI) citalopram or vehicle. Subsequent testing in an open field was carried out to investigate potential effects of the antidepressants on locomotor- and anxiety-like behavior. An overall increase in distance from the feeder and biting behavior was found over the course of the extinction trials. Both, citalopram and clomipramine decreased the distance from the pellet feeder during the initial extinction trials compared to the vehicle-treated group. The attenuation of withdrawal behavior by the antidepressants supports the hypothesis that avoidance/withdrawal behavior during extinction trials can serve as a marker for extinction-induced depression and suggests the utility of this paradigm as a rodent model of depression.

Antidepressants reduce extinction-induced withdrawal and biting behaviors: a model for depressive-like behavior

Neuroscience, May 1, 2012

The withholding of expected rewards results in extinction of behavior and, hypothetically, to dep... more The withholding of expected rewards results in extinction of behavior and, hypothetically, to depression-like symptoms. In a test of this hypothesis, we examined the effects of extinction of food-reinforced lever-pressing on collateral behaviors that might be indices of depression. Operant extinction is known to be aversive to the organism and results in avoidance behavior. We hypothesized that avoidance of, or withdrawal from, the former source of reward may serve as a marker for "despair." Adult male Wistar rats (n=6-7 animals per group) were exposed to a Skinner box attached to a second compartment of the same size, providing opportunity for the animals to leave the operant chamber and to enter the "withdrawal" compartment. The animals spent a portion of the time during the extinction trials in this second chamber. To assess the predictive validity of this behavior as a potential marker of "despair," we tested the effects of chronic administration of two common antidepressant drugs on this measure. The tricyclic antidepressant imipramine (20 mg/kg) as well as the selective serotonin reuptake inhibitor citalopram (20 mg/kg) reduced the number of entries and time spent in the withdrawal compartment. We propose that entries into and time spent in the withdrawal compartment may operationalize "avoidance," a core symptom of major depression. Rearing as well as biting behaviors during the extinction trials were also attenuated by the antidepressant treatment. These results lend support to the hypothesis that extinction of positively reinforced operants evokes behaviors that reflect elements of "despair/depression" because these behaviors are modulated by antidepressant treatment. The avoidance of the operant chamber as a consequence of extinction, together with rearing and biting behaviors, may serve as useful measures for the testing of antidepressant treatments.

A Dynamical Analysis via the Extended-Return-Map

Sleep, Apr 16, 2015

Studies on the GABA pathway. I. The inhibition of y-aminobutyric acid-a-ketoglutaric acid transam... more Studies on the GABA pathway. I. The inhibition of y-aminobutyric acid-a-ketoglutaric acid transaminase in vitro and in vivo by U-7524 (aminooxyacetic acid). Biochem. PharmacoI. 5: 523-331 (1961).

Experimental Brain Research, Oct 4, 1999

In the present study we analyzed the effect of continuous intraventricular infusion of the histam... more 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.

Pharmacological Reports, Sep 16, 2020

Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, ... more Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, and thus, involved in the pathogenesis of several psychiatric and neurodegenerative disorders. However, little is known about the role of particular enzymes of the ceramide metabolism in the mechanisms of normal behavioral plasticity. Here, we studied the contribution of neutral ceramidase (NC), one of the main enzymes mediating ceramide degradation, in the mechanisms of learning and memory in rats and non-human primates. Methods Naïve Wistar rats and black tufted-ear marmosets (Callithrix penicillata) were tested in several tests for short-and long-term memory and then divided into groups with various memory performance. The activities of NC and acid ceramidase (AC) were measured in these animals. Additionally, anxiety and depression-like behavior and brain levels of monoamines were assessed in the rats. Results We observed a predictive role of NC activity in the blood serum for superior performance of long-term object memory tasks in both species. A brain area analysis suggested that high NC activity in the ventral mesencephalon (VM) predicts better short-term memory performance in rats. High NC activity in the VM was also associated with worse long-term object memory, which might be mediated by an enhanced depression-like state and a monoaminergic imbalance. Conclusions Altogether, these data suggest a role for NC in short-and long-term memory of various mammalian species. Serum activity of NC may possess a predictive role in the assessing the performance of certain types of memory.

PLOS ONE, Sep 19, 2013

Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. el... more Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the aged mammalian brain, and whether a particular signature of aberrant proteostasis is related to behavioral performance of learning and memory. Young (adult, n = 30) and aged (2 years, n = 50) Wistar rats were tested in the Morris Water Maze (MWM) to distinguish superior and inferior performers. For both young and old rats, the best and worst performers in the MWM were selected and the insoluble proteome, termed aggregome, was purified from the hippocampus as evidence for aberrant proteostasis. Quantitative proteomics (iTRAQ) was performed. The aged inferior performers were considered as a model for spontaneous, age-associated cognitive impairment. Whereas variability of the insoluble proteome increased with age, absolute changes in the levels of insoluble proteins were small compared to the findings in the whole C. elegans insoluble proteome. However, we identified proteins with aberrant proteostasis in aging. For the cognitively impaired rats, we identified a changed molecular circuitry of proteins selectively involved in F-actin remodeling, synapse building and long-term depression: actin related protein 3 (ARP3), neurabin II (NEB2) and IQ motif and SEC7 domain-containing protein 1 (BRAG2). We demonstrate that aberrant proteostasis is a specific phenotype of brain aging in mammals. We identify a distinct molecular circuitry where changes in proteostasis are characteristic for poor learning and memory performance in the wild type, aged rat. Our findings 1. establish the search for aberrant proteostasis as a successful strategy to identify neuronal dysfunction in deficient cognitive behavior, 2. reveal a previously unknown functional network of proteins (ARP3, NEB2, BRAG2) involved in age-associated cognitive dysfunction.

Neutral Sphingomyelinase is an Affective Valence-Dependent Regulator of Learning and Memory

Cerebral Cortex, Oct 12, 2020

Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signalin... more Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signaling in the brain, but sphingolipid contribution to normal behavioral plasticity is little understood. Here we asked how the sphingolipid rheostat contributes to learning and memory of various dimensions. We investigated the role of these lipids in the mechanisms of two different types of memory, such as appetitively and aversively motivated memory, which are considered to be mediated by different neural mechanisms. We found an association between superior performance in short- and long-term appetitively motivated learning and regionally enhanced neutral sphingomyelinase (NSM) activity. An opposite interaction was observed in an aversively motivated task. A valence-dissociating role of NSM in learning was confirmed in mice with genetically reduced NSM activity. This role may be mediated by the NSM control of N-methyl-d-aspartate receptor subunit expression. In a translational approach, we confirmed a positive association of serum NSM activity with long-term appetitively motivated memory in nonhuman primates and in healthy humans. Altogether, these data suggest a new sphingolipid mechanism of de-novo learning and memory, which is based on NSM activity.

Functional Convergence of Motor and Social Processes in Lobule IV/V of the Mouse Cerebellum

The Cerebellum, Mar 4, 2021

Topographic organization of the cerebellum is largely segregated into the anterior and posterior ... more Topographic organization of the cerebellum is largely segregated into the anterior and posterior lobes that represent its “motor” and “non-motor” functions, respectively. Although patients with damage to the anterior cerebellum often exhibit motor deficits, it remains unclear whether and how such an injury affects cognitive and social behaviors. To address this, we perturbed the activity of major anterior lobule IV/V in mice by either neurotoxic lesion or chemogenetic excitation of Purkinje cells in the cerebellar cortex. We found that both of the manipulations impaired motor coordination, but not general locomotion or anxiety-related behavior. The lesioned animals showed memory deficits in object recognition and social-associative recognition tests, which were confounded by a lack of exploration. Chemogenetic excitation of Purkinje cells disrupted the animals’ social approach in a less-preferred context and social memory, without affecting their overall exploration and object-based memory. In a free social interaction test, the two groups exhibited less interaction with a stranger conspecific. Subsequent c-Fos imaging indicated that decreased neuronal activities in the medial prefrontal cortex, hippocampal dentate gyrus, parahippocampal cortices and basolateral amygdala, as well as disorganized modular structures of the brain networks might underlie the reduced social interaction. These findings suggest that the anterior cerebellum plays an intricate role in processing motor, cognitive and social functions.

Art, Aesthetics, and the Brain

Oxford University Press eBooks, Jun 1, 2015

SECTION ONE: FOUNDATIONAL ISSUES SECTION TWO: COGNITIVE NEUROSCIENCE OF VISUAL AESTHETICS AND ART... more SECTION ONE: FOUNDATIONAL ISSUES SECTION TWO: COGNITIVE NEUROSCIENCE OF VISUAL AESTHETICS AND ART SECTION THREE: COGNITIVE NEUROSCIENCE OF DANCE SECTION FOUR: COGNITIVE NEUROSCIENCE OF MUSIC SECTION FIVE: NEUROPSYCHOLOGY OF ART AND AESTHETICS SECTION SIX: THE EVOLUTION OF ART, AESTHETICS, AND THE BRAIN SECTION SEVEN: INTEGRATIVE APPROACHES

Intranasal dopamine treatment reinstates object-place memory in aged rats

Neurobiology of Learning and Memory, Oct 1, 2014

Following oral or IV administration, dopamine (DA) cannot cross the blood-brain barrier to a sign... more Following oral or IV administration, dopamine (DA) cannot cross the blood-brain barrier to a significant extent, but can enter the brain when administered via the nasal passages. Intranasal administration of DA was shown to increase extracellular DA in the striatum, to have antidepressant action and to improve attention and working memory in rats. Here we show that aged (22-24 months old) rats are deficient in an object-place learning task, but that this learning/memory is intact and comparable with that of adult rats upon pre-trial administration of 0.3 mg/kg DA gel into the nasal passages. This result raises the possibility of the therapeutic application of intranasal DA treatment for age-related cognitive disorders.

NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL/6 mice

Behavioural Pharmacology, May 1, 2003

The majority of N-methyl-D-aspartate receptors (NMDA-R) in the adult forebrain are di- or trihete... more The majority of N-methyl-D-aspartate receptors (NMDA-R) in the adult forebrain are di- or triheteromers composed of NR1, NR2A and NR2B subunits. Subunit non-selective NMDA-R antagonists produce anxiolytic-like effects together with motor and sensory side-effects. The graded anxiety test (GAT), permits the within-task distinction of drug effects on anxiety from those on activity and perception. By testing NMDA-R subunit selective agents in the GAT it might be possible to determine whether their effects on anxiety, activity and perception are interrelated, and whether separate NMDA-R subtypes are involved. Dextromethorphan (weakly NR2A-selective) (10 and 30 mg/kg, i.p.) and ifenprodil (highly NR2B-selective) (1, 3 and 5 mg/kg, i.p.) were tested in the GAT. Both drugs failed to induce anxiolysis devoid of side-effects. However, the 10 mg/kg dose of dextromethorpan showed an anxiolytic, whereas the 30 mg/kg dose showed an anxiogenic, behavioral profile. Since the selective blockade of the NR2B subunit by ifenprodil had no clear anxiolytic effect, the anxiolytic potential of NMDA subunit non-selective agents might involve NR2A-containing receptors.

Journal of Neural Transmission, Feb 1, 1994

The in vivomicrodialysis technique was used to measure extracellular concentrations of acetylchol... more The in vivomicrodialysis technique was used to measure extracellular concentrations of acetylcholine (ACh) in the neostriatum (NS) and nucleus accumbens (NAc) of freely moving rats after intraperitoneal administration of the muscarinic receptor antagonist scopolamine (0.5 mg/kg) or vehicle. Simultaneously, behavior was monitored. The administration of scopolamine induced an increase in extracellular ACh levels in the NS, which reached a maximum of about 185% within one hour after injection and returned to baseline values about three hours after injection. In the NAc, an increase of similar time-course was observed; however, this increase reached a maximum of 250%, which was significantly higher than the one observed in NS. These changes in ACh levels were accompanied by enhanced locomotion, rearing and grooming; however, the behavioral changes were of shorter time-course than those of extracellular ACh. The injection of vehicle did not affect ACh levels in NS, but induced a significant increase (60%) in the NAc. The levels of behavioral activity after vehicle injection did not differ from pre-injection levels. These results suggest, that the cholinergic systems in the NAc and NS are differently affected by peripheral administration of both scopolamine and vehicle. The differential effects of scopolamine in NS and NAc could reflect pharmacodynamic differences between these two striatal brain areas, perhaps due to a higher density of cholinergic interneurons or muscarinic autoreceptors in the NAc in comparsion to the NS. However, the increase of extracellular ACh observed after vehicle injection suggests that factors such as aversive stimulation through the injection procedure can increase ACh release in the NAc and that such a mechanism can interact within the action of scopolamine. Thus, the stronger action of scopolamine on extracellular ACh in the NAc might be an additive effect of the drug with that of the injection procedure. 14 M. Pfister et al.