Differential effects of D-cycloserine and amantadine on motor behavior and D2/3 receptor binding in the nigrostriatal and mesolimbic system of the adult rat.

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 D2/3R binding in the brain of adult rats in relation to motor behavior. D2/3R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [123I]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 D2/3R 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 D2/3R 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 D2/3R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D2/3R 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.

Intranasal dopamine attenuates fear responses induced by electric shock to the foot and by electrical stimulation of the dorsal periaqueductal gray matter.

PURPOSE: Intranasally applied dopamine (IN-DA), which likely reaches the brain via nasal-brain pathways and bypasses the blood-brain barrier, has been found to increase extracellular DA and bind to the DA2 transporter in the striatum. Recent studies suggest that DA plays a significant role in the processing of signaled and unconditioned aversive stimulation, including evidence that may attenuate responses to painful input. The purpose of this study was to examine the effects of IN-DA on fear-related behaviors induced by electric shock to the foot or by electrical stimulation of the dorsal periaqueductal gray matter (dPAG). METHODS: DA hydrochloride suspended in a viscous castor oil gel (1 or 2 mg/kg) was applied (IN-DA) in a volume of 5 µL into the nostrils of adult Wistar male rats in order to evaluate its effects on (a) freezing induced by electric shock to the foot and (b) thresholds of freezing and escape and duration of post-stimulation freezing induced by electrical stimulation of the dPAG. RESULTS: IN-DA attenuated freezing induced by electric shock to the foot in the three test trials, indicating that it reduced long-term fear responses. IN-DA also increased the threshold of dPAG stimulation-induced escape responses and reduced post-stimulation freezing. CONCLUSIONS: IN-DA, which has previously been shown to facilitate learning and to have antidepressive-like effects, attenuated unconditioned fear responses elicited by peripheral and intramesencephalic (dPAG) stimulation and reduced long-term conditioned fear responses.

Anxiogenic-like behavior and deficient attention/working memory in rats expressing the human DISC1 gene.

In humans, mutations in the Disrupted-in-schizophrenia 1 (DISC1) gene have been related to psychiatric disorders, including symptoms of abnormal cognitive and emotional behaviors. In our previous studies, overexpression of the human DISC1 gene in rats resulted in schizophrenia-like phenotypes showing deficits in motor learning, impaired cognitive function and dysfunctions of the dopamine system. Here we asked, whether the DISC1 overexpression affects locomotor activity in the open field (OF), anxiety in the elevated plus-maze (EPM), depression-related behavior in the forced swim test (FST), and attention-like/short-term working-memory in the spontaneous alternation behavior (SAB) in the T-maze in transgenic DISC1 (tgDISC1) rats and littermate controls (WT). TgDISC1 rats showed enhanced anxiety behavior in the EPM and an impairment in attention-like/short-term working-memory in the SAB. However, tgDISC1 animals showed no locomotor impairments or depression-like behavior in the OF and FST. These results suggest that DISC1 overexpression leads to higher anxiety level and an attention-like/working-memory deficit. These findings may expand the causal role of DISC1 in its contribution to multiple symptom dimensions of psychiatric disorders.

Amantadine enhances nigrostriatal and mesolimbic dopamine function in the rat brain in relation to motor and exploratory activity.

PURPOSE: The present study assessed the influence of the NMDA receptor (R) antagonist amantadine (AMA) on cerebral dopamine D2/3R binding in relation to motor and exploratory activity in the rat. METHODS: D2/3R binding was determined in anaesthetized animals with small animal SPECT in baseline and after challenge with AMA (10 or 40 mg/kg) using [123I]IBZM as radioligand. Immediately post-challenge and prior to radioligand administration, motor/exploratory behaviors were assessed for 30 min in an open field. Each rat underwent measurements with a dedicated small animal MRI in order to gain anatomical information. Regions of interest were defined on SPECT-MRI overlays. The regional binding potentials in baseline and post-challenge were estimated by computing ratios of the specifically bound compartments to the cerebellar reference region. RESULTS: 40 mg/kg AMA reduced D2/3R binding in nucleus accumbens, caudateputamen and thalamus, while 10 mg/kg decreased D2/3R binding in the anterodorsal hippocampus. The higher dose decreased ambulatory activity, rearing and grooming, but elevated sitting and head-shoulder motility relative to both vehicle and the lower dose in the first 15 min post-challenge. CONCLUSIONS: Results showed reductions of D2/3R binding in regions of the nigrostriatal and mesolimbic system after challenge with AMA, which reflect an increased availability of dopamine. Thereby, an inverse relationship between nigrostriatal and mesolimbic dopamine and motor/exploratory activity can be inferred. Findings may be relevant for the treatment of neurological and psychiatric conditions such as Parkinson's disease, Huntington's disease or schizophrenia, which are characterized by both dopaminergic and glutamatergic dysfunction.

Fellow travellers: Working memory and mental time travel in rodents.

The impairment of mental time travel is a severe cognitive symptom in patients with brain lesions and a number of neuropsychiatric disorders. Whether animals are also able to mentally travel in time both forward and backward is still a matter of debate. In this regard, we have proposed a continuum of mental time travel abilities across different animal species, with humans being the species with the ability to perform most sophisticated forms of mental time travel. In this review and perspective article, we delineate a novel approach to understand the evolution, characteristics and function of human and animal mental time travel. Furthermore, we propose a novel approach to measure mental time travel in rodents in a comprehensive manner using a test battery composed of well-validated and easy applicable tests.

Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene.

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. RESULTS: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. CONCLUSIONS: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.

Intranasal administration of dopamine attenuates unconditioned fear in that it reduces restraint-induced ultrasound vocalizations and escape from bright light.

BACKGROUND: Although substantial evidence suggests that dopamine (DA) enhances conditioned fear responses, few studies have examined the role of DA in unconditioned fear states. Whereas DA does not cross the blood-brain barrier, intranasally-applied dopamine reaches the brain directly via the nose-brain pathways in rodents, providing an alternative means of targeting DA receptors. Intranasal dopamine (IN-DA) has been demonstrated to bind to DA transporters and to increase extracellular DA in the striatum as well as having memory-promoting effects in rats. The purpose of this study was to examine the influence of IN-DA in three tests of fear/anxiety. METHODS: The three doses of DA hydrochloride (0.03, 0.3, or 1 mg/kg) were applied in a viscous castor oil gel in a volume of 5 µl to each of both nostrils of adult Wistar rats prior to testing of (a) escape from a bright light, using a two-chamber procedure, (b) restraint-induced 22 kHz ultrasound vocalizations (USVs), and (c) exploratory behavior in the elevated plus-maze (EPM). RESULTS: IN-DA dose-dependently reduced escape from bright light and the number of USV responses to restraint. It had no influence on the exploratory behavior in the EPM. CONCLUSIONS: IN-DA application reduced escape behavior in two tests of unconditioned fear (escape from bright light and USV response to immobilization). These findings may be interpreted in light of the known antidepressant action of IN-DA and DA reuptake blockers. The results also confirm the promise of the nasal route as an alternative means for targeting the brain's dopaminergic receptors with DA.

GABAergic control of neostriatal dopamine D2 receptor binding and behaviors in the rat.

PURPOSE: The present study assessed the influence of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline on neostriatal dopamine D2 receptor binding in relation to motor and exploratory behaviors in the rat. METHODS: D2 receptor binding was measured in baseline and after challenge with either 1mg/kg muscimol or 1mg/kg bicuculline. In additional rats, D2 receptor binding was measured after injection of saline. After treatment with muscimol, bicuculline and saline, motor and exploratory behaviors were assessed for 30min in an open field prior to administration of [123I]S-3-iodo-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide ([123I]IBZM). For baseline and challenges, striatal equilibrium ratios (V3″) were computed as estimation of the binding potential. RESULTS: Muscimol but not bicuculline reduced D2 receptor binding relative to baseline and to saline. Travelled distance, duration of rearing and frequency of rearing and of head-shoulder motility were lower after muscimol compared to saline. In contrast, duration of rearing and grooming and frequency of rearing, head-shoulder motility and grooming were elevated after bicuculline relative to saline. Moreover, bicuculline decreased duration of sitting and head-shoulder motility. CONCLUSIONS: The muscimol-induced decrease of motor/exploratory behaviors can be related to an elevation of striatal dopamine levels. In contrast, bicuculline is likely to elicit a decline of synaptic dopamine, which, however, is compensated by the time of D2 receptor imaging studies. The results indicate direct GABAergic control over D2 receptor binding in the neostriatum in relation to behavioral action, and, thus, complement earlier pharmacological studies.

Neuronal histamine and cognitive symptoms in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder characterized by extracellular amyloid plaque deposits, mainly composed of amyloid-beta peptide and intracellular neurofibrillary tangles consisting of aggregated hyperphosphorylated tau protein. Amyloid-beta represents a neurotoxic proteolytic cleavage product of amyloid precursor protein. The progressive cognitive decline that is associated with Alzheimer's disease has been mainly attributed to a deficit in cholinergic neurotransmission due to the continuous degeneration of cholinergic neurons e.g. in the basal forebrain. There is evidence suggesting that other neurotransmitter systems including neuronal histamine also contribute to the development and maintenance of Alzheimer's disease-related cognitive deficits. Pathological changes in the neuronal histaminergic system of such patients are highly predictive of ensuing cognitive deficits. Furthermore, histamine-related drugs, including histamine 3 receptor antagonists, have been demonstrated to alleviate cognitive symptoms in Alzheimer's disease. This review summarizes findings from animal and clinical research on the relationship between the neuronal histaminergic system and cognitive deterioration in Alzheimer's disease. The significance of the neuronal histaminergic system as a promising target for the development of more effective drugs for the treatment of cognitive symptoms is discussed. Furthermore, the option to use histamine-related agents as neurogenesis-stimulating therapy that counteracts progressive brain atrophy in Alzheimer's disease is considered. This article is part of a Special Issue entitled 'Histamine Receptors'.

Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer's disease.

Dopamine plays an important role in learning and memory processes. A deficit of this neurotransmitter as it is apparent in Alzheimer's disease (AD) may contribute to cognitive decline, a major symptom of AD patients. The aim of this study was to elucidate whether or not stimulation of the dopaminergic system leads to an improvement of cognitive function and reduction of non-cognitive behavioral alterations in a murine model of AD. Transgenic and wild type male mice of the TgCRND8 line were treated either with the dopamine precursor levodopa or vehicle and tested in two learning tasks, the object-recognition task and the Barnes maze test. Additionally 24 h spontaneous behavior in the home cage was analyzed. In both memory tasks wild type mice performed significantly better than transgenics. However, transgenics treated with levodopa showed a significant object recognition memory and improved acquisition of spatial memory in the Barnes maze compared to vehicle treated transgenics. Concerning spontaneous behavior transgenic mice performed much more stereotypies than wild types. However, there was a trend for reduced stereotypies in the levodopa group in the time the drug was active. Neurochemical analysis revealed elevated levels of dopamine in the neostriata and frontal cortices and reduced levels in the hippocampi of transgenic mice compared to wild types. Thus cognitive deficits and stereotypies may be due to changes in the dopaminergic system as they could be ameliorated by levodopa treatment, that might also have a therapeutic significance for AD.

Unrestricted somatic stem cells from human umbilical cord blood can be differentiated into neurons with a dopaminergic phenotype.

Recently, it has been shown that human unrestricted somatic stem cells (USSCs) from umbilical cord blood represent pluripotent, neonatal, nonhematopoietic stem cells with the potential to differentiate into the neural lineage. However, molecular and functional characterization of the neural phenotype and evaluation of the degree of maturity of the resulting cells are still lacking. In this study, we addressed the question of neuronal differentiation and maturation induced by a defined composition of growth and differentiation factors (XXL medium). We demonstrated the expression of different neuronal markers and their enrichment in USSC cultures during XXL medium incubation. Furthermore, we showed enrichment of USSCs expressing tyrosine hydroxylase (TH), an enzyme specific for dopaminergic neurons and other catecholamine-producing neurons, accompanied by induction of Nurr1, a factor regulating dopaminergic neurogenesis. The functionality of USSCs has been analyzed by patch-clamp recordings and high-performance liquid chromatography (HPLC). Voltage-gated sodium-channels could be identified in laminin-predifferentiated USSCs. In addition, HPLC analysis revealed synthesis and release of the neurotransmitter dopamine by USSC-derived cells, thus correlating well with the detection of TH transcripts and protein. This study provides novel insight into the potential of unrestricted somatic stem cells from human umbilical cord blood to acquire a neuronal phenotype and function.

Increases in extracellular levels of 5-HT and dopamine in the basolateral, but not in the central, nucleus of amygdala induced by aversive stimulation of the inferior colliculus.

Consistent evidence has shown that dopamine release in the prefrontal cortex is increased by electrical stimulation of the inferior colliculus (IC) as unconditioned stimulus. Recent reports have also demonstrated that inactivation of the basolateral nucleus of the amygdala (BLA) with muscimol enhances the behavioural consequences of the aversive stimulation of the IC and reduces the dopamine release in the prefrontal cortex. Moreover, neurotoxic lesions of the BLA enhance whereas those of the central nucleus of the amygdala (CeA) reduce the aversiveness of the electrical stimulation of the IC. Based on these findings the present study examined the effects of the electrical stimulation of the IC on the extracellular levels of serotonin and dopamine in the BLA and CeA. To this end, rats implanted with a stimulation electrode in the IC also bore a microdialysis probe in the BLA or CeA for determination of the release of dopamine and serotonin. IC electrical stimulation at the freezing and escape thresholds increased the levels of serotonin ( approximately 70%) and dopamine ( approximately 60%) in the BLA related to the basal values. Similarly, the metabolites DOPAC and 5-HIAA increased in a parallel fashion in BLA. No significant changes could be detected in these biogenic amines and metabolites in CeA following IC aversive stimulation. These findings point to a differential role of serotonergic and dopaminergic mechanisms of the BLA and CeA in the setting up of adaptive responses to fear states generated at the inferior colliculus level.

Effects of chronic intraventricular infusion of heparin glycosaminoglycan on learning and brain acetylcholine parameters in aged rats.

We reported previously that the glycosaminoglycan heparin (HP) has the facility to improve learning in adult rodents when administered into the nucleus basalis of the ventral pallidum. Here we gauged the effects of chronic intraventricular infusion of HP (20 ng per day over 28 days) in 26-month-old rats in terms of Morris water maze performance, habituation to a novel open field, retention of a step-through inhibitory avoidance task and changes in forebrain acetylcholine (ACh) levels. Control groups included vehicle-infused old and adult (3-month-old) rats. The chronic infusion of HP did not significantly influence the performance of the old animals in any of the learning and memory tasks employed. HP only slightly facilitated the retention of the inhibitory avoidance task and the rate of habituation in the open-field paradigm. In the water maze, the glycosaminoglycan did not counteract the navigation deficits observed for aged controls and even impaired performance during the initial place-learning trials. After behavioural testing, tissue levels of ACh were determined in frontal cortex, ventral striatum, neostriatum and hippocampus without detecting any obvious neurochemical differences between groups. The current results, together with our previous work, indicate that HP differentially affects learning and memory parameters in adult and aged rats. Thus, whereas the glycosaminoglycan proved effective in facilitating mnemonic functions in normal adult animals, no such a clear-cut beneficial effect was observed in behaviourally impaired old rats.

The relevance of neuronal substrates of defense in the midbrain tectum to anxiety and stress: empirical and conceptual considerations.

The medial hypothalamus, amygdala, and dorsal periaqueductal gray constitute the main neural substrates for the integration of aversive states in the brain. More recently, some regions of the mesencephalon, such as the superior and inferior colliculi have also been proposed as part of this system. In fact, fear-like behaviors often result when these sites are electrically or chemically stimulated. Both the behavioral and autonomic consequences of electrical stimulation of the mesencephalic tectum have been shown to be attenuated by minor tranquilizers, probably through enhancement of gamma-aminobutyric acid (GABA)-mediated neurotransmission, which exerts a tonic inhibitory control on the neural circuits responsible for the so-called defense behavior repertoire. Besides GABA, also 5-hydroxy tryptamine serotonin (5-HT), opioids, neuropeptides, histaminergic and excitatory amino acids have all been implicated in the regulation of anxiety-related behaviors induced by stimulation of midbrain tectum. Efforts have been made to characterize how these neurotransmitters interact with each other in the organization of these reactions to aversive stimulation. In this review, we summarize the evidence linking the brain's defense response systems to the concept of fear-anxiety. Furthermore, a case is made for the consideration of the relevance of this body of data to the search for the physiological underpinnings of depression and its consequences.