Abstract: Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise.
Abstract: In this study the immediate-early gene Fos was used to investigate the response to different novel stimuli in a wide array of brain regions including the hippocampus, the rhinal cortex, the frontal cortex and different components of the striatal complex. Independent groups of CD-1 mice were exposed to three different novelty conditions: (1) novel environment (empty open field); (2) complex novel environment (i.e. open field containing objects); and (3) identity-based detection of novel objects. We observed that a complex novel environment and a knowledge-based novelty modulated Fos levels in both the dorsal and the ventral components of the striatum, while Fos immunoreactivity in the medial temporal lobe was only increased after exposure to novel environments, regardless of their complexity. Finally, we observed a strong increase of Fos levels in the prefrontal cortex in all the three novel conditions examined, indicating a major involvement of this structure in novelty assessment. Overall the present study demonstrates that distinct brain regions are recruited in different kinds of novelty and emphasizes the role of the striatal complex in processing complex novel information.
Abstract: Several studies have demonstrated that exposure to both acute and chronic aversive stimuli can affect neural activity in different brain areas. In particular it has been shown that stressful events can induce not only short-term changes in neural transmission and gene regulation, but also long-term changes that can lead to structural modification. In this study we investigated, in CD1 mice, the effects of single or repeated exposures to restraint stress (2h for 1 or 5 consecutive days) in the frontal cortex on a crucial class of gene expression regulators, the microRNAs (miRs).First we performed a microarray profiling on RNA extracted from the frontal cortex of mice exposed to acute or repeated restraint stress. The results indicated a prominent increase in the expression levels of different miRs after acute stress while only minor changes were observed after repeated restraint. The Northern blot analysis on selected miRs confirmed an increase after acute restraint for let-7a, miR-9 and miR 26-a/b. Finally, Northern blot analysis of the selected miRs on RNA extracted from the hippocampus of stressed mice demonstrated that such changes were region specific, as no differences were observed in the hippocampus. These data suggest that control of mRNA translation through miRs is an additional mechanism by which stressful events regulates protein expression in the frontal cortex.
Abstract: Spatial memory formation is a dynamic process requiring a series of cellular and molecular steps, such as gene expression and protein translation, leading to morphological changes that have been envisaged as the structural bases for the engram. Despite the role suggested for medial temporal lobe plasticity in spatial memory, recent behavioral observations implicate specific components of the striatal complex in spatial information processing. However, the potential occurrence of neural plasticity within this structure after spatial learning has never been investigated. In this study we demonstrate that blockade of cAMP response element binding protein-induced transcription or inhibition of protein synthesis or extracellular proteolytic activity in the ventral striatum impairs long-term spatial memory. These findings demonstrate that, in the ventral striatum, similarly to what happens in the hippocampus, several key molecular events crucial for the expression of neural plasticity are required in the early stages of spatial memory formation.
Abstract: Visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson's disease (PD), and they are frequently associated to motor symptoms in the early stages of the disease when dopamine loss is moderate and still restricted to the caudate-putamen. The metabotropic glutamate receptor 5 (mGluR5) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has beneficial effects on motor symptoms in animal models of PD. However, the effects of MPEP on the cognitive deficits of the disease have never been investigated. Thus, the purpose of this study was to explore its therapeutic potentials by investigating its effects on the visuo-spatial deficits induced by 6-hydroxydopamine (6-OHDA) lesions of dorsal striatum in CD1 mice. The results demonstrated that systemic injections of MPEP (6, 12, and 24 mg/kg, i.p.) impair visuo-spatial discrimination in intact mice at high concentrations, whereas lower doses (1.5 and 3 mg/kg, i.p.) were void of effects. Nevertheless, when an ineffective dose (MPEP 3 mg/kg) was injected, either acutely or subchronically (8 days), it antagonized the visuo-spatial discrimination deficit induced by bilateral dopamine lesion of the striatum. Furthermore, the same treatment increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion. These results confirm the therapeutic potential of mGluR5 blockade on motor symptoms induced by reduced striatal dopamine function. Further, they demonstrate that mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion.
Abstract: Recent evidence demonstrated that dopamine within the nucleus accumbens mediates consolidation of both associative and nonassociative memories. However, the specific contribution of the nucleus accumbens subregions, core and shell, and of D1 and D2 receptors subtypes has not been yet clarified. The aim of this study was, therefore, to directly compare the effect of D1 and D2 dopamine receptor blockade within the core and the shell subregions of the nucleus accumbens on memory consolidation. Using the one-trial inhibitory avoidance task in CD1 mice, we demonstrated that SCH 23390 (vehicle, 12.5, 25, 50 ng/side) administration within the core, but not the shell, impaired step-through latency 24 h after the administration if injected immediately, but not 120 min post-training. Interestingly, sulpiride (vehicle, 25, 50 ng/side) injection in both the core and the shell of the accumbens affected step-through latency 24 h later; also, in this case the impairment was time dependent. These data provide the most complete and direct demonstration to date that early consolidation of aversive memory requires D2 receptor activation in both nucleus accumbens subregions, and D1 activation selectively in the nucleus accumbens core.
Abstract: Glutamatergic transmission within the nucleus accumbens (Nac) is considered to subserve the transfer of different types of information from the cortical and limbic regions. In particular, it has been suggested that glutamatergic afferences from the hippocampus and the prefrontal cortex provide the main source of contextual information to the Nac. Accordingly, several authors have demonstrated that the blockade of glutamate receptors within the Nac impairs various spatial tasks. However, the exact role of the different classes of glutamate receptors within the Nac in short-term spatial memory is still not clear. In this study we investigated the involvement of two major classes of glutamate receptors, NMDA and AMPA receptors, within the Nac in the acquisition of spatial information, using the Morris water maze task. Focal injections of the NMDA antagonist, AP-5 (0.1 and 0.15 microg/side), and the AMPA antagonist, DNQX (0.005, 0.01 microg/side), were performed before a massed training phase, and mice were tested for retention immediately after. NMDA and AMPA receptor blockade induced no effect during training. On the contrary, injection of the two glutamatergic antagonists impaired spatial localization during the probe test. These data demonstrate an involvement of the Nac in short-term spatial learning. Moreover, they prove that within this structure the short-term processing of spatial information needs the activation of both NMDA and AMPA receptors.
Abstract: Drugs activating group III metabotropic glutamate receptors (mGluRs) represent therapeutic alternatives to L-DOPA (L-3,4-dihydroxyphenylalanine) for the treatment of Parkinson's disease (PD). Their presynaptic location at GABAergic and glutamatergic synapses within basal ganglia nuclei provide a critical target to reduce abnormal activities associated with PD. The effects of selective group III mGluR agonists (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) infused into the globus pallidus (GP) or the substantia nigra pars reticulata (SNr) were thus studied in rat models of PD. Bilateral infusions of ACPT-I (1, 2.5, and 5 nmol/microl) into the GP fully reverse the severe akinetic deficits produced by 6-hydroxydopamine nigrostriatal dopamine lesions in a reaction-time task without affecting the performance of controls. Similar results were observed after L-AP4 (1 nmol) or picrotoxin, a GABA(A) receptor antagonist, infused into the GP. In addition, intrapallidal ACPT-I counteracts haloperidol-induced catalepsy. This effect is reversed by concomitant administration of a selective group III receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine. In contrast, ACPT-I (0.05, 0.1, and 0.25 nmol) infusions into the SNr enhance the lesion-induced akinetic deficits in control and lesioned rats and do not reverse haloperidol-induced catalepsy. L-AP4 (0.05 nmol) and picrotoxin in the SNr produce the same effects. Together, these results show that activation of group III mGluRs in the GP provides benefits in parkinsonian rats, presumably by modulating GABAergic neurotransmission. The opposite effects produced by group III mGluR activation in the SNr, also observed with a selective mGluR8 agonist, support the use of subtype-selective group III mGluR agonists as a potential antiparkinsonian strategy.
Abstract: Accumulating evidence in humans demonstrated that visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson disease (PD). These deficits have been generally attributed to cortical dopamine degeneration. However, more recent evidence suggests that dopamine loss in the striatum is responsible for the visuo-spatial abnormalities in PD. Studies based on animal models of PD did not specifically address this question.
Abstract: Profilins are actin binding proteins essential for regulating cytoskeletal dynamics, however, their function in the mammalian nervous system is unknown. Here, we provide evidence that in mouse brain profilin1 and profilin2 have distinct roles in regulating synaptic actin polymerization with profilin2 preferring a WAVE-complex-mediated pathway. Mice lacking profilin2 show a block in synaptic actin polymerization in response to depolarization, which is accompanied by increased synaptic excitability of glutamatergic neurons due to higher vesicle exocytosis. These alterations in neurotransmitter release correlate with a hyperactivation of the striatum and enhanced novelty-seeking behavior in profilin2 mutant mice. Our results highlight a novel, profilin2-dependent pathway, regulating synaptic physiology, neuronal excitability, and complex behavior.
Abstract: Behaviourally relevant novel stimuli are known to activate the mesocorticolimbic dopaminergic (DAergic) system. In this study we tested the reactivity of this system in response to distinct kinds of novelty processing. Using the in vivo microdialysis technique, we measured extracellular amounts of dopamine (DA) in different DAergic terminal regions during a social learning task in rats. In the first session (40 min) rats were exposed to two never previously encountered juveniles (i.e. unconditional novelty). Afterwards, the animals were divided into three groups: Control group was not exposed to any other stimulus; Discrimination group was exposed to one familiar and one new juvenile (i.e. novel stimulus discrimination); and Recognition group was re-exposed to the two familiar juveniles (i.e. familiarity recognition). In both the medial prefrontal cortex and the nucleus accumbens shell DA increased in response to the first presentation of the juveniles, showing that both structures are involved in processing unconditional social novelty. During the novel stimulus discrimination, we found no change in the prefrontal cortex, although DA increased in the accumbal shell in comparison with the group exposed to two familiar juveniles, showing that the shell is also involved in processing novel social stimulus discrimination. None of the stimuli presented affected DA in the accumbal core. This study provided the original evidence that DA in the various terminal regions is differentially coupled to distinct aspects of novelty processing.
Abstract: There is now accumulating evidence that the striatal complex in its two major components, the dorsal striatum and the nucleus accumbens, contributes to spatial memory. However, the possibility that different striatal subregions might modulate specific aspects of spatial navigation has not been completely elucidated. Therefore, in this study, two different learning procedures were used to determine whether the two striatal components could be distinguished on the basis of their involvement in spatial learning using different frames of reference: allocentric and egocentric. The task used involved the detection of a spatial change in the configuration of four objects placed in an arena, after the mice had had the opportunity to experience the objects in a constant position for three previous sessions. In the first part of the study we investigated whether changes in the place where the animals were introduced into the arena during habituation and testing could induce a preferential use of an egocentric or an allocentric frame of reference. In the second part of the study we performed focal injections of the N-methyl-d-aspartate (NMDA) receptors' antagonist, AP-5, within the two subregions immediately after training. The results indicate that using the two behavioral procedures, the animals rely on an egocentric and an allocentric spatial frame of reference. Furthermore, they demonstrate that AP-5 (37.5, 75, and 150 ng/side) injections into the dorsal striatum selectively impaired consolidation of spatial information in the egocentric but not in the allocentric procedure. Intra-accumbens AP-5 administration, instead, impaired animals trained using both procedures.
Abstract: The nucleus accumbens receives glutamatergic and dopaminergic inputs converging onto common dendrites. Recent behavioral data demonstrated that intra-accumbens administrations of either glutamate or dopamine (DA) antagonist impair spatial memory consolidation. Thus, also based on the biochemical and molecular findings demonstrating interactions among the different receptors subtypes for glutamate and dopamine, it is conceivable that memory consolidation within this structure might be modulated by glutamate-dopamine receptor interactions.
Abstract: Nucleus accumbens dopamine is known to play an important role in motor activity and in behaviours governed by drugs and natural reinforcers, as well as in non-associative forms of learning. At the same time, activation of D1 and D2 dopamine receptors has been suggested to promote intracellular events related to neural plasticity. Therefore, in this study we wished to investigate the role of the two classes of dopamine receptors within the nucleus accumbens on the consolidation of spatial information. On day 1, CD1 male mice were placed in an open field containing five different objects and, immediately after three sessions of habituation, the animals were focally injected within the nucleus accumbens with either the D1 antagonist SCH 23390 (12.5, 25 or 50 ng/side), or the D2 antagonist sulpiride (25, 50, 75 or 100 ng/side). Twenty-four hours later the ability of mice to discriminate an object displacement was assessed. Both the D1 and the D2 antagonists impaired the ability of mice to detect the spatial change. If the highest doses of the two antagonists were injected 2 h after the end of the last of the habituation sessions, no effect was observed in the reactivity to spatial change examined 24 h later. These data demonstrate that activation of both D1 and D2 receptors within the accumbens is necessary in the early stages of the consolidation of spatial information. The data are discussed in terms of involvement of nucleus accumbens dopamine in information processing in the absence of explicit reinforcers.
Abstract: We used the cDNA microarray technique to monitor simultaneously possible changes induced by hypergravity in the expression level of thousands of hippocampal genes. We tested the mRNA level of about 5000 genes in the hippocampus of mice subjected to 1.09 g (1g) or to 1.85 g (2g) for five repeated 1-h daily rotations in a centrifuge (g = 9.81 m/s2). Data were compared with those obtained for mice kept stationary (C). The ratios 1g/C and 2g/C identified genes affected by rotation and rotation + hypergravity, respectively, whereas 2g/1g ratio identified those affected by hypergravity. We found that about 200 genes were affected by rotation and/or rotation + hypergravity. Almost all the genes affected by rotation + hypergravity were up-regulated, only five being down-regulated. The modulated genes code for proteins involved in a wide range of cellular functions (DNA/RNA metabolism, protein processing, intermediate metabolism, cytoskeleton and motility, cell cycle and apoptosis, signal transduction, neuronal structure/function), suggesting that rotation + hypergravity may affect several aspects of the hippocampal function in order to compensate for environmental changes. Six genes directly or indirectly involved in synaptic transmission and plasticity (proSAAS, neuroblastoma ras oncogene, ESTs moderately similar to thymosin beta-10, syndet, inhibin beta E and Ngfi-A binding protein 2) were found to be significantly modulated by hypergravity and unaffected or only slightly affected by rotation. The modulation by hypergravity of these genes suggests that this stimulus might induce plastic remodelling of the hippocampal circuits, possibly both at structural and functional level.
Abstract: Research on the role of the nucleus accumbens in behaviour has been largely focused on the functions of this structure in conditioning to appetitive stimuli. It has been suggested that a network comprising the nucleus accumbens and its convergent inputs might mediate dissociable functions in the acquisition, the consolidation and the retrieval of information. However, findings related to a role of this structure in aversive conditioning are somewhat contradictory, and its involvement in this form of learning is still under debate. Moreover, very little evidence is available on the step of information processing mediated by the accumbens. Thus the purpose of this study was to investigate the effects of the blockade of the AMPA and NMDA glutamate receptors, which have been suggested to mediate the transmission of information from the limbic system to this structure, on a classical aversive conditioning task - the one-trial step through inhibitory avoidance paradigm (24 h interval between training and testing). Intra-accumbens focal injections of AP-5 and DNQX (NMDA and AMPA antagonists, respectively) were performed immediately after training, before training and before testing in mice. The NMDA antagonist (37.5, 75 and 150 ng per side) impaired animal performance only if administered immediately after but not before training or before testing. Conversely, DNQX (0.5, 1.0 and 5.0 ng per side) reduced the step through latencies when administered before training and before testing. These findings suggest that NMDA receptor activation within the accumbens is necessary in formation but not expression of memory for inhibitory avoidance. AMPA receptors, instead, are necessary for the acquisition and the expression but not consolidation of inhibitory avoidance memory.
Abstract: Generally recognition memory is distinguished into spatial and object memories that have been suggested to relay at a cortical level on different neural substrates. Recent studies point to a possible involvement of the nucleus accumbens (Nac) in spatial memory, demonstrating that blockade of glutamate antagonists within this structure impairs acquisition and consolidation of spatial information, while not many data are available on the potential role of this structure in object recognition. Thus in this study we wanted to investigate the effects of intra-accumbens focal administrations of NMDA antagonist, AP-5 (0.05, 0.1, 0.15 or 0.2 microg per side), and AMPA antagonist, DNQX (0.0005 or 0.001 microg per side), in object recognition memory. The spontaneous preference displayed by mice for novel objects was taken as an index for measuring object recognition. Pre-training focal administrations of both antagonists impaired the ability of mice to selectively explore the novel object in test session. However, the AMPA antagonist induced also a decrease in exploration and locomotion. In order to assess whether glutamate receptors located within the Nac were also involved in subsequent steps of object information processing, we performed additional experiments injecting AP-5 and DNQX immediately after training and testing the animals 24-h later. In this case, AP-5 but not the AMPA antagonist impaired exploration of the novel object. These results demonstrate that the Nac is involved in object recognition, and confirm that the different glutamate receptors mediate different component of information processing within the accumbens.
Abstract: Studies in humans have revealed that exposure to altered gravity may lead to impairments in cognitive functions. The objective of this study was to test whether mice exposed to hypergravity using a centrifuge apparatus showed learning impairments in a spatial learning task. Mice rotating at 1G or at 2G acceleration gravity and non-rotating controls were tested for reactivity to a spatial change after either a single 1 h or five repeated 1 h daily rotations in the centrifuge. While no differences among groups were found in the performance after single exposure to altered gravity, 5 days of repeated exposures to 1G or 2G gravity conditions significantly affected mouse ability to discriminate a new spatial arrangement. Additionally, this effect was stronger in the animals repeatedly exposed to 2G rather than to 1G conditions.
Abstract: Cognitive deficits are a key feature of schizophrenia. N-Methyl-D-aspartate (NMDA) receptor antagonists and amphetamine are known to induce psychotic behaviors and cognitive deficits in animals and humans, often affecting visuo-spatial abilities. Phencyclidine (PCP), MK-801 and amphetamine (AMPH) have been used in pharmacological animal models of schizophrenia, but none of these models has focused so far on spatial learning after repeated administration of the drugs. The objective of this study was to test whether repeated administration of PCP, AMPH or MK-801 influenced the performance of mice in a non-associative spatial learning test. CD-1 male mice were given i.p. daily injections of either saline, PCP (5.0, 10.0 mg/kg), AMPH (2.5, 5 mg/kg) or MK-801 (0.3, 0.6 mg/kg), for 5 days. On day 6 all mice were tested in an open field containing five different objects. After three sessions of habituation, each animal's reactivity to object displacement and object substitution was assessed. No significant differences among treatment groups were observed in object exploration or locomotion during the habituation phase. Five days of repeated PCP, AMPH or MK-801 administration selectively and differentially impaired the ability of mice to discriminate a spatial change, while leaving intact the ability to react to a non-spatial change. These data suggest that neurobiological adaptations to drug regimens known to induce psychotic behaviors and alterations in locomotor activity or stereotypies can also alter spatial learning, as assessed in this test, thus indicating that these regimens could also mimic some of the cognitive deficits observed in schizophrenia.
Abstract: This study investigated the role of dorsal striatum in spatial memory in mice. The mice were tested for their ability to detect a spatial displacement 24 hr after training. In order to manipulate the dorsal striatum, focal administrations of the N-methyl-D-aspartate (NMDA) antagonist D-2-amino-5 phosphonopentanoic acid (AP-5) were performed immediately after training. AP-5 impaired the mice's ability to detect the spatial change only if their initial position was constant during training and testing. These findings demonstrate that NMDA receptor blockade within the dorsal striatum impairs spatial memory consolidation in a task in which no explicit reward or procedural learning is involved. The results are discussed with reference to a possible selective involvement of this structure in processing spatial information acquired through an egocentric, but not an allocentric, frame of reference.
Abstract: Recent evidence now points to a role of glutamate transmission within the nucleus accumbens (Nacc) in spatial learning and memory. Unfortunately, the role of the distinct classes of glutamate receptors within this structure in mediating the different steps of the memorization process is not clear. The aim of this study therefore was to further investigate this issue, trying to assess the involvement of the two classes of glutamate receptors within the Nacc in consolidation of spatial information using an associative spatial task, the water maze. For this purpose, focal injections of the NMDA antagonist, AP-5, and of the AMPA antagonist, DNQX, have been performed immediately after the training phase, and mice have been tested for retention 24 h later. Two different versions of the water-maze task have been used: In the place version, animals could learn the position of the platform using visual distal cues, and in the cue version, the location of the platform was indicated by a single proximal cue. The results demonstrated that posttraining NMDA receptor blockade affects mice response in the place but not in the cue water-maze task. On the contrary, AMPA receptor blockade induced no effect in either version of the task. These data confirm a functional dissociation between glutamate receptors located in the Nacc in modulating spatial memory consolidation and indicate that they are specifically involved in consolidation of information necessary to acquire a place but not to a guidance strategy.
Abstract: mdx mice are considered as a genetic homologous of human Duchenne muscular dystrophy. Recent evidence demonstrates that in mouse sympathetic ganglion dystrophin is involved in the stabilization of nicotinic acetylcholine receptor clusters. The purpose of this study was to verify possible effects of dystrophin alterations at the central level. This was assessed by evaluating the response to nicotine administration in mdx and wild-type mice. Thus the effects of post-training nicotine administrations (0.1, 0.25 and 0.5 mg/kg) were tested in mice subjected to a passive avoidance memory task, that measures the ability of mice to remember on test day a shock received 24 h before. Nicotine enhanced memory in wild-type as well as in mdx mice. However, the doses needed to increase memory in mdx were higher than in wild-type. These results are discussed in terms of possible functional changes in central nicotinic acetylcholine receptor in mdx mice.
Abstract: Pharmacological manipulation of both dopamine and glutamate systems affects motor responses in laboratory animals. The two systems, however, seem to act in opposite ways, since direct or indirect activation of dopamine receptors induces similar stimulatory effects to those seen following blockade of N-methyl-D-aspartate receptors. In the present study we compared the pattern of c-fos activation induced by systemic and intra-accumbens administration of the non-competitive N-methyl-D-aspartate antagonist MK-801 and the indirect dopamine agonist amphetamine. Systemic MK-801 induced c-fos mRNA expression in the motor cortex and preferentially in the motor thalamus, i.e. ventrolateral nucleus. Systemic amphetamine, on the other hand, enhanced c-fos mRNA expression in the shell of the accumbens and in limbic thalamic nuclei such as the anteroventral and anterodorsal nuclei. The main effect observed after intra-accumbens administrations of either drug was enhanced c-fos expression in the thalamus, somewhat similar to what seen following systemic administration. In fact also in this case there was a preferential activation of the limbic thalamus by amphetamine and the motor thalamus by MK-801. The present results confirm that different neural substrates underlie behavioral effects induced by systemic administrations of N-methyl-D-aspartate receptor antagonists and dopamine agonists. Further they suggest that intra-accumbens manipulation of the two neural systems could affect different efferent pathways from this structure activating different thalamic targets.
Abstract: Most of the research on ventral striatal functions has been focused on their role in modulating reward and motivation. More recently, a possible role of this structure in cognitive functions has been suggested. However, very little information is available on the involvement of the nucleus accumbens in the different stages of the consolidation process. In this study, the effect of focal injections of AP-5 and DNQX, competitive antagonists at the NMDA and AMPA receptors, respectively, was examined in a nonassociative task designed to estimate the ability of mice to react to spatial changes. The task consists of placing the animals in an open field containing five objects; after three sessions of habituation, their reactivity to object displacement was examined 24 hr later. AP-5 injections administered after training impaired the ability of mice to detect the spatial novelty but did not affect response when injected 120 min after training or before testing. On the contrary, DNQX did not affect response when administered immediately or 120 min after training but did impair spatial discrimination when administered before training or testing. These data demonstrate a double dissociation between glutamate receptor subtypes, such that accumbens NMDA receptors are important for consolidation and not ongoing discrimination of spatial information, whereas AMPA receptors have an opposite role in these processes.
Abstract: We have recently shown that focal administration of dizocilpine hydrogen maleate (MK-801, a non-competitive N-methyl-D-aspartate antagonist) within the nucleus accumbens increases locomotor activity in a dopamine-independent manner. The purpose of this study was to investigate the neural network underlying locomotor stimulation induced by N-methyl-D-aspartate receptor blockade in the accumbens. In the first experiment, we examined the effect of different doses (1, 5 and 25 nmol) of the active and inactive enantiomers of the N-methyl-D-aspartate antagonist, (+)- and (-)-MK-801, respectively, focally administered in the nucleus accumbens. Only the active enantiomer induced a significant increase in locomotor activity; furthermore, the effect induced by the two highest doses of (+)-MK-801 was significantly different from that induced by (-)-MK-801. In the second part of the study, we performed ibotenic acid lesions to the major output nuclei of the accumbens, the ventral pallidum, mediodorsal thalamus, ventrolateral/ventromedial thalamus and pedunculopontine tegmental nucleus, to observe their effect on locomotor activity induced by focal (+)-MK-801 (25 nmol) administration into the accumbens. None of the lesions had any effect on spontaneous locomotor activity. Hyperactivity induced by accumbens MK-801 administrations was unaffected by ibotenic acid lesions of the pedunculopontine tegmental nucleus, while lesions of the mediodorsal thalamus induced only a partial inhibition. In contrast, ibotenic acid lesions of the ventral pallidum and ventrolateral/ventromedial thalamus completely blocked the motor response induced by accumbens MK-801. These data indicate that the intact mediodorsal thalamus, which has been proposed as a part of the loop that relays accumbens information to the prefrontal cortex, does not seem to be a structure of primary importance in MK-801 locomotor activity. On the contrary, the motor nuclei of the thalamus appear to play a more relevant role, suggesting that different neural substrates may mediate dopamine and glutamate functional output from the nucleus accumbens.
Abstract: While experimental evidence shows that dopamine (DA) systems have an important role in locomotor function and in motivation, their role in the reactivity to spatial and non-spatial novelty is less well established.
Abstract: Some evidence suggests an involvement of nucleus accumbens in spatial learning. However, it is controversial whether the mesoaccumbens dopaminergic pathways play a specific role in the acquisition of spatial information.
Abstract: The purpose of this study was to compare the effects of selective lesions of the three main sources of limbic afferents to the nucleus accumbens-fornix, prelimbic cortex and amygdala-with those induced by N-methyl-D-aspartate receptor blockage in this structure, in a non-associative task designed to estimate the ability of rodents to encode spatial and non-spatial relationships between discrete stimuli. The task consists of placing mice in an open field containing five objects and, after three sessions of habituation, examining their reactivity to object displacement (spatial novelty) and object substitution (object novelty). Focal administrations of the competitive N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonopentanoic acid (0.1 microg/side) induced a selective impairment in the ability of mice to react to the spatial change. Lesions to the different structures affect the response of mice to spatial and non-spatial novelty in different ways. In particular, while fornix lesions induced a decrease in re-exploration of the displaced objects, prelimbic cortex lesions enhanced the exploration of both displaced and non-displaced objects. Finally, the basolateral amygdala lesions did not induce any impairment in the detection of the displaced objects but decreased the latencies to approach novel objects. It is concluded that N-methyl-D-aspartate receptor blockage in the nucleus accumbens subsumes the effects of the three lesions. Some hypotheses on the role of glutamatergic transmission in the accumbens on information processing are briefly discussed.
Abstract: Phencyclidine (PCP) and phencyclidine-like drugs (TCP, dexoxadrol, MK-801, and SKF 10,047) were evaluated for their ability to induce rotational behavior in rats with unilateral 6-OHDA lesions of the medial forebrain bundle and for their ability to alter striatal dopamine (DA) overflow with microdialysis procedures. All of the compounds tested produced rotational behavior ipsilateral to the lesion, suggesting that they were enhancing extracellular dopamine in the intact striatum. The microdialysis studies, however, did not support this contention. There appeared to be a complete dissociation between the ability of the five compounds to produce ipsilateral rotations and their ability to enhance extracellular dopamine levels in the striatum. PCP was the only compound able to elicit significant increases in striatal dopamine overflow following i.p. injections and also produce dramatic rotational behavior. MK-801 was the most potent compound in enhancing rotational output while it had no effect at all on striatal dopamine overflow. Dexoxadrol also produced significant rotational output without having any effect on extracellular levels of dopamine following i.p. injections. TCP and SKF 10,047, at doses which produced significant rotational behavior, only elevated dopamine 16% and 12%, respectively, at peak effect. It is most parsimonious to conclude that the effects of PCP-like drugs on nigro-striatal function are mediated through their ability to act as indirect NMDA receptor antagonists and not through their ability to alter striatal dopamine activity.
Abstract: This study evaluated and compared the role of mesoaccumbens dopamine and the ventral pallidal region in the locomotor stimulatory action of the non-competitive N-methyl-D-aspartate antagonist dizocilpine maleate and dopamine agonists. Intra-accumbens injections of both amphetamine (1, 5 and 25 nmol) and dizocilpine maleate (1, 5, 25 and 50 nmol) induced a dose-dependent increase in locomotor activity. The N-methyl-D-aspartate antagonist was somewhat less effective than amphetamine. 6-Hydroxydopamine dopamine-depleting lesions of the nucleus accumbens completely blocked locomotor stimulation induced by focal administrations of amphetamine (5 nmol), but were ineffective in altering the actions of dizocilpine maleate (50 nmol). Ibotenic acid lesions of the ventral pallidal region and muscimol injections into this area also prevented the stimulatory effects of systemic amphetamine (1 mg/kg), while having no effect on the locomotor-activating actions of systemic dizocilpine maleate (0.3 mg/kg). Microdialysis studies revealed that systemically administered apomorphine (2 mg/kg) significantly decreased extracellular GABA in the pallidum, which was accompanied by substantial increases in locomotor output. Systemically administered dizocilpine maleate (0.3 mg/kg), on the other hand, also increased locomotor activity without having any effect on pallidal GABA. These data, taken together, indicate that while the locomotor effects of dopamine agonists are dependent upon intact mesoaccumbens dopamine and involve GABAergic efferents from the nucleus accumbens to the ventral pallidum, dizocilpine maleate's stimulatory actions are independent of such mechanisms.
Abstract: The aim of this study was to investigate the role played by intra-accumbens N-methyl-D-aspartate (NMDA) receptors in spatial information encoding. For this purpose, the effect of local administration of both competitive (AP-5) and non-competitive (MK-801) NMDA antagonists was assessed in a task designed to estimate the ability of rodents to encode spatial relationships between discrete stimuli. The task consists of placing mice in an open field containing five objects and, after three sessions of habituation, examining their reactivity to object displacement (spatial novelty) and object substitution (object novelty). The results show that both doses of MK-801 (0.15 and 0.3 microg/side) induced a selective impairment in the capability of mice to detect spatial novelty. A similar effect was obtained by injecting the low dose of the competitive antagonist AP-5 (0.1 microg/side), whereas the high dose (0.15 microg/side) abolished detection of both spatial and object novelty. Taken together, these results show that intra-accumbens injections of low doses of competitive and non-competitive NMDA antagonists can produce selective deficits in processing spatial information resembling those observed after hippocampal damage. Moreover, the fact that pharmacological treatments spare memory processes involved in habituation suggests that NMDA antagonists may interfere with the formation of spatial representations rather than producing memory deficits per se.
Abstract: This study investigated the effects of stress on brain dopamine receptor densities in two inbred strains of mice. Analysis of [3H]SCH23390 binding by quantitative autoradiography revealed that repeated restraint stress significantly increases D1-like receptor density in the nucleus accumbens of mice of the DBA/2 strain whist reducing it in the caudate-putamen of C57BL/6 mice. No significant changes in D2-like receptor quantified by [3H](-)-sulpiride binding were observed in caudate, substantia nigra and accumbens of stressed C57BL/6 mice. Instead, in DBA/2 mice, stress significantly increased D2-like receptor density in the nucleus accumbens whilst reducing it in the substantia nigra. Finally, stress significantly increased D2-like receptor density within the ventral tegmental area of C57BL/6 mice whilst significantly reducing it in mice of the DBA/2 strain. These results indicate that stress promotes major changes in mesoaccumbens and nigrostriatal dopamine receptor densities. The direction of these changes depends on receptor subtype, brain area and strain. Moreover, the opposite changes of D2-like receptor densities promoted by stress in the ventral tegmental area of the two inbred strains of mice suggest that mesoaccumbens dopamine autoreceptors density might be controlled by a major genotype x stress interaction.
Abstract: Rats lesioned unilaterally in the medial forebrain bundle with 6-OHDA rotated ipsilateral to the lesion following injections of amphetamine, phencyclidine (PCP), and MK-801. Concurrent measurement of striatal dopamine (DA) in the intact striatum with in vivo microdialysis revealed a dissociation between rotational behavior and alterations in DA overflow induced by the three drugs. Amphetamine produced robust ipsilateral rotational behavior and a substantial elevation in striatal DA (approximately 130% increase at asymptote). PCP produced comparable increases in rotational behavior, but only approximately 30% increase in striatal DA. MK-801 also had a comparable behavioral effect but failed to alter DA overflow in the intact striatum. Since MK-801, a noncompetitive NMDA antagonist which does not enhance extracellular dopamine in the striatum, is able to produce ipsilateral rotational behavior in rats with unilateral nigrostriatal lesions, it is likely that the effects of PCP may also be determined predominantly through NMDA blockade in this model.
Abstract: The role of the nucleus accumbens (NA) in forming spatial representations was investigated in C57BL/6 (C57) and DBA/2 (DBA) inbred mice. One week before testing, bilateral excitotoxic lesions were performed in the NA using ibotenic acid. Testing consisted of placing mice in an arena containing 5 objects at a fixed location and, after habituation to the object configuration, examining their reactivity to the displacement (spatial novelty) or the substitution (object novelty) of some of these objects. C57 mice reacted to spatial novelty and DBA mice did not. Both strains, however, reacted to object novelty. The lesion had no effect on C57 mice's performance, but in the DBA mice, it promoted a clear reaction to spatial novelty that was absent in control animals. Radial maze performance also was improved in DBA with NA lesions. Results suggest the NA as a possible site for modulating spatially mediated behaviors in poor-performing subjects.
Abstract: Injections of glutamatergic NMDA as well as dopaminergic antagonists produce selective place- but not cue-learning deficits in associative spatial tasks. The present work was aimed at examining if the blockade of NMDA and dopaminergic receptors interferes with the encoding of spatial information in a non-associative task specifically designed for rodents. CD1 mice injected with MK-801 (0.1 and 0.25 mg/kg), haloperidol (0.04 and 0.08 mg/kg), a combination of the lower doses of each drug (haloperidol: 0.04 mg/kg and MK-801: 0.1 mg/kg) or saline were placed in an open field containing five objects and their reactivity to the displacement (spatial change) or the substitution (non-spatial change) of some of these objects was examined. The results show that saline-injected mice reacted to spatial as to non-spatial change by increasing the time spent exploring the displaced objects or the substituted one. Both doses of MK-801 prevented mice from detecting spatial change but did not affect their reactivity to the novel object. Both doses of haloperidol abolished the reactivity of mice to spatial change but the higher dose of the drug also altered the reaction to non-spatial change. Taken together, the present results indicate that the blockade of dopaminergic or glutamatergic NMDA receptors abolishes the detection of spatial novelty. The well-documented impairing effects of haloperidol and MK-801 on spatial learning may, therefore, be the consequence of a drug-induced inability in forming and/or updating spatial representations. The effects of haloperidol was, however, less specific than that of MK-801, since haloperidol always modified activity together with the response to spatial change and, at the higher dose, abolished the detection of both spatial and non-spatial change. Finally, haloperidol pretreatment was found to enhance the effect of MK-801 thus suggesting a possible interaction between the two systems in modulating these behavioral responses.
Abstract: This study explores the functional interaction between glutamatergic and dopaminergic systems in the modulation of two behavioral responses: locomotor activity and memory consolidation assessed with one-trial inhibitory avoidance. In agreement with previous reports, the NMDA receptor antagonist, (+)-MK-801 ((+)-5-methyl-10,11-dihydro(a,d) cyclohepten-5,10-imine hydrogen maleate), dose dependently enhanced locomotor activity in mice. The selective dopamine D1 receptor antagonist SCH 23390 at doses up to 0.05 mg/kg was unable to affect MK-801-induced locomotor activity, while (-)-sulpiride, but only at high doses (30 mg/kg), and haloperidol (0.05 mg/kg) blocked the MK-801 effect. Hypermotility induced by MK-801 was enhanced by repeated administration of haloperidol (once daily administration for 14 days of 4 mg/kg) or (-)-sulpiride (125 mg/kg), but not SCH 23390 (0.5 mg/kg). Dopamine D1 (SKF 38393)- and D2 (quinpirole)-selective agonists enhanced retention of one-trial inhibitory avoidance performance whilst NMDA receptor antagonists 3-(2-D-carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP) and MK-801 impaired it. Moreover we observed that the NMDA receptor antagonist-induced impairment of memory consolidation was attenuated by subeffective doses of SKF 38393 (5 mg/kg) and quinpirole (0.25 mg/kg). Impairment of the response induced by post-trial injections of CPP and MK-801, in the one-trial inhibitory avoidance test, was highly enhanced by 14 days of daily administration of haloperidol (4 mg/kg), sulpiride (25 mg/kg) but also SCH 23390 (0.5 mg/kg). These results suggest that different neural mechanisms underlie the functional interaction between the two neural systems in the modulation of these behavioral responses. Further, the results of the chronic study revealed a possible heterologous regulation of NMDA receptors.
Abstract: The effect of the administration of the muscarinic cholinergic agonist oxotremorine on locomotor activity was investigated in DBA/2 mice subjected to chronic restraint stress of different durations (120 min daily for 10, 14 or 18 days). Oxotremorine induced a depressant effect on locomotion, which was reduced after 10 and 14 days of restraint, but not after a 18-day restraint stress. Acetylcholine (ACh) content was significantly reduced in prefrontal cortex after 10 and 14 days of stress but returned to control values after 18 days of restraint. No changes in ACh content were observed in nucleus accumbens and striatum. These results are discussed in terms of possible changes in muscarinic receptor sensitivity.
Abstract: The effects of pretreatment with the non-competitive NMDA antagonist (+)MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day x 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.
Abstract: Post-training administration of the N-methyl-D-aspartate (NMDA) receptors antagonist CPP, at doses of 0.5 and 1.0 mg/kg, impaired, in dose-dependent fashion, retention of the inhibitory avoidance response in C57BL/6J (C57) mice. Post-training subeffective doses of selective D1 and D2 dopamine receptor agonists, were able to antagonize the action of CPP, while subeffective doses of SCH 23390 and (-) sulpiride, respectively, D1- and D2-selective antagonists, enhanced the effects of the NMDA antagonist. Furthermore, subchronic blockade of dopamine receptor through a 10-day daily treatment with 4 mg/kg of haloperidol induced an adaptation of both the dopaminergic and the glutamatergic system. The possible upregulation of D2 receptors, in response to repeated injection with haloperidol is shown in the one-trial inhibitory avoidance by an increased response to the D2 agonist. In addition, our data show a potentiation of CPP effects after the same treatment. These results suggest a complex interaction between dopamine and glutamate in modulating one-trial inhibitory avoidance behavior in mice.
Abstract: Post-training administration of the N-methyl-D-aspartate (NMDA) antagonists CPP (0.5 and 1.0 mg/kg) and MK-801 (0.25 and 0.5 mg/kg) impaired, in a dose dependent fashion, the one-trial inhibitory avoidance response in NMRI mice. The D1 dopamine (DA) agonist SKF 38393 (10 and 20 mg/kg) and the D2 agonist quinpirole (0.5 and 1.0 mg/kg) instead facilitate the response in the same behavioral paradigm. Sub-chronic blockade of NMDA receptors with MK-801 (0.25 mg/kg once a day for 14 days) did not change the response to both competitive (CPP) and non-competitive (MK-801) NMDA antagonists. The same chronic treatment with MK-801 induced an increased response to both SKF 38393 and quinpirole. These data suggest that repeated administration of MK-801 induce an upregulation of both D1 and D2 DA receptors without affecting NMDA receptors.
Abstract: The non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 (dizocilpine) was tested, alone or in combination with chlorpromazine, in mice previously trained in the shuttlebox. The lowest doses of dizocilpine (0.02 and 0.04 mg kg-1) attenuated the disrupting action of the neuroleptic (1.5 mg kg-1) on avoidance-performance, while avoidance depression induced by 1.5 and 2 mg kg-1 chlorpromazine was completely or almost completely reversed by 0.08 mg kg-1 NMDA antagonist. The highest dose (0.16 mg kg-1) of dizocilpine did not ameliorate avoidance-performance of mice receiving 2 mg kg-1 chlorpromazine, perhaps because of ataxic effects produced by the drug combination, at these doses. The results support suggestions for a potential use of NMDA antagonists in the treatment of extrapyramidal side-effects of neuroleptics.
Abstract: The extracellular concentration of dopamine in the ventral striatum was measured daily by means of brain microdialysis. Chronic cocaine (10 mg/kg twice daily) altered the dopamine output compared to that in vehicle-injected rats, inducing a pronounced increase in the first 3 days followed by a clear-cut decrease. This reduction in the output of dopamine during chronic cocaine as well as during withdrawal may be neurochemical substrate for the addictive properties of cocaine.
Abstract: Many investigations using the microdialysis technique have been performed in anesthetized animals, both in this laboratory and elsewhere. Concern arises with this preparation that the anesthetic may compromise neuronal function, or that it may interact with test drugs affecting neurotransmitter overflow. In addition, in these studies the microdialysis probe typically is introduced into the brain on the day of testing, and data collection commences within an hour or two following probe insertion. It has been suggested that transmitter recovered in the perfusate probably represents leakage due to tissue damage as well as exocytotic release, and may not accurately reflect neuronal responses to the manipulations of interest. Such potential confounds present important implications for the interpretation of data from these studies. The present investigation examined the effects of chloral hydrate anesthetic on (1) basal dopamine (DA) overflow in the anterior striatum, and (2) DA responses to systemically delivered drugs of two different classes known to influence DA activity. Three putative indices of impulse-dependent release were measured: (a) the time course and stability of basal DA overflow over several hours; (b) sodium channel involvement by adding tetrodotoxin (TTX) to the artificial CSF; and (c) calcium channel involvement using magnesium (Mg) in a calcium-free perfusate. Basal DA levels became stable in both conscious and anesthetized preparations by the second hour after probe insertion. Levels of recovered DA overflow in the anterior striata of conscious rats were approximately double those in chloral hydrate-anesthetized rats. Consistent with other findings, this suggests a general depression of CNS function by chloral hydrate.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Dopaminergic systems are thought to play a major role in the stimulant and reinforcing properties of drugs of abuse, including ethanol. The present study describes the effects of local perfusion with ethanol (and other alcohols) on extracellular dopamine in the striatum and nucleus accumbens. Following the establishment of basal dopamine levels (2-3 h), various concentrations of ethanol in artificial CSF (0.01-10% v/v) were slowly perfused through a microdialysis probe. Each dose of ethanol was found to increase dopamine concentrations in both the striatum and nucleus accumbens. This increase was dose-related in the striatum. The exclusion of calcium and inclusion of 12.5 mM magnesium in the perfusion medium prevented, or greatly attenuated the ethanol-induced dopamine (DA) release. Thus, the release of DA by ethanol is exocytotic in nature and involves calcium-dependent processes. The other alcohols tested, namely methanol and butanol, demonstrated a structure-activity relationship together with ethanol, in their ability to increase extracellular DA. The relative potency was butanol greater than ethanol greater than methanol. The diffusion of ethanol into the brain tissue was investigated following perfusion through the probe. Relatively low concentrations of ethanol were found in striatal tissue during perfusion and they declined rapidly with time, following the removal of ethanol from the perfusate. The concentrations of ethanol achieved in brain tissue following focal application through the microdialysis probe were relevant to human intoxication.
Abstract: Rats were administered various IP doses of the high-affinity dopamine (DA) reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR12909). The caudate nuclei were removed 60 min after drug administration and stored at -70 degrees C. Striatal membranes were prepared later. The results demonstrated that GBR12909 produced a dose-dependent decrease in the binding of [3H]cocaine or [3H]GBR12935 to the DA transporter (ED50 about 10 mg/kg). Saturation binding studies with [3H]GBR12935 showed that this was due to both an increase in the Kd, due to residual drug, and to a decrease in the Bmax. At a dose of 25 mg/kg IP, GBR12909 produced a 50% decrease in the Bmax, and a 3.4-fold increase in the Kd. In the in vivo microdialysis studies, GBR12909 (25 mg/kg IP) produced a modest, long-lasting and stable elevation of extracellular DA. Administration of cocaine through the microdialysis probe to rats pretreated with either saline or GBR12909 (25 mg/kg IP) produced a dose-dependent increase in extracellular DA in both groups. GBR12909 inhibited cocaine-induced increases in extracellular DA by about 50% at all doses. These data collectively indicate that at a dose sufficient to decrease by 50% the Bmax of [3H]GBR12935 binding sites, GBR12909 antagonizes the ability of cocaine to elevate extracellular DA by 50%. Further studies will be needed to evaluate a possible role for GBR12909 in the medical treatment of cocaine addiction.
Abstract: Regional neurotransmitter changes after acute and chronic electroconvulsive shock (ECS) were studied using the technique of repeated microdialysis. Microdialysis was carried out on alternate sides of the brains of anaesthetised rats before and during the first and the eighth ECS or sham (control) treatments. Extracellular fluid release of monoamines and their metabolites was measured in the frontal cortex, striatum and nucleus accumbens using HPLC with electrochemical detection. The first ECS produced selective regional responses, shown by increased concentrations of noradrenaline (NA) and dopamine (DA) in frontal cortex, by unchanged DA content in striatum, and by a small rise in NA and a fall in DA concentrations in nucleus accumbens. Concentrations of metabolites increased after ECS in all regions studied, and for homovanillic acid and dihydroxyphenylacetic acid, the temporal pattern of these changes did not resemble that of DA. Comparison of neurotransmitter responses as per cent of baseline release after the first and eighth ECS treatments showed they were identical. Basal release of monoamines and metabolites before the first ECS or sham treatment was similar in all regions studied. Prior to the eighth treatment, basal release of NA in the frontal cortex and DA in the striatum was elevated in the ECS-treated animals, while basal release of NA in the nucleus accumbens was reduced in both ECS- and sham-treated animals. These data suggest that acute and chronic ECS have different and region-specific effects on neurotransmitter release, although the overall pattern of these responses is not changed by chronic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The experiments reported in this study tested the hypothesis that tight binding dopamine (DA) reuptake inhibitors might act as cocaine antagonists. Binding studies demonstrated that the high affinity dopamine reuptake inhibitor, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR12909) produced a wash-resistant inhibition of the DA transporter in rat striatal membranes as labeled by [3H]cocaine or [3H]1-[2-(diphenyl- methoxy)ethyl]-4-(3-phenylpropyl)piperazine [( 3H]GBR12935), indicative of tight binding. In vivo microdialysis experiments showed that administration of 25 mg/kg GBR12909 to rats produced a modest, but not statistically significant, increase in the extracellular levels of striatal DA, while this same dose of GBR12909 inhibited the ability of cocaine to elevate extracellular DA levels by 64%. These data suggest that tight binding DA reuptake blockers may provide a fruitful approach for developing a cocaine antagonist.
Abstract: After two hours of immobilization stress, C57BL/6 mice presented a significant reduction of spontaneous locomotion and a slight reduction of spontaneous climbing. The effect of stress on locomotor activity disappeared after ten daily sessions of immobilization while this chronic treatment increased the effect of stress on spontaneous climbing. Twenty-four hr after the last stressful experience the mice showed an increase of spontaneous locomotion and a decrease of spontaneous climbing in comparison with unstressed mice. Following a single exposure to immobilization stress, an increase of DOPAC/DA and HVA/DA ratios was found in the striatum and in the nucleus accumbens. These effects were still evident following repeated exposure to this stressor but disappeared 24 hr after the last of ten daily stressful experiences. Finally, chronically stressed mice, tested 24 hr after the last stressful experience, showed an increased sensitivity to the inhibitory effects of low doses of apomorphine on climbing behavior and a decreased sensitivity to the inhibitory effects of the same doses of the dopamine agonist on locomotion. These results are discussed in terms of altered sensitivity of different populations of dopamine receptors following chronic stress.
Abstract: Corticotropin releasing factor (CRF) and sauvagine (SVG) when injected ICV both reduced aggressive behavior and sociability while increasing defensive behavior in isolated DBA/2 mice interacting with a group-housed intruder. SVG was more effective than CRF in producing such behavioral effects. These results add further evidence to the similarity between CRF and SVG, and are discussed in terms of the involvement of these peptides in emotional reactivity in the laboratory mouse.
