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A substantial amount of research has focused on determining the factors that alter the activity of substantia nigra dopamine neurons. Much of this research has indicated that several mechanisms that regulate dopamine neuron activity have... more
A substantial amount of research has focused on determining the factors that alter the activity of substantia nigra dopamine neurons. Much of this research has indicated that several mechanisms that regulate dopamine neuron activity have the capability to maintain the baseline activity of dopamine cells at a fairly constant rate. For example, the intrinsic membrane conductances present on dopamine neurons, which generate the spike activity of these cells, appear to maintain the activity of spontaneously active neurons and suppress the induction of activity in quiescent cells. In addition, dopamine cell activity can be regulated by afferent systems that appear to be capable of preventing dopamine neurons from displaying sustained variations in electrophysiological activity. Specifically, inputs from the striatum or from the subthalamic nucleus may each exert opposing influences on dopamine cell activity via direct vs. indirect afferent projection pathways. In addition, the dendritic release of dopamine may provide negative feedback; dopamine cell firing may increase the dendritic release of dopamine within the substantia nigra, providing a local feedback inhibition of dopamine neuron activity. Factors such as the intrinsic membrane properties, afferent input, and the dendritic release of dopamine all work together in a complex manner to regulate the activity level of dopamine neurons.
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ABSTRACT
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1. The present experiments investigated the effects of gamma-amino-butyric acidB (GABAB) receptor stimulation on the excitatory and inhibitory responses of neostriatal neurons evoked by stimulation of the subcortical white matter in a rat... more
1. The present experiments investigated the effects of gamma-amino-butyric acidB (GABAB) receptor stimulation on the excitatory and inhibitory responses of neostriatal neurons evoked by stimulation of the subcortical white matter in a rat neostriatal slice preparation. 2. Intracellular recordings showed that single-impulse stimulation of the corpus callosum evoked monosynaptic, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive excitatory postsynaptic potentials (EPSPs) that were attenuated by the GABAB receptor agonist, p-chlorophenyl-GABA (baclofen, 0.5-10 microM) in a concentration-dependent manner. Baclofen also blocked the GABAA-mediated inhibition of neostriatal cell responses, which were revealed by paired-impulse stimulation of the subcortical white matter. Both of these effects persisted in slices in which the anterior cortex was removed, indicating that the site of action for baclofen was intrinsic to the neostriatum. The GABAB antagonist 3-amino-2-hydroxy-2-(4-chlorophenyl)-propanesulfonic acid (saclofen, 250-500 microM) reversed the depressant actions of baclofen on both the excitatory and inhibitory responses of neostriatal cells. 3. Concentrations of baclofen as high as 100 microM, which markedly attenuated EPSP amplitude, did not exert direct effects on resting membrane potential, current-voltage relationship, input resistance, or spike threshold and thus appeared to have no postsynaptic effect on the population of neurons recorded. 4. These results indicate that, in contrast to other regions of the CNS, the depressant effects of baclofen on glutamate-dependent EPSPs are mediated exclusively through GABAB receptors located presynaptically on the terminals of glutamatergic afferents.(ABSTRACT TRUNCATED AT 250 WORDS)
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Research Interests: Electrophysiology, Prefrontal Cortex, Dopamine, Vitamin D receptor, Animals, and 13 moreMale, Microelectrodes, Neurons, Microdialysis, Rats, Neuronal Activity, Action potential, Membrane Potential, Action Potentials, Chloral Hydrate, Infusion Pumps, Excitatory Postsynaptic Potentials, and Dopamine antagonists
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Intracerebral injections of the neurotoxin 6-hydroxydopamine (6-HDA) can produce selective, near-total destruction of the dopamine (DA)-containing neurons of the nigrostriatal bundle. The dysfunctions in animals with these lesions show... more
Intracerebral injections of the neurotoxin 6-hydroxydopamine (6-HDA) can produce selective, near-total destruction of the dopamine (DA)-containing neurons of the nigrostriatal bundle. The dysfunctions in animals with these lesions show many parallels with those present in Parkinsonian patients. Among these are the extensive loss of DA neurons in the basal ganglia, neurological impairments including akinesia, paradoxical kinesia in response to activating conditions, and improved sensory-motor function after the administration of DOPA. Moreover, as with patients with preclinical Parkinsonism, 6-HDA-treated rats with less extensive lesions show few or no behavioral dysfunctions, but are unusually sensitive to the akinesia-inducing effects of stress and dopaminergic antagonists. In this review, we summarize the behavioral effects of 6-HDA-induced depletion of striatal DA in the rat and then focus on the compensatory changes that may underlie the preclinical stage of the disorder. These compensations appear to include an increase in the number of active DA neurons, an increase in the release of DA per impulse from residual terminals, and a decrease in the amount of DA inactivated by high affinity uptake. Collectively, these alterations permit a few residual DA neurons to maintain a normal level of control over cellular activity in the striatum.
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A goal of this part is to examine the functional impact of catecholaminergic systems on CNS function as it relates to normal and pathological states. The participants achieve their objectives individually by relating their high-quality... more
A goal of this part is to examine the functional impact of catecholaminergic systems on CNS function as it relates to normal and pathological states. The participants achieve their objectives individually by relating their high-quality work on this expansive topic, while maintaining a focus on the functional implications of their findings. Nonetheless, despite the necessarily broad nature of the topics presented, there is a remarkable degree of convergence of information. Several subthemes have emerged as a consequence of considering this work in its entirety. First is the importance of examining neurotransmitter effects, not in isolation, but in terms of interactions with other neurotransmitter systems. History has shown that a limited focus often produces confusing or inconsistent results, which become increasingly clear on consideration of the state of the organism. Second is the importance of examining pharmacological and pathophysiological interactions in light of the anatomy of the system and how developmental influences can alter this relationship. Such very general considerations have been found to provide an essential ingredient in understanding the nature of catecholamine function within this complex system.
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Research Interests: Dopamine, Caudate Nucleus, Animals, Male, Substantia nigra, and 4 moreNeurons, Haloperidol, Rats, and Time Factors
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1. The physiology of ventral pallidal (VP) cells was investigated using in vivo intracellular recording and staining techniques in adult rats. Based on electrophysiological criteria, three different types of cells were found: type A... more
1. The physiology of ventral pallidal (VP) cells was investigated using in vivo intracellular recording and staining techniques in adult rats. Based on electrophysiological criteria, three different types of cells were found: type A cells, which fired phasic spikes that did not exhibit a substantial afterhyperpolarization (AHP), type B cells, which exhibited a slow ramplike depolarization that preceded the short-duration action potential; the spike was followed by a prominent AHP, and type C cells, which were the only cells that fired spikes in couplets or bursts, with the spikes in a burst exhibiting a progressive increase in duration and a decrease in amplitude. These cells also exhibited a rebound low threshold spikelike event. Furthermore, 18% of the VP cells recorded exhibited a slow subthreshold oscillation of the membrane potential (< 1 Hz). 2. The response of VP cells to stimulation of fibers arising from the prefrontal cortex, nucleus accumbens, and mediodorsal thalamic nucleus (MD) was examined. In contrast to our initial predictions, all cells responded to nucleus accumbens stimulation with excitation. Type A and B cells responded to nucleus accumbens stimulation with excitation and to MD stimulation with antidromic-like responses, orthodromic excitation, or evoked inhibitory postsynaptic potentials. Only type A cells responded to prefrontal cortical stimulation. Type C cells only responded to stimulation of the nucleus accumbens, which resulted in evoked excitatory postsynaptic potentials. 3. The cells in the VP therefore can be segregated into three physiologically defined groups according to action potential discharge patterns and their response to afferent fiber stimulation.
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In addition to firing in a single spiking mode, dopamine (DA) cells have been observed to fire in a bursting pattern with consecutive spikes in a burst displaying progressively decreasing amplitude and increasing duration. In vivo... more
In addition to firing in a single spiking mode, dopamine (DA) cells have been observed to fire in a bursting pattern with consecutive spikes in a burst displaying progressively decreasing amplitude and increasing duration. In vivo intracellular recording demonstrated the bursts to typically ride on a depolarizing wave (5 to 15 mV amplitude). Although the burst-firing frequency of DA cells showed little correlation with the base line firing rate, increases in firing rate were usually associated with an increase in burst firing. Increases in burst firing could also be elicited by intracellular calcium injection and could be prevented by intracellular injection of EGTA, suggesting a calcium involvement in bursting. Blockade of potassium conductances with extracellular iontophoresis of barium or intracellular injection of tetraethylammonium bromide could also trigger an increased degree of burst firing in DA cells. These data suggest that the increased calcium influx accompanying an inc...
Acute administration of the antipsychotic drug haloperidol causes an increase in the firing rate and in the proportion of spontaneously active dopamine neurons in the substantia nigra. In contrast, repeated administration of haloperidol... more
Acute administration of the antipsychotic drug haloperidol causes an increase in the firing rate and in the proportion of spontaneously active dopamine neurons in the substantia nigra. In contrast, repeated administration of haloperidol for 21 days results in a dramatic decrease in the number of dopamine neurons displaying spontaneous electrophysiological activity. In vivo intracellular recordings revealed that these nonfiring dopamine neurons have a membrane potential significantly more depolarized than dopamine neurons in control rats, although their input resistances were equivalent. Neurons displaying this depolarization block could not be activated by depolarizing current injection, but could be made to fire in response to hyperpolarization of the membrane. Furthermore, administration of autoreceptor-selective doses of the direct acting dopamine agonist apomorphine hyperpolarized inactivated dopamine neurons in treated rats, resulting in initiation of spontaneous activity. Thus...
Dopamine (DA) neurons have been recorded in vivo in four states of activity: hyperpolarized, nonfiring; single spike firing; burst firing; and depolarization inactivation. Nonfiring DA neurons can be made to fire by iontophoretic... more
Dopamine (DA) neurons have been recorded in vivo in four states of activity: hyperpolarized, nonfiring; single spike firing; burst firing; and depolarization inactivation. Nonfiring DA neurons can be made to fire by iontophoretic application of the excitatory substances glutamate and cholecystokinin, or by depolarizing current injection. Spontaneously active DA cells typically fire in a slow (3 to 8 Hz) irregular pattern. In vivo intracellular recordings revealed that this pattern is sustained by the alternation of two currents: a spontaneously occurring slow depolarization (13 +/- 3 mV amplitude, 78 +/- 40 msec duration) which brings the membrane potential of the DA cell to spike threshold (-42 mV), and an afterhyperpolarization mediated by a calcium-activated potassium conductance (IK(Ca)). The slow depolarization is a pacemaker-like conductance, with a rate of rise proportional to the membrane potential. The regular pacemaker pattern of the spontaneously occurring slow depolariza...
Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic... more
Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic use; however, very few have examined the effect of acute administration on the negative affective state after acute drug withdrawal. One dose of amphetamine was injected into Sprague-Dawley rats. Despair behavior using the modified forced swim test (FST) and dopamine (DA) activity in the ventral tegmental area using in vivo electrophysiological recordings were studied 18 h, 48 h and 72 h after injection of amphetamine. The effects of inactivation of the BLA and ketamine administration on VTA DA neuron activity and passivity in the modified FST were examined. Eighteen hours following amphetamine withdrawal there was a substantial decrease in the number of active DA neurons, as well as an increase in time spent immobile in the modified FST, which retu...
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... Focus on Hippocampal Disruption of Dopamine System Regulation Anthony A. Grace Introduction ... These data suggest that the DA system itself is normal; however, it is believed to be regulated in an abnormal manner (Grace, 1991, 2000;... more
... Focus on Hippocampal Disruption of Dopamine System Regulation Anthony A. Grace Introduction ... These data suggest that the DA system itself is normal; however, it is believed to be regulated in an abnormal manner (Grace, 1991, 2000; Bertolino et al., 1999). ...
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... Under this condition, the rat will exhibit perseveration, or the inability to change task performance in ... ders, such as compulsive gambling, eating, shopping, and other involvements [87]. ... has been associated with taking a... more
... Under this condition, the rat will exhibit perseveration, or the inability to change task performance in ... ders, such as compulsive gambling, eating, shopping, and other involvements [87]. ... has been associated with taking a direct-acting dopamine agonist, such as pramipexole [90,91 ...
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APA PsycNET Our Apologies! - The following features are not available with your current Browser configuration. - alerts user that their session is about to expire - display, print, save, export, and email selected records - get My ...
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Intracellular recordings were obtained from rat ventral pallidal (VP) and mediodorsal thalamic (MD) cells in vivo and the effects of antipsychotic drugs on their basal and evoked electrophysiological characteristics were assessed.... more
Intracellular recordings were obtained from rat ventral pallidal (VP) and mediodorsal thalamic (MD) cells in vivo and the effects of antipsychotic drugs on their basal and evoked electrophysiological characteristics were assessed. Administration of either haloperidol or clozapine caused a significant decrease in the average firing rate, accompanied by a hyperpolarization of the membrane potential in the VP cells recorded. However, neither drug induced a substantial change in the other basic membrane properties of the MD cells or VP cells tested. In addition, in 50% of the MD cells tested, both antipsychotic drugs caused a change in spike discharge from an oscillatory pattern to a tonic discharge mode. In rats that had received ibotenic acid lesions of the prefrontal cortex (PFCtx) 4-8 weeks prior to recording, cells in the VP exhibited similar changes in firing frequency in response to haloperidol administration as those in the intact rats. However, in contrast to the intact rats, M...
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Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets.... more
Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5...
Alteration in normal hippocampal (HPC) function attributed to reduced parvalbumin (PV) expression has been consistently reported in schizophrenia patients and in animal models of schizophrenia. However, it is unclear whether there is an... more
Alteration in normal hippocampal (HPC) function attributed to reduced parvalbumin (PV) expression has been consistently reported in schizophrenia patients and in animal models of schizophrenia. However, it is unclear whether there is an overall loss of interneurons as opposed to a reduction in activity-dependent PV content. Co-expression of PV and the constitutively expressed substance P (SP)-receptor protein has been utilized in other models to ascertain the degree of cell survival, as opposed to reduction in activity-dependent PV content, in the HPC. The present study measured the co-expression of PV and SP-receptors in the dentate and dorsal and ventral CA3 subregions of the HPC in the methylazoymethanol acetate (MAM) rat neurodevelopmental model of schizophrenia. In addition, these changes were compared at the post-natal day 27 (PND27) and post-natal day 240 (PND > 240) time points. Brains from PND27 and PND > 240 MAM (n = 8) and saline (SAL, n = 8) treated offspring were ...
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One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic... more
One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressants, such as selective serotonin reuptake inhibitors, require a month or longer to be expressed, with about a third of major depressive disorder patients resistant to treatment. Clinical studies have shown that a low dose of ketamine exhibits fast-acting relatively sustained antidepressant action, even in treatment-resistant patients. However, the mechanisms of ketamine action at a systems level remain unclear. Wistar-Kyoto rats were exposed to inescapable, uncontrollable footshocks. To evaluate learned helplessness behavior, we used an active avoidance task in a shuttle box equipped with an electrical grid floor. After helplessness assessment, we performed in vivo electrophysiological recordings first from ventral tegmental area dopaminerg...