Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and prod... more Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and produce the dopamine (DA)-related behaviors of motor activation and catalepsy, respectively. However, a clear relationship between dopaminergic activity and behavior has been very difficult to demonstrate in the awake animal, thus challenging existing notions about the mechanism of these drugs. The present study examined whether the drug-induced behaviors are linked to a presynaptic site of action, the DA transporter (DAT) for psychomotor stimulants and the DA autoreceptor for neuroleptics. Doses of nomifensine (7 mg/kg i.p.), a DA uptake inhibitor, and haloperidol (0.5 mg/kg i.p.), a dopaminergic antagonist, were selected to examine characteristic behavioral patterns for each drug: stimulant-induced motor activation in the case of nomifensine and neuroleptic-induced catalepsy in the case of haloperidol. Presynaptic mechanisms were quantified in situ from extracellular DA dynamics evoked by electrical stimulation and recorded by voltammetry in the freely moving animal. In the first experiment, the maximal concentration of electrically evoked DA ([DA] max) measured in the caudate-putamen was found to reflect the local, instantaneous change in presynaptic DAT or DA autoreceptor activity according to the ascribed action of the drug injected. A positive temporal association was found between [DA] max and motor activation following nomifensine (r)99.0؍ and a negative correlation was found between [DA] max and catalepsy following haloperidol (r)69.0؊؍ in the second experiment. Taken together, the results suggest that a dopaminergic presynaptic site is a target of systemically applied psychomotor stimulants and regulates the postsynaptic action of neuroleptics during behavior. This finding was made possible by a voltammetric microprobe with millisecond temporal resolution and its use in the awake animal to assess release and uptake, two key mechanisms of dopaminergic neurotransmission. Moreover, the results indicate that presynaptic mechanisms may play a more important role in DA-behavior relationships than is currently thought.
As one of the primary targets of the striatum, the substantia nigra pars reticulata (SNr) has bee... more As one of the primary targets of the striatum, the substantia nigra pars reticulata (SNr) has been hypothesized to play a role in normal motor behavior. Specifically, inhibition of usually high, tonic SNr output is predicted to correlate with motor activation. While support for this has come primarily from electrophysiological studies in primates performing goal-directed movements, we tested this hypothesis in rats behaving in an open-field arena. SNr single-unit activity was recorded during spontaneous bouts of open-field behavior (e.g., head and body movements, locomotion) and after rats were given D-amphetamine (1.0 mg/kg, s.c.), which reliably increases motor activity and elevates the firing of motor-related striatal neurons. Prior to drug administration, SNr neurons had either regular, slightly irregular or irregular firing patterns when animals rested quietly. During movement, some inhibitions were observed, but the majority ( approximately 79%) of analyzed units increased firing by as much as 38%. Regardless of the predrug behavioral response of the cell, amphetamine strongly inhibited firing rate ( approximately 90% below nonmovement baseline) and changed firing pattern such that all cells fired irregularly. Subsequent injection with the dopamine antagonist haloperidol (1.0 mg/kg, s.c.) reversed amphetamine-induced inhibitions in all tested cells, which supports a role for dopamine in this effect. These results suggest that the pattern of striatal activity established by amphetamine, which may be critical for determining the drug-induced behavioral pattern, is represented in the SNr regardless of the predrug behavioral response of the cell.
Understanding cortical information processing in Huntington's disease (HD), a genetic neurologica... more Understanding cortical information processing in Huntington's disease (HD), a genetic neurological disorder characterized by prominent motor and cognitive abnormalities, is key to understanding the mechanisms underlying the HD behavioral phenotype. We recorded extracellular spike activity in two symptomatic, freely behaving mouse models: R6/2 transgenics, which are based on a CBA ϫ C57BL/6 background and show robust behavioral symptoms, and HD knock-in (KI) mice, which have a 129sv background and express relatively mild behavioral signs. We focused on prefrontal cortex and assessed firing patterns of individually recorded neurons as well as the amount of synchrony between simultaneously recorded neuronal pairs. At the single-unit level, spike trains in R6/2 transgenics were less variable and had a faster rate than their corresponding wild-type (WT) littermates but showed significantly less bursting. In contrast, KI and WT firing patterns were closely matched. An assessment of both WTs revealed that the R6/2 and KI difference could not be explained by a difference in WT electrophysiology. Thus, the altered pattern of individual spike trains in R6/2 mice appears to parallel their aggressive form of symptom expression. Both WT lines, however, showed a high proportion of synchrony between neuronal pairs (Ͼ85%) that was significantly attenuated in both corresponding HD models (decreases of ϳ20% and ϳ30% in R6/2s and knock-ins, respectively). The loss of spike synchrony, regardless of symptom severity, suggests a population-level deficit in cortical information processing that underlies HD progression.
Abnormal gamma band power across cortex and striatum is an important phenotype of Huntington’s di... more Abnormal gamma band power across cortex and striatum is an important phenotype of Huntington’s disease (HD) in both patients and animal models, but neither the origin nor the functional relevance of this phenotype is well understood. Here, we analyzed local field potential (LFP) activity in freely behaving, symptomatic R6/2 and Q175 mouse models and corresponding wild-type (WT) controls. We focused on periods of quiet rest, which show strong γ activity in HD mice. Simultaneous recording from motor cortex and its target area in dorsal striatum in the R6/2 model revealed exaggerated functional coupling over that observed in WT between the phase of delta frequencies (1–4 Hz) in cortex and striatum and striatal amplitude modulation of low γ frequencies (25–55 Hz; i.e., phase-amplitude coupling, PAC), but no evidence that abnormal cortical activity alone can account for the increase in striatal γ power. Both HD mouse models had stronger coupling of γ amplitude to δ phase and more unimoda...
Circadian rhythms organize behavior and physiological processes to be appropriate to the predicta... more Circadian rhythms organize behavior and physiological processes to be appropriate to the predictable cycle of daily events. These rhythms are entrained by stimuli that provide time of day cues (zeitgebers), such as light, which regulates the sleep-wake cycle and associated rhythms. But other events, including meals, social cues, and bouts of locomotor activity, can act as zeitgebers. Recent evidence shows that most organs and tissues contain cells that are capable of some degree of independent circadian cycling, suggesting the circadian system is more broadly and diffusely distributed. Within laboratory studies of behavior, circadian rhythms tend to be treated as a complication to be minimized, but they offer a useful model of predictable shifts in behavioral tendencies. In the present review, we summarize the evidence that formed the basis for a hypothesis that drugs of abuse can entrain circadian rhythms and describe the outcome of a series of experiments designed to test that hypothesis. We propose that such drug-entrained rhythms may contribute to demonstrated daily variations in drug metabolism, tolerance, and sensitivity to drug reward. Of particular importance, these rhythms may be evoked by a single episode of drug taking, strengthen with repeated episodes, and reemerge after long periods of abstinence, thereby contributing to drug abuse, addiction, and relapse.
Voltammetric recordings with electrochemically modified carbon-fiber electrodes were obtained fro... more Voltammetric recordings with electrochemically modified carbon-fiber electrodes were obtained from specific regions of the forebrain in rats given free-choice access to a novel environment. Entry into novelty increased the catechol signal in the medial prefrontal cortex and shell of the nucleus accumbens by more than 100%, but had no consistent effect in either the neostriatum or accumbal core. In both the medial prefrontal cortex and accumbal shell, moreover, the novelty-induced increase in catecholaminergic activity was detectable only during the initial entry into the novel compartment and did not reappear when animals returned to the familiar environment. These results support increasing evidence for a functional distinction between the accumbal core and shell, with the latter having been linked to brain reward mechanisms. The results also indicate that novelty activates, albeit very transiently, some of the same neurochemical systems believed to play a critical role in the reinforcing effects of certain drugs of abuse.
<b>Copyright information:</b>Taken from "Extracellular ascorbate modulates gluta... more <b>Copyright information:</b>Taken from "Extracellular ascorbate modulates glutamate dynamics: role of behavioral activation"http://www.biomedcentral.com/1471-2202/8/32BMC Neuroscience 2007;8():32-32.Published online 16 May 2007PMCID:PMC1884166. A combination of 250 μM-AA CSF and "Lights ON" conditions were utilized wherever white or grey-filled icons appear. Black-filled icons indicate when animals were either responding to darkness (A &amp; B), treated with 1000 μM AA (C &amp; D), or both (B &amp; D). The within-subjects factor was AA-treatment, as all animals were treated with both AA levels, 250 μM and 1000 μM AA, in separate dialysis sessions during the experimental period indicated below each graph. Separate graphs depict the GLU level changes occurring in response to lights-out (A &amp; B), or AA treatment (C &amp; D). The boxes within each graph depict time points where separate analyses were performed (last baseline through 45 min dashed, last baseline through 75 min solid). Repeated measures ANOVA analyses within the dashed boxes were significant in A, B, &amp; C. The first 45-min was the only period during which a significant GLU increases in response to AA treatment across collections was exposed, and only during the "LIGHTS ON" experiment (C). Note the large effects of darkness exposure (Experimental period, black-filled icons) on striatal GLU levels depicted in graphs A &amp; B. When the two "Post" collections (black &amp; grey-filled versus white-filled) were included, significant increases in GLU levels occurred across all collections (15–120 min) compared to baseline when animals treated with 1000 μM AA were exposed to darkness (B). However increases in GLU were only significant during the Experimental period (15–75 min) when animals were treated with 250 μM AA (A).
The single gene mutation that causes Huntington's disease (HD) is present throughout the body wit... more The single gene mutation that causes Huntington's disease (HD) is present throughout the body with the potential for eventually disrupting a wide range of autonomic, endocrine, and muscular functions. But the symptoms most commonly associated with HD-a triad of cognitive, emotional, and motor abnormalities-typically emerge first, and represent signs of brain dysfunction even before a formal HD diagnosis is made. 1 In most cases, symptom onset occurs in the prime of life, worsens over time, and ends in death within 10-15 years. 2 Hope for a cure or at least an effective treatment emerged when the mutant huntingtin gene (mHTT) was identified in the early 1990s, 3 but the hope is still elusive. Although the huntingtin gene has 67 exons, the mutation consists of an unstable CAG repeat in exon 1. 4 A typical number of repeats are fewer than 30, but as the number approaches 39, HD
Originally sold as a bronchodilator in the early 1930s, amphetamine soon became known for its sti... more Originally sold as a bronchodilator in the early 1930s, amphetamine soon became known for its stimulant effects on behavior (Angrist, 1983). The drug has been used to overcome fatigue and to improve performance on certain types of motor or cognitive tasks (Koelega, 1993; Laties & Weiss, 1981). These stimulant effects often occur in conjunction with feelings of euphoria, a combination that has led to the widespread abuse of amphetamine and its analogs, including a pure form of methamphetamine known as “ice,” which emerged on the recreational drug scene in the late 1980s (Cho, 1990). Invariably, abuse of these drugs induces a psychosis that is clinically similar to paranoid schizophrenia (Akiyama, Hamamura, Ujike, Kanzaki, & Otsuki, 1991; Snyder, 1973).
The striatum receives cortical information via glutamatergic connections and processes it for out... more The striatum receives cortical information via glutamatergic connections and processes it for output to nigral or pallidal neurons (Parent and Hazrati, 1995). Dopamine, which is released from thinly myelinated fibers that collateralize extensively throughout the striatum, appears ...
Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and prod... more Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and produce the dopamine (DA)-related behaviors of motor activation and catalepsy, respectively. However, a clear relationship between dopaminergic activity and behavior has been very difficult to demonstrate in the awake animal, thus challenging existing notions about the mechanism of these drugs. The present study examined whether the drug-induced behaviors are linked to a presynaptic site of action, the DA transporter (DAT) for psychomotor stimulants and the DA autoreceptor for neuroleptics. Doses of nomifensine (7 mg/kg i.p.), a DA uptake inhibitor, and haloperidol (0.5 mg/kg i.p.), a dopaminergic antagonist, were selected to examine characteristic behavioral patterns for each drug: stimulant-induced motor activation in the case of nomifensine and neuroleptic-induced catalepsy in the case of haloperidol. Presynaptic mechanisms were quantified in situ from extracellular DA dynamics evoked by electrical stimulation and recorded by voltammetry in the freely moving animal. In the first experiment, the maximal concentration of electrically evoked DA ([DA] max) measured in the caudate-putamen was found to reflect the local, instantaneous change in presynaptic DAT or DA autoreceptor activity according to the ascribed action of the drug injected. A positive temporal association was found between [DA] max and motor activation following nomifensine (r)99.0؍ and a negative correlation was found between [DA] max and catalepsy following haloperidol (r)69.0؊؍ in the second experiment. Taken together, the results suggest that a dopaminergic presynaptic site is a target of systemically applied psychomotor stimulants and regulates the postsynaptic action of neuroleptics during behavior. This finding was made possible by a voltammetric microprobe with millisecond temporal resolution and its use in the awake animal to assess release and uptake, two key mechanisms of dopaminergic neurotransmission. Moreover, the results indicate that presynaptic mechanisms may play a more important role in DA-behavior relationships than is currently thought.
As one of the primary targets of the striatum, the substantia nigra pars reticulata (SNr) has bee... more As one of the primary targets of the striatum, the substantia nigra pars reticulata (SNr) has been hypothesized to play a role in normal motor behavior. Specifically, inhibition of usually high, tonic SNr output is predicted to correlate with motor activation. While support for this has come primarily from electrophysiological studies in primates performing goal-directed movements, we tested this hypothesis in rats behaving in an open-field arena. SNr single-unit activity was recorded during spontaneous bouts of open-field behavior (e.g., head and body movements, locomotion) and after rats were given D-amphetamine (1.0 mg/kg, s.c.), which reliably increases motor activity and elevates the firing of motor-related striatal neurons. Prior to drug administration, SNr neurons had either regular, slightly irregular or irregular firing patterns when animals rested quietly. During movement, some inhibitions were observed, but the majority ( approximately 79%) of analyzed units increased firing by as much as 38%. Regardless of the predrug behavioral response of the cell, amphetamine strongly inhibited firing rate ( approximately 90% below nonmovement baseline) and changed firing pattern such that all cells fired irregularly. Subsequent injection with the dopamine antagonist haloperidol (1.0 mg/kg, s.c.) reversed amphetamine-induced inhibitions in all tested cells, which supports a role for dopamine in this effect. These results suggest that the pattern of striatal activity established by amphetamine, which may be critical for determining the drug-induced behavioral pattern, is represented in the SNr regardless of the predrug behavioral response of the cell.
Understanding cortical information processing in Huntington's disease (HD), a genetic neurologica... more Understanding cortical information processing in Huntington's disease (HD), a genetic neurological disorder characterized by prominent motor and cognitive abnormalities, is key to understanding the mechanisms underlying the HD behavioral phenotype. We recorded extracellular spike activity in two symptomatic, freely behaving mouse models: R6/2 transgenics, which are based on a CBA ϫ C57BL/6 background and show robust behavioral symptoms, and HD knock-in (KI) mice, which have a 129sv background and express relatively mild behavioral signs. We focused on prefrontal cortex and assessed firing patterns of individually recorded neurons as well as the amount of synchrony between simultaneously recorded neuronal pairs. At the single-unit level, spike trains in R6/2 transgenics were less variable and had a faster rate than their corresponding wild-type (WT) littermates but showed significantly less bursting. In contrast, KI and WT firing patterns were closely matched. An assessment of both WTs revealed that the R6/2 and KI difference could not be explained by a difference in WT electrophysiology. Thus, the altered pattern of individual spike trains in R6/2 mice appears to parallel their aggressive form of symptom expression. Both WT lines, however, showed a high proportion of synchrony between neuronal pairs (Ͼ85%) that was significantly attenuated in both corresponding HD models (decreases of ϳ20% and ϳ30% in R6/2s and knock-ins, respectively). The loss of spike synchrony, regardless of symptom severity, suggests a population-level deficit in cortical information processing that underlies HD progression.
Abnormal gamma band power across cortex and striatum is an important phenotype of Huntington’s di... more Abnormal gamma band power across cortex and striatum is an important phenotype of Huntington’s disease (HD) in both patients and animal models, but neither the origin nor the functional relevance of this phenotype is well understood. Here, we analyzed local field potential (LFP) activity in freely behaving, symptomatic R6/2 and Q175 mouse models and corresponding wild-type (WT) controls. We focused on periods of quiet rest, which show strong γ activity in HD mice. Simultaneous recording from motor cortex and its target area in dorsal striatum in the R6/2 model revealed exaggerated functional coupling over that observed in WT between the phase of delta frequencies (1–4 Hz) in cortex and striatum and striatal amplitude modulation of low γ frequencies (25–55 Hz; i.e., phase-amplitude coupling, PAC), but no evidence that abnormal cortical activity alone can account for the increase in striatal γ power. Both HD mouse models had stronger coupling of γ amplitude to δ phase and more unimoda...
Circadian rhythms organize behavior and physiological processes to be appropriate to the predicta... more Circadian rhythms organize behavior and physiological processes to be appropriate to the predictable cycle of daily events. These rhythms are entrained by stimuli that provide time of day cues (zeitgebers), such as light, which regulates the sleep-wake cycle and associated rhythms. But other events, including meals, social cues, and bouts of locomotor activity, can act as zeitgebers. Recent evidence shows that most organs and tissues contain cells that are capable of some degree of independent circadian cycling, suggesting the circadian system is more broadly and diffusely distributed. Within laboratory studies of behavior, circadian rhythms tend to be treated as a complication to be minimized, but they offer a useful model of predictable shifts in behavioral tendencies. In the present review, we summarize the evidence that formed the basis for a hypothesis that drugs of abuse can entrain circadian rhythms and describe the outcome of a series of experiments designed to test that hypothesis. We propose that such drug-entrained rhythms may contribute to demonstrated daily variations in drug metabolism, tolerance, and sensitivity to drug reward. Of particular importance, these rhythms may be evoked by a single episode of drug taking, strengthen with repeated episodes, and reemerge after long periods of abstinence, thereby contributing to drug abuse, addiction, and relapse.
Voltammetric recordings with electrochemically modified carbon-fiber electrodes were obtained fro... more Voltammetric recordings with electrochemically modified carbon-fiber electrodes were obtained from specific regions of the forebrain in rats given free-choice access to a novel environment. Entry into novelty increased the catechol signal in the medial prefrontal cortex and shell of the nucleus accumbens by more than 100%, but had no consistent effect in either the neostriatum or accumbal core. In both the medial prefrontal cortex and accumbal shell, moreover, the novelty-induced increase in catecholaminergic activity was detectable only during the initial entry into the novel compartment and did not reappear when animals returned to the familiar environment. These results support increasing evidence for a functional distinction between the accumbal core and shell, with the latter having been linked to brain reward mechanisms. The results also indicate that novelty activates, albeit very transiently, some of the same neurochemical systems believed to play a critical role in the reinforcing effects of certain drugs of abuse.
<b>Copyright information:</b>Taken from "Extracellular ascorbate modulates gluta... more <b>Copyright information:</b>Taken from "Extracellular ascorbate modulates glutamate dynamics: role of behavioral activation"http://www.biomedcentral.com/1471-2202/8/32BMC Neuroscience 2007;8():32-32.Published online 16 May 2007PMCID:PMC1884166. A combination of 250 μM-AA CSF and "Lights ON" conditions were utilized wherever white or grey-filled icons appear. Black-filled icons indicate when animals were either responding to darkness (A &amp; B), treated with 1000 μM AA (C &amp; D), or both (B &amp; D). The within-subjects factor was AA-treatment, as all animals were treated with both AA levels, 250 μM and 1000 μM AA, in separate dialysis sessions during the experimental period indicated below each graph. Separate graphs depict the GLU level changes occurring in response to lights-out (A &amp; B), or AA treatment (C &amp; D). The boxes within each graph depict time points where separate analyses were performed (last baseline through 45 min dashed, last baseline through 75 min solid). Repeated measures ANOVA analyses within the dashed boxes were significant in A, B, &amp; C. The first 45-min was the only period during which a significant GLU increases in response to AA treatment across collections was exposed, and only during the "LIGHTS ON" experiment (C). Note the large effects of darkness exposure (Experimental period, black-filled icons) on striatal GLU levels depicted in graphs A &amp; B. When the two "Post" collections (black &amp; grey-filled versus white-filled) were included, significant increases in GLU levels occurred across all collections (15–120 min) compared to baseline when animals treated with 1000 μM AA were exposed to darkness (B). However increases in GLU were only significant during the Experimental period (15–75 min) when animals were treated with 250 μM AA (A).
The single gene mutation that causes Huntington's disease (HD) is present throughout the body wit... more The single gene mutation that causes Huntington's disease (HD) is present throughout the body with the potential for eventually disrupting a wide range of autonomic, endocrine, and muscular functions. But the symptoms most commonly associated with HD-a triad of cognitive, emotional, and motor abnormalities-typically emerge first, and represent signs of brain dysfunction even before a formal HD diagnosis is made. 1 In most cases, symptom onset occurs in the prime of life, worsens over time, and ends in death within 10-15 years. 2 Hope for a cure or at least an effective treatment emerged when the mutant huntingtin gene (mHTT) was identified in the early 1990s, 3 but the hope is still elusive. Although the huntingtin gene has 67 exons, the mutation consists of an unstable CAG repeat in exon 1. 4 A typical number of repeats are fewer than 30, but as the number approaches 39, HD
Originally sold as a bronchodilator in the early 1930s, amphetamine soon became known for its sti... more Originally sold as a bronchodilator in the early 1930s, amphetamine soon became known for its stimulant effects on behavior (Angrist, 1983). The drug has been used to overcome fatigue and to improve performance on certain types of motor or cognitive tasks (Koelega, 1993; Laties & Weiss, 1981). These stimulant effects often occur in conjunction with feelings of euphoria, a combination that has led to the widespread abuse of amphetamine and its analogs, including a pure form of methamphetamine known as “ice,” which emerged on the recreational drug scene in the late 1980s (Cho, 1990). Invariably, abuse of these drugs induces a psychosis that is clinically similar to paranoid schizophrenia (Akiyama, Hamamura, Ujike, Kanzaki, & Otsuki, 1991; Snyder, 1973).
The striatum receives cortical information via glutamatergic connections and processes it for out... more The striatum receives cortical information via glutamatergic connections and processes it for output to nigral or pallidal neurons (Parent and Hazrati, 1995). Dopamine, which is released from thinly myelinated fibers that collateralize extensively throughout the striatum, appears ...
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