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G V Rebec

Publications and source records attributed to G V Rebec.

At least 37 records · Page 2Linked to original sources
PubMed1998

Amphetamine effects on striatal neurons: implications for models of dopamine function.

Models of dopamine function based on the bidirectional neuromodulation of afferents (40, 95) were tested by determining whether cortical ablation would affect the excitatory and inhibitory effects of amphetamine (AMPH) on striatal neurons in freely moving rats. By minimizing pre-and post-AMPH behavioral differences, behavioral clamping revealed that cortical ablation blocked the capacity of AMPH to produce a net excitation of striatal neurons that had shown AMPH-induced excitations under non-clamping conditions. Cortical ablation did not affect AMPH-induced neuronal inhibitions under behavioral clamping conditions. These results suggest that AMPH, possibly by enhancing dopaminergic neuromodulation, facilities or inhibits the activity of neurons that respectively receive substantial or little cortical input. Thus, the findings support models that assign dopamine the capacity to increase the gain of neuronal information processing. Basic research relevant to these models is reviewed and potential clinical implications are discussed.

Amphetamine↗
PubMed1998

Neuroethological assessment of amphetamine-induced behavioral changes and their reversal by neuroleptics: focus on the amygdala and nucleus accumbens.

1. An ethological approach was combined with intracerebral infusions of amphetamine to broaden understanding of how this drug acts on mesolimbic neuronal systems to alter behavior. 2. Rats, tested in sets of three, were allowed to interact with each other or with various novel objects in an open-field arena. Specific behavioral responses were assessed and grouped into several broad categories: motivation (movement directed toward novel objects), social (movement involving contact with other rats), and motor (movement without obvious direction toward environmental stimuli) as well as no movement (quiet rest). 3. Infusion of d-amphetamine (10 micrograms/microliter) into either the amygdala or nucleus accumbens elevated motor behavior relative to control rats in the set, but only amygdaloid infusions also increased the motivation score. Intra-amygdaloid clozapine or haloperidol blocked the increase in this score, but only clozapine also blocked the motor effects of intra-amygdaloid amphetamine. 4. Although neither neuroleptic in the accumbens blocked the amphetamine-induced increase in the motor category, both clozapine and haloperidol lowered the motivation score below the amphetamine level. 5. The results suggest a role for the amygdala in the motivational component of amphetamine-induced behavioral effects. Both neuroleptics, moreover, appear to reverse this component perhaps by acting via either amygdaloid or accumbal mechanisms. Although follow-up studies are warranted, a neuroethological approach is likely to shed new light on the neuronal systems underlying the complex behavioral changes induced by amphetamine and related stimulants.

Amphetamine↗
PubMed1998

Heterogeneity of ventral tegmental area neurons: single-unit recording and iontophoresis in awake, unrestrained rats.

Single-unit recording combined with iontophoresis of dopamine, GABA, and glutamate was used in awake, unrestrained rats to characterize the electrophysiological and receptor properties of neurons in the ventral tegmental area under naturally occurring behavioural conditions. All isolated ventral tegmental area units (n=90) were analysed and compared with cells (n=58) recorded from dorsally adjacent areas of the pre-rubral area and red nucleus. Two distinct neuronal groups were identified in the ventral tegmental area: units with triphasic, long-duration spikes (78/90) and units with biphasic, short-duration spikes (12/90). Although all long-spike units discharged in an irregular, bursting pattern with varying degrees of within-burst decrements in spike amplitude, they could be further subdivided into at least three distinct subgroups. Type I long-spike units (36/78) discharged at a relatively slow and stable rate (mean: 6.03 imp/s; range: 0.42-15.78) with no evident fluctuations during movement. These cells were inhibited by dopamine and GABA and responded to glutamate with a low-magnitude excitation accompanied by a pronounced decrement in spike amplitude and a powerful rebound inhibition. Type II long-spike units (23/78) had relatively high and unstable discharge rates (mean: 22.82 imp/s; range: 4.42-59.67) and showed movement-related phasic activations frequently followed by partial or complete cessation of firing. Some Type II cells (4/9) were inhibited by dopamine, but all were excited by glutamate at very low currents (0-10 nA). With an increase in current, the glutamate-induced excitation often (18/22) progressed into a cessation of firing. All these cells were inhibited by GABA followed by a strong rebound excitation (8/9), which also frequently (6/8) resulted in cessation of firing. Type III long-spike units (19/78) had properties that differed from either Type I or Type II cells, including a lack of spontaneous firing (5/19). Short-spike ventral tegmental area units were either silent (4/12) and unresponsive to dopamine and GABA or spontaneously active (range: 0.89-34.13 imp/s) and inhibited by GABA and, in some cases (2/8). by dopamine; all were phasically activated during movement and glutamate iontophoresis. It appears that ventral tegmental area neurons, including those with long-duration spikes, do not comprise a uniform population in awake, unrestrained rats. Type I, long-spike units match the characteristics of histochemically-identified dopamine neurons, and they appear to express dopamine autoreceptors, which may explain the relatively slow, stable rate of activity and the limited responsiveness to excitatory inputs. Although the nature of the other long-spike units in our sample is unclear, they may include dopamine neurons without autoreceptors as well as non-dopamine cells. The heterogeneity of ventral tegmental area neurons is an important consideration for further attempts to assess the role of the mesocorticolimbic dopamine system in motivated behaviour.

Animals↗
PubMed1998

Real-time assessments of dopamine function during behavior: single-unit recording, iontophoresis, and fast-scan cyclic voltammetry in awake, unrestrained rats.

Although ample evidence implicates the dopamine (DA) projection to the neostriatum and nucleus accumbens in motor and motivational processes, relatively little information is available on how DA alters neostriatal or accumbal functions under naturally occurring behavioral conditions. Further insight into neuron-behavior relationships can be achieved with the application of single-unit recording techniques, including iontophoresis and fast-scan cyclic voltammetry (FSCV), to awake, unrestrained animals. Single-unit recording has revealed that amphetamine, a widely abused psychomotor stimulant, activates motor-, but inhibits nonmotor-related neurons in neostriatum and nucleus accumbens. Although either response can be blocked by DA receptor antagonists, the amphetamine-induced activation also depends on an intact corticostriatal system, suggesting a role for glutamate (GLU). Both neostriatal and accumbal neurons are sensitive to iontophoretic application of either DA or GLU, but when applied during low-dose application of DA, the GLU signal is enhanced relative to background activity. In effect, DA appears to modulate GLU by strengthening the GLU signal-to-noise ratio. To assess DA release under behaviorally relevant conditions, FSCV has been used to obtain real-time measurements of DA efflux in a free-choice novelty test. DA efflux increased only during the brief period of entry into novelty, and the increase was confined to accumbal shell and the shell-core transition zone, the so-called shore. Neither accumbal core nor the overlying neostriatum showed a novelty-related DA change. Thus, DA release during behavior is not uniform and in the case of novelty appears targeted to the limbic-related area of accumbal shell. Further application of these and other in vivo technologies to ambulant animals is required to identify the complex mechanisms underlying both the release of DA and its effect on neostriatal and accumbal neurons during behavior.

Alcoholism↗
PubMed1997

Regional and temporal differences in real-time dopamine efflux in the nucleus accumbens during free-choice novelty.

To assess dopamine efflux during novelty-seeking behavior in rats, fast-scan cyclic voltammetry in the nucleus accumbens was combined with free-choice entry into a novel environment. Cyclic voltammograms, confirmed by in vitro testing, revealed that entry into novel, but not familiar, surroundings increased dopamine efflux in a regionally and temporally distinct pattern. Whereas dopamine failed to change in the core region of the accumbens and overlying neostriatum, an abrupt increase occurred in accumbal shell, a limbic-related area implicated in goal-directed behavior. Although the dopamine response was confined to the brief period of entry into novelty (approximately 8 s duration), a less rapid and more persistent dopamine change (> 20 s duration) occurred in the shell-core transition zone, the so-called shore. These results suggest that novelty mimics other positively reinforcing stimuli in enhancing dopamine transmission in the nucleus accumbens, but the regional and temporal heterogeneity of this effect may represent different aspects of accumbal dopamine function.

Animals↗
PubMed1997

Quinpirole inhibits striatal and excites pallidal neurons in freely moving rats.

The activity of single neurons in the striatum of freely moving rats was recorded in response to systemic administration of dopamine agonists selective for either the D1 or D2 family of receptors. At a dose that induced behavioral activation, SKF-38393 (5.0 mg/kg s.c.), a D1 agonist, had no consistent effect on striatal activity, whereas quinpirole (1.0-5.0 mg/kg s.c.), a D2 agonist, inhibited the great majority of striatal neurons. In addition, quinpirole (1.0 mg/kg s.c.) excited neurons of the globus pallidus, which receives an inhibitory projection from the striatum. These results are consistent with models of the basal ganglia in which dopamine, via D2 receptors, inhibits striatopallidal activity, resulting in a disinhibition of neurons in globus pallidus.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Iontophoresis of amphetamine in the neostriatum and nucleus accumbens of awake, unrestrained rats.

When administered systemically to ambulant animals, amphetamine (AMPH) has both excitatory and inhibitory effects on single-unit activity in the neostriatum and nucleus accumbens. To determine the extent to which these results reflect a direct action of the drug, AMPH was applied iontophoretically to neostriatal and accumbal neurons under naturally occurring behavioral conditions. AMPH dose-dependently (5-40 nA) inhibited the vast majority of spontaneously active units. The inhibition, which was evident at low ejection currents (5-10 nA), had relatively short onset (4-12 s) and offset (6-24 s) latencies, and was positively correlated with basal firing rate. Even stronger dose-dependent inhibitory responses were recorded when neurons having no or a very low rate of spontaneous activity were tonically activated by continuous, low-current applications of glutamate (Glu). Systemic injection of either SCH-23390 (0.1 mg/kg) or haloperidol (0.2 mg/kg), relatively selective D1 and D2 receptor antagonists, respectively, blocked the AMPH-induced inhibition. Prolonged AMPH iontophoresis (2-3 min; 5-30 nA) inhibited both spontaneous impulse activity and Glu-induced excitations, resulting in a complete blockade of the Glu response at relatively high AMPH ejection currents (> or = 20 nA). Taken together, these results suggest that although dopamine is largely responsible for the inhibitory effects of iontophoretic AMPH, dopamine alone cannot account for the complex response of neostriatal and accumbal neurons to systemic AMPH administration.

Action Potentials↗
PubMed1997

Activity of presumed dopamine neurons in the ventral tegmental area during heroin self-administration.

To assess the pattern of mesocorticolimbic dopamine (DA) activity associated with drug-seeking and drug-taking behavior, we monitored the firing rate of presumed DA neurons in the ventral tegmental area of trained rats during i.v. heroin self-administration (SA). Relative to a slow and irregular basal activity, the first SA of each session was preceded by a phasic increase and followed by a more persistent increase in discharge rate that peaked approximately 15-20 min later at the time of the second SA. All subsequent SAs were associated with a biphasic neuronal change: a transient decrease followed by a gradual increase that peaked just before the next SA. Our results support mesocorticolimbic DA activation in heroin-seeking behavior but suggest a transient inhibition of DA activity correlated with heroin reward.

Animals↗
PubMed1997

Responses of neurons in dorsal striatum during amphetamine-induced focused stereotypy.

The phase of highly focused, repetitive behavior (stereotypy) induced by amphetamine in rats emerges after an initial period of locomotor activation. To assess the neuronal correlates of this behavioral transition, single-unit activity was recorded from the dorsal striatum of awake, unrestrained rats. Units were first characterized in terms of their responsiveness to spontaneous movement. Various types of motor-related neurons were identified. Some increased activity above resting baseline during specific movements such as forward locomotion or turning of the head, while others were excited during periods of general behavioral activation. Neurons that showed no consistent change in firing rate during overt movement were classified separately. Administration of 5.0 mg/kg d-amphetamine caused a steady increase in the overall neuronal response through both the locomotor and stereotypy phases. An analysis of specific neuronal types, however, revealed distinct, phase-related shifts in firing rate. Locomotor-related neurons discharged rapidly during the early phase of the amphetamine response and then declined toward baseline as focused stereotypy emerged. Cells found to be excited primarily during head movements showed relatively small changes shortly after drug administration but increased markedly in conjunction with intense head-movement activity associated with focused stereotypy. Other neurons, which increased activity nonselectively to a wide range of movements, showed progressive increases in firing rate during both behavioral phases elicited by the drug. Subsequent administration of 1.0 mg/kg haloperidol typically reversed the neuronal changes and blocked amphetamine-induced focused stereotypy. Nonmotor-related cells responded inconsistently to amphetamine, showing an inhibition, excitation, or no change in rate. Previous assessments of neuron-behavior relationships have shown that changes in motor-related neuronal activity are not secondary to amphetamine-induced behavioral changes, though this finding may not apply in all cases. At doses capable of eliciting focused stereotypy, therefore, amphetamine appears to trigger a complex pattern of striatal activity that governs the behavioral response. This conclusion supports steadily increasing evidence that the role of striatal neurons in amphetamine-induced focused stereotypy is shaped by multiple synaptic mechanisms.

Amphetamine↗
PubMed1997

Transient increases in catecholaminergic activity in medial prefrontal cortex and nucleus accumbens shell during novelty.

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.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Real-time measurement of electrically evoked extracellular dopamine in the striatum of freely moving rats.

The real-time measurement of electrically evoked dopamine was established in brain extracellular fluid of freely moving rats. Dopamine was monitored by fast-scan cyclic voltammetry at carbon fiber microelectrodes lowered into the striatum by means of a detachable micromanipulator. A stimulating electrode, previously implanted in the substantia nigra, was used to evoke striatal dopamine efflux. Evoked extracellular dopamine was both current and frequency dependent. When low current intensities (+/-125 microA) and frequencies (10-20 Hz) were applied, detectable levels of dopamine were elicited without a perceptible behavioral response. Reproducible concentrations of extracellular dopamine could be evoked in the same rat for at least 2 months. These concentrations, moreover, were significantly higher in freely moving rats compared with rats anesthetized with Equithesin. Analysis of measured curves for dopamine uptake and release rates revealed that anesthesia inhibits release but does not affect uptake. It is concluded that (a) fast-scan cyclic voltammetry at carbon fiber microelectrodes is a viable technique for the measurement of electrically evoked dopamine in brain extracellular fluid of freely moving rats, (b) it is possible to determine in situ rate constants for dopamine release and uptake from these temporally and spatially resolved measurements of levels of dopamine, and (c) transient changes in extracellular dopamine levels elicited by electrical stimulation are affected by anesthesia.

Anesthesia↗
PubMed1996

Modulatory action of dopamine on acetylcholine-responsive striatal and accumbal neurons in awake, unrestrained rats.

In ambulant rats, iontophoresis of low concentrations of dopamine (DA) enhances the response of neurons in striatum and nucleus accumbens to iontophoretic glutamate. In an extension of this line of investigation, we tested the effects of acetylcholine (ACh), a presumed modulator of neuronal function in these same brain regions, and assessed possible DA-ACh interactions. Data were obtained from spontaneously active neurons known to respond to ACh (5-30 nA) when the animals rested quietly with no overt movement. ACh iontophoresis either excited or inhibited striatal and accumbal activity but excitatory effects predominated in both areas. With multiple applications of ACh, especially at the lowest currents tested, either response often was interspersed with instances of no change in firing rate. Responsiveness to ACh also diminished during periods of spontaneous movement when basal firing showed phasic increases in activity. In fact, neurons with the highest rates of basal activity showed the smallest magnitude response to ACh. Prolonged applications (120-180 s) of DA attenuated basal firing as well as the iontophoretic effects of ACh both during the DA application itself and for up to 1 min after DA ejection offset. The result of these inhibitory effects was no net change in the relative magnitude of the ACh response. Thus, although ACh can modulate striatal and accumbal neuronal activity, DA does not regulate this effect in the same way that it regulates the neuronal responsiveness to glutamate.

Acetylcholine↗
PubMed1996

Amygdaloid neurons respond to clozapine rather than haloperidol in behaving rats pretreated with intra-amygdaloid amphetamine.

Single-unit activity was recorded from the amygdaloid complex in freely moving rats during an infusion of amphetamine directly into the recording site. Relative to the quiet resting period prior to the infusion, amphetamine routinely increased neuronal activity within 5-15 min after infusion onset, and this response continued for at least another 30 min. It was generally accompanied by marked increases in sniffing, rearing, locomotion, and grooming as well as by a tendency to turn to the ipsilateral side. Haloperidol and clozapine, typical and atypical antipsychotic drugs, respectively, were then tested in their ability to reverse these neuronal and behavioral effects. Both antipsychotics were administered subcutaneously at behaviorally effective doses within 10 min after termination of the amphetamine infusion. Haloperidol (1.0 mg/kg) failed to reverse the amphetamine-induced increase in amygdaloid neuronal activity and required more than 20 min to exert a partial blockade of the accompanying behavioral activation. Clozapine (10.0 mg/kg), in contrast, blocked the excitatory effects of amphetamine on all tested neurons and also blocked most amphetamine-induced behaviors within 10 min. Taken together, these results, which support other lines of electrophysiological evidence, point to the amygdala as a critical site in the differential behavioral effects of typical and atypical antipsychotic drugs.

Amphetamine↗
PubMed1996

Localization of motor- and nonmotor-related neurons within the matrix-striosome organization of rat striatum.

Striatal neurons can be classified as movement- and nonmovement-related depending on their ability to change firing rate in close temporal association with spontaneous movement in an open-field arena. The present study assessed the location of these cell types within the compartmental organization of the striatum by combining single-unit recording techniques in freely moving rats with calbindin immunohistochemistry. Movement-related neurons were found predominately either in the matrix or along the matrix-striosome border. Most of these neurons were nonselective in that they increased activity whenever the animals changed from a quiet resting posture to any form of behavioral activation (e.g., grooming, locomotion, rearing). The remaining neurons in this group responded exclusively to movements of the head. Nonselective units discharged at a significantly slower rate than head-movement units during both quiet rest and periods of actual movement. Nonmovement-related neurons, which failed to show a reliable change in activity to overt behavior, comprised a relatively small portion of the neuronal sample but were also located in either the matrix or along the matrix-striosome border. Collectively, these results suggest that even though striatal neurons can be distinguished on the basis of their responsiveness to ongoing behavior in an open-field paradigm, such distinctions are not clearly linked to sites within the matrix or its striosomal borders.

Animals↗
PubMed1996

Dopaminergic modulation of glutamate-induced excitations of neurons in the neostriatum and nucleus accumbens of awake, unrestrained rats.

1. Single-unit recording and iontophoresis were used in awake, unrestrained rats to assess the action of dopamine (DA) and glutamate (GLU) on the spontaneous activity of neurons in the neostriatum and nucleus accumbens. 2. A total of 88 neurons (40 neostriatal and 48 accumbal) was recorded from 7 rats during 13 recording sessions. During quiet rest, spontaneously active neurons discharged at a slow rate and irregular pattern of activity. Accumbal neurons had a significantly faster level of basal activity than neostriatal neurons (modal values of 10.3 vs. 2.1 imp/s, respectively). 3. Neuronal responses to separate applications of DA and GLU (5-80 nA; 15-30 s) were tested on 40 and 76 units (195 and 227 applications), respectively, during the quiet resting period. The effect of prolonged DA iontophoresis (5-80 nA; 2-3 min) on GLU-induced changes in impulse activity was tested on 38 units (72 applications). 4. GLU activated all cells in both structures. This response appeared with a latency of 0.5-4.0 s at different ejection currents (5-40 nA; mean threshold of 22.2 nA) and was highly variable (103-11,520% of basal activity). Response magnitude correlated strongly with the rate of basal activity (r = 0.822). 5. DA inhibited 75% of spontaneously active neostriatal and accumbal cells with a mean threshold of 20.4 nA. In contrast to the GLU excitation, the DA-induced inhibition was relatively weak in magnitude (10-90% of basal activity) and occurred with relatively longer on- and offset latencies than GLU (2-20 s). The inhibitory effect of DA was absent during phasic activations of neuronal activity associated with movement. Two neostriatal neurons responded to DA with a dose-dependent excitation. 6. Prolonged DA iontophoresis altered both basal impulse activity (causing a decrease in 36 of 72 applications and an increase in 4) and the magnitude of the GLU-induced activation (decreasing it in 27 of 72 applications and increasing it in 12). The net result was an overall enhancement of the GLU response relative to the DA-induced change in basal activity (74% of cases). This increase in the GLU response occurred at relatively low DA ejection currents (10-30 nA). It was stronger in the nucleus accumbens than in the neostriatum and was most evident on cells having both a moderate level of basal activity and a relatively small initial response to GLU. When DA was ejected at high currents (> 40 nA) and/or the magnitude of the preceding GLU-induced activation was high (> 800% of basal activity), DA tended to decrease the GLU response. 7. DA appears to exert a slight depression of striatal and accumbal activity, which has the effect of amplifying the phasic activation induced by GLU. Because forebrain DA release occurs in response to behaviorally important stimuli, the DA-induced modulation of the GLU response may play an important role in regulating goal-directed behavior.

Animals↗
PubMed1995

Ascorbate potentiates amphetamine-induced conditioned place preference and forebrain dopamine release in rats.

In order to evaluate the effects of ascorbate, which is known to modulate dopamine neurotransmission, on the reinforcing effects of amphetamine, we coadministered ascorbate and amphetamine during the acquisition of conditioned place preference (CPP) in rats. Our results indicate that 100 mg/kg ascorbate potentiates the CPP induced by 0.5 mg/kg, but not 1.0 mg/kg, amphetamine. A higher dose of ascorbate (500 mg/kg) did not influence the CPP induced by either dose of amphetamine. In vitro release assays revealed that, whereas ascorbate alone (0.01-1.0 mM) did not influence striatal dopamine levels, this vitamin potentiated amphetamine-induced dopamine release in both the nucleus accumbens and neostriatum. Collectively, these results raise the possibility that ascorbate potentiates amphetamine-induced CPP by increasing the ability of this psychostimulant to release dopamine.

Amphetamine↗
PubMed1995

Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine.

Amphetamine and related drugs of abuse facilitate dopamine transmission in the striatum. This action is believed to underlie the increase in firing of striatal motor-related neurons after amphetamine administration in behaving rats. The present study extended this electrophysiological investigation to phencyclidine (PCP), a nonamphetamine psychomotor stimulant that acts primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. Like amphetamine, PCP (1.0, 2.5, or 5.0 mg/kg) increased the activity of striatal motor-related neurons concomitant with behavioral activation. These effects were blocked by subsequent administration of either 1.0 mg/kg haloperidol or 20.0 mg/kg clozapine, typical and atypical neuroleptics, respectively. Dizocilpine (MK- 801), another noncompetitive NMDA antagonist, mimicked the effect of PCP. Collectively, these results indicate that amphetamine and NMDA antagonists exert comparable effects on striatal motor-related neurons, suggesting that the response of these cells to psychomotor stimulants is regulated by a dopaminergic-glutamatergic influence.

Animals↗