Biomedical subjects

G V Rebec

Publications and source records attributed to G V Rebec.

At least 55 records · Page 3Linked to original sources

PubMed1995

Amphetamine, cocaine, and dizocilpine enhance performance on a lever-release, conditioned avoidance response task in rats.

A lever-release version of the conditioned avoidance response (CAR) task was used to assess the behavioral effects of several psychomotor stimulants in rats. The indirect dopamine agonists, d-amphetamine (0.1 and 0.25 mg/kg) and cocaine (7.5 and 15 mg/kg), enhanced performance on this task. Both drugs increased percent avoidance responses and decreased avoidance latency. A higher dose of amphetamine (0.5 mg/kg) also decreased avoidance latency but failed to improve percent avoidance. Similar effects were seen at low (0.01 and 0.025 mg/kg) and high (0.05 mg/kg) doses of dizocilpine (MK-801), a stimulant that acts as a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors. When combined with haloperidol (0.1 mg/kg), a dopamine antagonist, amphetamine (0.25 mg/kg) and dizocilpine (0.025 mg/kg) had differential effects on the lever-release CAR task. Thus, amphetamine-haloperidol was significantly better than haloperidol alone on percent avoidance but not on avoidance latency, whereas dizocilpine-haloperidol had the opposite effect: significantly better than haloperidol alone on avoidance latency but not on percent avoidance. Taken together, these results provide further support for dopaminergic mechanisms in CAR performance but suggest an opposing glutamatergic influence.

Amphetamine↗

PubMed1995

Iontophoresis in the neostriatum of awake, unrestrained rats: differential effects of dopamine, glutamate and ascorbate on motor- and nonmotor-related neurons.

The neostriatum and its major afferent transmitters, dopamine and glutamate, play a critical role in behavior, but relatively little information is available on their postsynaptic effects in behaving animals. As a first step in addressing this shortcoming, single-unit electrophysiology was combined with iontophoresis in the neostriatum of awake, unrestrained rats. Relative to periods of quiet rest, most neurons (58 of 77) changed discharge rate in close temporal association with movement, while the remainder showed no such relationship. When animals resumed a resting posture, iontophoretic current-response curves were established for dopamine and glutamate as well as for ascorbate, a modulator of neostriatal function released from glutamatergic terminals. Application of either glutamate or ascorbate produced current-dependent increases in activity in all neurons, although this effect was somewhat less pronounced for nonmotor cells. In both types of neurons, the excitatory effect of ascorbate either diminished or shifted to an inhibition at high ejection currents. Dopamine, on the other hand, routinely excited motor-related, but inhibited nonmotor-related neurons. Further assessment of motor-related neurons revealed that in most cases the excitatory effects of either glutamate or dopamine alone were supra-additive when these compounds were either administered together or co-administered with ascorbate. Our results suggest that the response of neostriatal neurons to glutamate or dopamine depends, at least in part, on the motor responsiveness of these cells. Motor-related neurons, moreover, respond to the co-administration of glutamate and dopamine with synergistic increases in firing rate. Ascorbate also influences neostriatal activity, but the postsynaptic action of this substance cannot be explained as a simple interaction with either glutamatergic or dopaminergic mechanisms.

Animals↗

PubMed1994

Cortical lesions attenuate the opposing effects of amphetamine and haloperidol on neostriatal neurons in freely moving rats.

Neuronal activity was recorded from the neostriatum of freely moving rats at least 1 week following either sham or bilateral ablations of frontal and somatosensory cortex. In both groups of animals, the majority of neurons increased firing rate in close temporal association with spontaneous movement. No group differences emerged either with respect to baseline firing rates or open-field behavior. Following amphetamine administration, however, the excitatory response of motor-related neurons was suppressed in cortical-lesioned rats. A behavioral clamping procedure, which assessed neuronal activity during matched pre- and post-amphetamine behaviors, confirmed these results, suggesting that the amphetamine-induced changes in neuronal activity reflect a direct drug effect independent of behavioral feedback. In animals that received a subsequent injection of 1.0 mg/kg haloperidol, cortical lesions attenuated the ability of this neuroleptic to block both the behavioral and neuronal effects of amphetamine. Collectively, these results support mounting evidence for an important modulatory influence of cortical afferents on the amphetamine-induced excitation of neostriatal neurons and the reversal of this effect by haloperidol.

Amphetamine↗

PubMed1994

Performance on a lever-release, conditioned avoidance response task involves both dopamine D1 and D2 receptors.

SCH-23390 (0.01 and 0.05 mg/kg s.c.), a dopamine D1 receptor antagonist, or eticlopride (0.01 and 0.05 mg/kg s.c.), a dopamine D2 receptor antagonist, dose-dependently impaired performance on a lever-release conditioned avoidance response (CAR) task by decreasing percent avoidance responses and increasing avoidance latency. When combined, these drugs impaired CAR performance in an additive fashion. Lever-release CAR performance, therefore, requires activation of both dopamine D1 and D2 receptors.

Animals↗

PubMed1994

Neuronal activity in rabbit neostriatum during classical eyelid conditioning.

Extracellular multiple- and single-unit recordings were made from the neostriatum of rabbits during classical eyelid conditioning. Neostriatal neurons processed information regarding the conditioned auditory stimulus (CS) and conditioned eyelid response (CR) as well as the unconditioned stimulus/response (US/UR). These data are consistent with previous reports that neostriatal neurons respond to movement and movement-related sensory stimuli. In most cases, neostriatal neurons increased activity to the US during the early phase of training, but to the CR as training progressed. A close temporal correlation was found between neuronal activity and CR onset with unit discharges typically preceding CR onset by 10-50 ms. The activity of some multiple and single units was monitored after injection of haloperidol, a neuroleptic and dopamine antagonist known to disrupt neostriatal function. Interestingly, haloperidol caused a greater disruption of CRs at low-intensity than at high-intensity CSs, but conditioning-related neuronal activity was disrupted equally at both intensities. These data are discussed in terms of a possible role for the neostriatum in eyelid conditioning.

Animals↗

PubMed1994

Repeated treatment with ascorbate or haloperidol, but not clozapine, elevates extracellular ascorbate in the neostriatum of freely moving rats.

Acute administration of neuroleptic drugs alters the extracellular level of ascorbate in the neostriatum, and increasing evidence suggests a role for this vitamin in the behavioral, and possibly therapeutic, effects of these drugs. To shed further light on this issue, extracellular ascorbate was recorded in the neostriatum and nucleus accumbens of awake, behaving rats following chronic treatment with either classical (haloperidol) or atypical (clozapine) neuroleptics or ascorbate itself. Electrochemically modified, carbon-fiber microelectrodes were lowered in place the day after the last of 21 daily injections of either haloperidol (0.5 mg/kg, SC), clozapine (20 mg/kg, IP), sodium ascorbate (500 mg/kg, IP) or vehicle. Voltammetric measurements were obtained during quiet rest and following administration of d-amphetamine (2.5 mg/kg). Repeated treatment with either haloperidol or ascorbate elevated basal extracellular ascorbate and potentiated the amphetamine-induced increase in ascorbate release in neostriatum but not nucleus accumbens. Both treatment groups also showed a significant increase in amphetamine-induced sniffing and repetitive head movements compared to vehicle-treated animals. In contrast, repeated clozapine had no effect on extracellular ascorbate in either neostriatum or nucleus accumbens, but increased the locomotor response to an amphetamine challenge. Thus, to the extent that increases in neostriatal ascorbate exert neuroleptic-like effects, such effects are likely to parallel haloperidol rather than clozapine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

A methodology for determining the patch-matrix compartmental location of extracellular single-unit recordings in the striatum of freely moving rats.

A methodology was developed to combine extracellular electrophysiological recording techniques in awake, behaving rats with immunohistochemical protocols to determine the placement of recording sites in the patch (striosome) or matrix (extrastriosome) regions of the striatum. The recording system includes a 3-barrel glass micropipette, which can be used to deposit Pontamine Sky Blue to mark a small number of neurons at the recording site. Subsequent immunostaining for calbindin allows the site to be localized within the patch-matrix organization. Other dyes or neuroanatomical probes can be ejected from other barrels of the recording pipette to label afferent and efferent structures. The methodology can be applied to many brain regions, providing for integrative studies of behavior and nervous system structure and function.

Animals↗

PubMed1994

A vitamin as neuromodulator: ascorbate release into the extracellular fluid of the brain regulates dopaminergic and glutamatergic transmission.

Ascorbate is an antioxidant vitamin that the brain accumulates from the blood supply and maintains at a relatively high concentration under widely varying conditions. Although neurons are known to use this vitamin in many different chemical and enzymatic reactions, only recently has sufficient evidence emerged to suggest a role for ascorbate in interneuronal communication. Ascorbate is released from glutamatergic neurons as part of the glutamate reuptake process, in which the high-affinity glutamate transporter exchanges ascorbate for glutamate. This heteroexchange process, which also may occur in glial cells, ensures a relatively high level of extracellular ascorbate in many forebrain regions. Ascorbate release is regulated, at least in part, by dopaminergic mechanisms, which appear to involve both the D1 and D2 family of dopamine receptors. Thus, amphetamine, GBR-12909, apomorphine, and the combined administration of D1 and D2 agonists all facilitate ascorbate release from glutamatergic terminals in the neostriatum, and this effect is blocked by dopamine receptor antagonists. Even though the neostriatum itself contains a high concentration of dopamine receptors, the critical site for dopamine-mediated ascorbate release in the neostriatum is the substantia nigra. Intranigral dopamine regulates the activity of nigrothalamic efferents, which in turn regulate thalamocortical fibers and eventually the glutamatergic corticoneostriatal pathway. In addition, neostriatonigral fibers project to nigrothalamic efferents, completing a complex multisynaptic loop that plays a major role in neostriatal ascorbate release. Although extracellular ascorbate appears to modulate the synaptic action of dopamine, the mechanisms underlying this effect are unclear. Evidence from receptor binding studies suggests that ascorbate alters dopamine receptors either as an allosteric inhibitor or as an inducer of iron-dependent lipid peroxidation. The applicability of these studies to dopamine receptor function, however, remains to be established in view of reports that ascorbate can protect against lipid peroxidation in vivo. Nevertheless, ample behavioral evidence supports an antidopaminergic action of ascorbate. Systemic, intraventricular, or intraneostriatal ascorbate administration, for example, attenuates the behavioral effects of amphetamine and potentiates the behavioral response to haloperidol. Some of these behavioral effects, however, may be dose-dependent in that treatment with relatively low doses of ascorbate has been reported to enhance dopamine-mediated behaviors. Ascorbate also appears to modulate glutamatergic transmission in the neostriatum. In fact, by facilitating glutamate release, ascorbate may indirectly oppose the action of dopamine, though the nature of the neostriatal dopaminergic-glutamatergic interaction is far from settled. Ascorbate also may alter the redox state of the NMDA glutamate receptor thus block NMDA-gated channel function.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Amphetamine promotes neostriatal ascorbate release via a nigro-thalamo-cortico-neostriatal loop.

In the neostriatum, amphetamine and other dopamine agonists elevate the extracellular level of ascorbate, which is known to modulate neostriatal function. Although both D1 and D2 receptors have been linked to neostriatal ascorbate release, ample evidence suggests it is controlled by areas outside the neostriatum. The present series of experiments used selective lesions and intracerebral drug infusions to probe the involvement of the ventromedial thalamus and substantia nigra pars reticulata. Our results implicate both of these sites in amphetamine-induced increases in the release of neostriatal ascorbate. Thus, whereas unilateral electrolytic lesions of the substantia nigra pars reticulata completely abolished the ability of systemic amphetamine (2.5 mg/kg) to increase extracellular ascorbate in ipsilateral neostriatum, intranigral infusions of this drug (10 and 30 micrograms/microliters) elevated neostriatal ascorbate release. This infusion effect, moreover, was blocked by electrolytic lesions of the ipsilateral ventromedial thalamus, which receives input from the substantia nigra pars reticulata and projects to the cerebral cortex. These results, combined with previous evidence implicating cortical projections to neostriatum as the source of extracellular ascorbate, suggest that neostriatal ascorbate release is regulated, at least in part, by a nigro-thalamo-cortico-neostriatal pathway.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Neuronal and behavioral correlates of intrastriatal infusions of amphetamine in freely moving rats.

When injected systemically in rats, amphetamine routinely activates striatal neurons that increase firing rate in close temporal association with movement but suppresses nonmotor-related neurons. To assess the role of striatal mechanisms in these opposing effects, D-amphetamine (20 micrograms/microliters) was infused (10 microliters/h) directly into the striatum of awake, behaving rats and single-unit activity was recorded simultaneously at the infusion site. Intrastriatal amphetamine reliably activated motor-related, but suppressed nonmotor-related neuronal activity shortly after infusion onset. These changes in firing rate preceded overt behavioral changes, in most cases by several minutes. When they did emerge, behavioral responses were characterized mainly by focused sniffing and head bobbing. Interestingly, the strongest behavioral responses, as measured by onset latency and response magnitude, were likely to result from infusions into motor-related rather than nonmotor-related recording sites. Systemic injection of haloperidol (1.0 mg/kg) shortly after infusion offset suppressed both behavior and striatal neuronal activity. Control infusions of intrastriatal saline had no consistent effect on either striatal neuronal activity or behavior. Collectively, these results indicate that the divergence in firing rate between motor- and nonmotor-related striatal neurons reflects an intrinsic action of amphetamine in the striatum rather than a secondary effect of behavioral feedback. Moreover, the linkage of motor-related striatal areas with the strongest behavioral responses to amphetamine suggests important functional differences between motor- and nonmotor-related striatal neurons.

Amphetamine↗

PubMed1993

The involvement of D1 and D2 dopamine receptors in amphetamine-induced changes in striatal unit activity in behaving rats.

Selective D1 (SCH-23390) and D2 (eticlopride and sulpiride) dopamine receptor antagonists were assessed for their ability to reverse the effects of 1.0 mg/kg D-amphetamine on excitatory motor-related neurons in the striatum of freely moving rats. SCH-23390 (0.125, 0.25, 0.5 and 1.0 mg/kg) rapidly and consistently blocked amphetamine-induced neuronal excitations as did eticlopride (0.25 and 1.0 mg/kg). In contrast, (-)-sulpiride (10, 20 and 40 mg/kg) failed to alter the neuronal response to amphetamine. Similarly, SCH-23390 and eticlopride also blocked the behavioral effects of amphetamine, but sulpiride did not. Collectively, these results support the involvement of D1 and D2 dopamine receptors in the excitatory effects of amphetamine on striatal neurons, but suggest caution in assessing the neuronal and behavioral effects of sulpiride.

Animals↗

PubMed1993

Responses of rat striatal neurons during performance of a lever-release version of the conditioned avoidance response task.

Neural activity was recorded from 218 sites in the striatum (caudate-putamen and nucleus accumbens) of rats trained on a lever-release version of the conditioned avoidance response (CAR) task, in which an auditory signal elicits a short-latency, forelimb withdrawal. > 80% of these recording sites showed task-related activity, including neurons that responded to the auditory stimulus (signal-related cells), the lever-release (response-related cells), or both of these events (signal/response-related cells). Histological analysis revealed a predominance of signal-related neurons in medial striatum, whereas lateral recording sites mainly showed response-related activity. Haloperidol (0.1 mg/kg s.c.), a widely used neuroleptic that impairs CAR performance, significantly attenuated task-related neural activity without altering the latency of the neural response or spontaneous firing rate. Collectively, these results, which demonstrate the usefulness of the lever-release CAR paradigm for assessing striatal function, suggest that the sensory and motor aspects of the CAR task are processed by different striatal regions. Moreover, haloperidol appears to disrupt the striatal processing of both sensory and motor information.

Acoustic Stimulation↗

PubMed1993

A simple micromanipulator for multiple uses in freely moving rats: electrophysiology, voltammetry, and simultaneous intracerebral infusions.

An inexpensive, easily fabricated micromanipulator is described that can be used for single-unit recording or voltammetry in freely moving rats. The basic design is configured around the standard coupling system between a plastic syringe and corresponding needle hub. The device can be used with glass or metal microelectrodes for electrophysiology or carbon-fiber or carbon-disk microelectrodes for voltammetry. With either recording technique, the micromanipulator also can accommodate a 33-ga infusion cannula, which allows drugs to be administered directly to the recording site. The entire assembly is lightweight and can be used with a head-mounted amplifier system for relatively noise-free recording.

Action Potentials↗

PubMed1993

Striatal single-unit responses to amphetamine and neuroleptics in freely moving rats.

Single-unit recordings from 50 striatal neurons in freely moving rats revealed generally low activity (< 3 spikes/sec) during resting behavior and movement-related excitations in most (n = 36) neurons. While activating behavior, d-amphetamine (1.0 mg/kg, sc) usually excited and inhibited motor- and nonmotor-related neurons, respectively, relative to resting baseline firing rates. A behavioral clamping analysis, which controlled for neuronal effects secondary to behavior, yielded results suggesting a primary, amphetamine-induced excitation of striatal motor-related neurons. Haloperidol (0.1-1.0 mg/kg) strongly inhibited behavior and neuronal activity when injected 30 min after amphetamine. Clozapine (5.0-30.0 mg/kg) inhibited only selected behaviors, but reliably produced haloperidol-like reversals of amphetamine-induced neuronal excitations. A literature review revealed that the neuronal results in behaving animals differ markedly from the inhibitory striatal responses to amphetamine and the excitatory responses to dopamine antagonists often found in immobilized or anesthetized rat preparations. These contrasting, preparation-dependent results support a model based on drug interactions with a proposed neuromodulatory function of striatal dopamine, which is to facilitate or attenuate the activity of neurons receiving, respectively, substantial, or little excitatory afferent input.

Amphetamine↗

PubMed1993

Intraneostriatal administration of glutamate antagonists increases behavioral activation and decreases neostriatal ascorbate via nondopaminergic mechanisms.

Behavioral findings suggest that the effects of neostriatal glutamate and ascorbate are opposed to those of neostriatal dopamine. Recent evidence also indicates that glutamate and ascorbate are linked via a carrier-mediated heteroexchange process, suggesting that ascorbate may act through the glutamate system to influence behavior. In order to assess glutamate-ascorbate interactions and their influence on the behavioral output of the basal ganglia, glutamate and homocysteic acid (a glutamate reuptake blocker) as well as NMDA antagonists were infused into the neostriatum of freely moving rats while extracellular neostriatal ascorbate was monitored via electrochemically modified carbon-fiber electrodes. Neostriatal 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, also was recorded in order to assess the dependency of any drug effect on the nigrostriatal dopamine system. Intraneostriatal infusions of L-glutamate (1 micrograms/microliters), but not L-homocysteic acid (30 micrograms/microliters), elevated extracellular neostriatal ascorbate levels. Neither of these drugs had any effect on neostriatal DOPAC or overt behavioral activity. Intraneostriatal infusion of the noncompetitive NMDA antagonist dizocilpine (MK-801; 3 micrograms/microliters) or the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonene (CPPene; 5 micrograms/microliters) decreased neostriatal ascorbate but had no effect on neostriatal DOPAC. Both dizocilpine and CPPene activated behavior in intact and sham-lesioned animals as well as in animals with near-total depletions of neostriatal dopamine following a 6-hydroxydopamine lesion. When administered systemically, however, dizocilpine (1.0 mg/kg) significantly increased neostriatal DOPAC. This effect appears to be regulated via midbrain NMDA receptors, in that this effect was completely abolished by electrolytic lesions of the substantia nigra pars reticulata.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Unilateral neostriatal kainate, but not 6-OHDA, lesions block dopamine agonist-induced ascorbate release in the neostriatum of freely moving rats.

Unilateral kainate lesions of the neostriatum and 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle were used to assess the role of neostriatal and ascending dopaminergic neurons, respectively, on dopamine-agonist induced release of neostriatal ascorbate as measured voltammetrically in freely moving rats. Electrochemically modified, carbon-fiber electrodes recorded the effects of direct (a combination of 10 mg/kg SKF-38393 and 1.0 mg/kg quinpirole) as well as indirect (2.5 mg/kg D-amphetamine or 20.0 mg/kg GBR-12909) dopamine agonists. Relative to controls, kainate, but not 6-OHDA, lesions abolished the ability of both direct and indirect dopamine agonists to induce neostriatal ascorbate release. These results suggest that unlike dopaminergic afferents, neostriatal output pathways play a critical role in the modulation of neostriatal ascorbate levels.

Animals↗

PubMed1992

Dopamine-, NMDA- and sigma-receptor antagonists exert differential effects on basal and amphetamine-induced changes in neostriatal ascorbate and DOPAC in awake, behaving rats.

Amphetamine and other dopamine agonists elevate the extracellular level of neostriatal ascorbate, which has been shown to modulate neuronal function. To assess the receptor mechanisms underlying neostriatal ascorbate release, drug-induced changes in both basal and amphetamine-induced ascorbate release were monitored voltammetrically in the neostriatum of freely moving rats. A variety of dopamine receptor antagonists decreased basal ascorbate and reversed the increase induced by 2.5 mg/kg D-amphetamine. Thus, compared to vehicle treatment, administration of classical (haloperidol) and atypical (clozapine) neuroleptics or selective D1 (SCH-23390) and D2 (sulpiride) antagonists completely reversed the amphetamine-induced rise in ascorbate and also lowered basal levels by 20-40%. These same effects occurred following injection of dizocilpine (MK-801), a non-competitive NMDA antagonist, whereas BMY-14802, a sigma ligand, reversed the amphetamine-induced rise without altering basal levels. Simultaneous measurements of extracellular DOPAC, a major dopamine metabolite, revealed that haloperidol, clozapine, sulpiride and BMY-14802 elevated basal levels and reversed the amphetamine-induced decline. Dizocilpine also increased basal DOPAC but failed to alter the DOPAC response to amphetamine, whereas both basal and amphetamine-induced changes in DOPAC were unaffected by SCH-23390. A combination of subthreshold doses of SCH-23390 and sulpiride, however, reversed both the amphetamine-induced release of ascorbate and the corresponding decline in DOPAC. Collectively, these results suggest that whereas dopamine, sigma, and NMDA receptors modulate neostriatal ascorbate release, they exert an opposing influence on extracellular DOPAC. All drugs attenuated at least some components of the amphetamine behavioral response, suggesting a role for multiple mechanisms in the behavioral effects of this drug.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

BMY-14802, a sigma ligand and potential antipsychotic drug, reverses amphetamine-induced changes in neostriatal single-unit activity in freely moving rats.

The effects of BMY-14802 (5, 10, or 20 mg/kg), a sigma-receptor ligand showing preclinical evidence of antipsychotic efficacy, were tested on single-unit activity in the neostriatum of freely moving rats with or without pretreatment with 1.0 mg/kg D-amphetamine. Relative to resting baseline, amphetamine activated the large majority of neurons that changed firing rate in close temporal association with movement. All doses of BMY-14802 reversed this neuronal response, but the effect was most pronounced at 20 mg/kg. This dose, however, was equally likely to reverse or to induce a haloperidol-like potentiation of those neurons inhibited by amphetamine. In contrast, 10 mg/kg BMY-14802 consistently reversed amphetamine-induced neuronal inhibitions. All doses of BMY-14802 attenuated the locomotor effects of amphetamine, but only the higher doses also blocked other aspects of the amphetamine behavioral response. By itself, BMY-14802 dose dependently inhibited motor-related neurons, but elicited less behavioral activation than amphetamine. BMY-14802 (20 mg/kg) also induced hindlimb ataxia and occasional backwards locomotion. Haloperidol (1.0 mg/kg) reliably suppressed both behavior and neuronal activity when injected 30 min after BMY-14802, whether or not amphetamine pretreatment was given. Thus, BMY-14802 shares with other neuroleptics the capacity to reverse amphetamine-induced excitations of neostriatal motor-related neurons, whereas other effects of BMY-14802 reveal some haloperidol-like actions at 20 mg/kg that do not occur at lower doses.

Amphetamine↗