Biomedical subjects

G V Rebec

Publications and source records attributed to G V Rebec.

At least 73 records · Page 4Linked to original sources

PubMed1992

A lever-release version of the conditioned avoidance response paradigm: effects of haloperidol, clozapine, sulpiride, and BMY-14802.

Rats trained on a lever-release version of the conditioned avoidance response (CAR) task were used to test the behavioral effects of established and putative antipsychotic drugs. Baseline CAR latencies decreased as the conditioned-unconditioned stimulus interval was shortened from 500 to 250 ms. Haloperidol, clozapine, and BMY-14802 decreased successful avoidance responses and increased avoidance latencies in a dose-dependent manner without affecting the latency of escape responses. In contrast, sulpiride failed to affect either successful avoidance response rates or avoidance latency. Sulpiride, however, significantly attenuated d-amphetamine-induced locomotion and rearing compared to vehicle-treated controls. Similar effects of these antipsychotics have been reported on shuttlebox avoidance, and these results now are confirmed in a CAR paradigm that achieves greater control over behavior. Because this paradigm elicits a discrete forelimb response without activating numerous muscle groups, it is potentially useful as a tool for examining neuronal mechanisms underlying the behavioral effects of antipsychotic drugs.

Animals↗

PubMed1991

Bilateral cortical ablations attenuate amphetamine-induced excitations of neostriatal motor-related neurons in freely moving rats.

Single-unit recordings from neostriatal neurons showing movement-related excitations were obtained in freely moving, cortically ablated rats and sham-lesioned controls. D-Amphetamine (AMPH, 1.0 mg/kg s.c.) increased neuronal activity relative to resting baseline firing rates in both groups of animals, but cortical ablation significantly attenuated this effect. A behavioral clamping analysis, which compared neuronal activity during identically rated pre- and post-AMPH behaviors, revealed that: (a) AMPH enhanced movement-related neuronal activity in sham-lesioned controls, but not in cortically ablated rats; and (b) the drug-induced neuronal activation in control rats was not simply secondary to the behavioral activation produced by AMPH. In contrast to its neuronal effects, cortical ablation did not affect ratings of AMPH-induced locomotion, rearing, or head movements, though sniffing scores showed a positive correlation with lesion size. Thus, corticostriatal projections are critically involved in AMPH-induced excitations of neostriatal motor-related neurons.

Action Potentials↗

PubMed1991

Regional distribution of ascorbate and 3,4-dihydroxyphenylacetic acid (DOPAC) in rat striatum.

In vivo voltammetry was used to study the regional distribution of extracellular ascorbate (AA) and 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, in the striatum of the rat. An electrochemically-modified carbon-fiber electrode, which provides distinct oxidation curves for each of these substances, was lowered in 1-mm increments through one of four striatal regions selected to sample the entire extent of this structure, including the nucleus accumbens. In anteromedial striatum, the level of AA was highest in the most dorsal and ventral aspects and lowest in the middle, whereas DOPAC levels generally showed the opposite pattern. This inverse relationship between AA and DOPAC was not evident in either lateral or posterior areas. To the extent that AA and DOPAC are released from different axon terminals, as mounting evidence suggests, regional differences in the extracellular concentration of these compounds may reflect the different and, in some cases, reciprocal distributions of two neuronal populations.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Acute and long-term amphetamine treatments alter extracellular ascorbate in neostriatum but not nucleus accumbens of freely moving rats.

The ability of amphetamine to alter the extracellular level of ascorbate, an apparent modulator of neostriatal function, was assessed voltammetrically in the neostriatum and nucleus accumbens of awake, behaving rats. Whereas acute administration (1.0 and 5.0 mg/kg d-amphetamine) produced a dose-dependent rise in neostriatal ascorbate, there was no change in the nucleus accumbens. Vehicle injections had no significant effect on ascorbate levels in either location. Administration of 5.0 mg/kg d-amphetamine for one week enhanced neostriatal ascorbate release even further, but this effect returned to acute levels when treatment continued for a second week. Multiple amphetamine injections for up to two weeks failed to alter extracellular ascorbate in the nucleus accumbens. The results of these experiments confirm a site-specific action of amphetamine on ascorbate release and suggest complex changes in the extracellular level of this substance in the neostriatum with long-term treatment.

Amphetamine↗

PubMed1991

Chronic ascorbate potentiates the effects of chronic haloperidol on behavioral supersensitivity but not D2 dopamine receptor binding.

Ample behavioral evidence suggests that ascorbate parallels the action of haloperidol, a widely used neuroleptic. To determine the extent to which this parallel extends to chronic treatment, 21 days of exposure to ascorbate (100 or 500 mg/kg) alone or combined with haloperidol (0.5 mg/kg) were assessed on stereotyped behavior and neostriatal D2 dopamine receptor binding in rats. Our results indicate that when challenged with the dopamine agonist, apomorphine (0.5 mg/kg), animals chronically treated with haloperidol or high-dose ascorbate alone display a supersensitive sniffing response relative to controls, while animals chronically treated with the combination of haloperidol and high-dose ascorbate display a further potentiation of sniffing relative to the haloperidol groups. In addition, [3H]spiperone saturation studies showed, as expected, an up-regulation of striatal D2 dopamine receptors in rats treated with haloperidol as reflected by a change in receptor density (Bmax) but not affinity (KD). Ascorbate treatment, however, had no effect on D2 receptor density or the distribution of [3H]apomorphine in whole brain. Even though chronic treatment with the haloperidol-high-dose-ascorbate combination produced an up-regulation of striatal D2 dopamine receptors, this treatment did not cause a further up-regulation relative to haloperidol alone nor did it have any effect on [3H]apomorphine distribution. Taken together, these findings indicate that although chronic ascorbate produces behavioral supersensitivity to apomorphine through central mechanisms, they appear to differ from those induced by chronic haloperidol.

Amphetamines↗

PubMed1990

Stimulation of both D1 and D2 dopamine receptors increases behavioral activation and ascorbate release in the neostriatum of freely moving rats.

Electrochemically modified carbon-fiber electrodes were used to assess the effects of indirect (amphetamine and GBR-12909) as well as direct D1 (SKF-38393) and D2 (quinpirole) dopamine agonists on extracellular ascorbate in the neostriatum of awake, behaving rats. Relative to controls, 2.5 mg/kg d-amphetamine and 20.0 mg/kg GBR-12909 produced marked behavioral activation concomitant with a significant increase in ascorbate. Comparable effects were observed following the combined administration of 10.0 mg/kg SKF-38393 and 1.0 mg/kg quinpirole, but not after either of these drugs alone. Thus, behavioral activation and release of neostriatal ascorbate were closely related to the concurrent stimulation of both D1 and D2 dopamine receptors.

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

PubMed1990

Corticostriatal and thalamic regulation of amphetamine-induced ascorbate release in the neostriatum.

Lesions of cerebral cortex and ventromedial nucleus (VM) of the thalamus were made in rats to investigate the contribution of these structures to amphetamine (AMPH)-induced ascorbate (AA) release in the neostriatum as measured by in vivo voltammetry. Following a recovery period of at least one week, rats were anesthetized, and electrochemically modified, carbon-fiber electrodes were lowered into the neostriatum. Compared to data obtained from sham-operated and unoperated controls, bilateral aspiration lesions of cerebral cortex significantly lowered both the basal level of AA and the amount of AA released by AMPH in the neostriatum. Similar results were obtained after bilateral, but not unilateral electrolytic lesions of the VM thalamus. Collectively, these results suggest that the corticostriatal pathway and the VM thalamic nuclei participate in the regulation of basal and AMPH-induced AA release in the neostriatum.

Animals↗

PubMed1990

Intrastriatal infusions of ascorbate antagonize the behavioral response to amphetamine.

Compared to saline, bilateral infusions of ascorbate (AA) into the neostriatum of freely moving rats attenuated rearing, head bobbing, and sniffing at various times after systemic amphetamine administration. Comparable AA infusions into overlying cerebral cortex failed to alter the amphetamine behavioral response. Intrastriatal AA also enhanced the ability of haloperidol to antagonize amphetamine-induced forepaw shuffling and locomotion. Voltammetric measurements in separate animals revealed a linear increase in neostriatal AA that remained within reasonable physiological limits over the course of the AA infusion. Thus, endogenous AA may modulate behavior via mechanisms intrinsic to the neostriatum.

Administration, Intranasal↗

PubMed1990

Interference by DOPAC and ascorbate during attempts to measure drug-induced changes in neostriatal dopamine with Nafion-coated, carbon-fiber electrodes.

The selectivity of Nafion-coated, carbon-fiber electrodes was evaluated for the voltammetric detection of dopamine in the presence of 3,4-dihydroxyphenylacetic acid (DOPAC) and ascorbate, which are interferant anions in the brain. Nafion coating was applied to both polished carbon-disk electrodes and electrochemically modified electrodes. During in vitro testing, polished disk electrodes showed the greatest selectivity for dopamine at the fastest scan rate tested (300 V s-1), but the drift in signal made slow changes in dopamine difficult to determine. Electrochemically modified electrodes already provide an ascorbate wave distinct from that for dopamine, but Nafion coating actually decreased dopamine selectivity with respect to DOPAC. In vivo testing was carried out in the neostriatum of urethane-anesthetized rats in response to drug- or stimulation-induced increases in dopamine transmission. Administration of haloperidol (0.5 mg kg-1) followed by GBR 12909 (20 mg kg-1), which is known to cause a 10-fold increase in extracellular dopamine, failed to produce a selective signal for dopamine when measured voltammetrically. Comparable results were obtained following administration of amphetamine (2.5 mg kg-1), which also increases dopamine overflow. Voltammetric detection of dopamine was possible, however, during electrical stimulation of dopaminergic afferents in the medial forebrain bundle. Thus, voltammetry with Nafion-coated electrodes is best suited to the measurement of transient changes in extracellular dopamine rather than the relatively prolonged changes in dopamine overflow produced by various drugs.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Serotonergic dorsal raphe neurons: changes in spontaneous neuronal activity and responsiveness to 5-MeODMT following long-term amphetamine administration.

Single-unit activity, characteristic of serotonergic neurons, was recorded in the dorsal raphe nucleus of urethane-anesthetized rats pretreated twice daily with saline or with 10.0 mg/kg D-amphetamine for 6 days. Compared to controls, amphetamine-pretreated animals showed a trend toward increased spontaneous firing rate and decreased responsiveness to 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), a serotonergic autoreceptor agonist. The most pronounced effect of amphetamine pretreatment, however, was a highly significant correlation between spontaneous neuronal activity, measured as either firing rate or interspike interval, and the 5-MeODMT response. Faster firing cells required predictably higher doses of 5-MeODMT to produce an inhibition. No such relationship was observed in control animals. Taken together, these results suggest that repeated administration of relatively high doses of amphetamine produces complex changes in the dorsal raphe including a shift in the sensitivity of serotonergic autoreceptors.

Action Potentials↗

PubMed1989

Amphetamine-induced excitations predominate in single neostriatal neurons showing motor-related activity.

Neostriatal single-unit activity was recorded in freely moving rats. A majority (62%) of the 24 recorded neurons were activated during motor behavior such as locomotion (n = 11) or head movements (n = 4). The behavioral response to amphetamine (1.0 mg/kg) was associated with increases (n = 17) or decreases (n = 7) in firing rate. A significantly greater proportion of motor-related neurons were excited by the drug compared to nonmotor-related cells. These results, which confirm the heterogeneity of amphetamine-induced effects in the neostriatum, indicate that the baseline motor-response characteristics of neostriatal neurons may determine their response to amphetamine.

Action Potentials↗

PubMed1989

Blockade of both D1- and D2-dopamine receptors inhibits amphetamine-induced ascorbate release in the neostriatum.

In vivo recordings with electrochemically modified microvoltammetric electrodes revealed that several neuroleptic drugs, including haloperidol, clozapine, and thioridazine, blocked the rise in extracellular ascorbate produced by amphetamine in the neostriatum of urethane-anesthetized rats. This effect was also observed in animals that received a combined injection of Sch-23390 and sulpiride, but not when either of these drugs were administered alone or in combination with the 5-HT2 blocker, ritanserin. These results indicate that a combined blockade of D1- and D2-dopamine receptors blocks amphetamine-induced ascorbate release.

Amphetamines↗

PubMed1989

A simple device for the reliable production of varnish-insulated, high-impedance tungsten microelectrodes.

The construction and operation of a simple device that produces varnish-insulated, high-impedance tungsten microelectrodes for single-unit recording is described. In essence, the device operates as a high-voltage pulse generator whose output creates an arc between a fully insulated tungsten microelectrode and a polished counter-electrode. As a result, insulation is removed reliably and symmetrically from the microelectrode tip. The device is constructed with a minimal outlay of time, skill, and money.

Electrophysiology↗

PubMed1988

Heterogeneous responses of neostriatal neurons to amphetamine in freely moving rats.

Single-unit activity was recorded from the neostriatum of unrestrained, behaving rats. Neuronal discharges were found to vary with specific motor responses, general changes in motor activity, or the presentation of orienting stimuli. In each case, however, 1.0 mg/kg D-amphetamine produced approximately equal numbers of excitations and inhibitions. A subsequent injection of a higher dose (5.0 mg/kg) either produced a greater change in firing rate in the same direction or reversed the direction of the low-dose response. Amphetamine, therefore, does not produce uniformly excitatory effects in the neostriatum of ambulant animals. In fact, the neuronal response to amphetamine appears to reflect a complex interaction of several factors, including ongoing behavior and drug dose.

Action Potentials↗

PubMed1988

Clozapine and haloperidol in the amygdaloid complex: differential effects on dopamine transmission with long-term treatment.

Single-unit recording techniques and liquid chromatography with electrochemical detection were used to measure the effects of neuroleptic pretreatment on the efficacy of dopamine transmission in the amygdaloid complex. Rats received twice-daily injections of clozapine (10.0 mg/kg), haloperidol (1.0 mg/kg), or vehicle for 6 days. During withdrawal from haloperidol, but not clozapine, amygdaloid neurons were significantly more responsive to iontophoretic application of dopamine. Neither drug altered the neuronal response to norepinephrine or acetylcholine. Tolerance developed to the ability of haloperidol to increase the amygdaloid level of 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, but such an effect did not occur with clozapine. In fact, clozapine pretreatment led to a significant increase in both DOPAC and dopamine levels in the amygdaloid complex. These results suggest that a differential action of these drugs on dopamine transmission may explain their differential effects on postsynaptic dopamine receptors.

Acetylcholine↗

PubMed1988

Reciprocal zones of excitation and inhibition in the neostriatum.

Single-unit activity was recorded in the rat neostriatum at different distances from the point of an infusion of either glutamate or serotonin. In each case, firing rate at the distant site (0.8-1.5 mm) was the mirror image of that at the near site (0.1-0.3 mm). These reciprocal changes were blocked by a subsequent injection of haloperidol, a dopamine antagonist. It appears that a lateral inhibitory network, intrinsic to the neostriatum and possibly modulated by dopamine, plays an important role in the operation of the neostriatum.

Action Potentials↗

PubMed1988

Ascorbate antagonizes the behavioral effects of amphetamine by a central mechanism.

The behavioral response to amphetamine was monitored in rats that received simultaneous intraventricular infusions of saline or ascorbate. Both groups of animals displayed comparable responses, although ascorbate significantly delayed the onset of amphetamine-induced locomotion and rearing. In rats pretreated with a threshold dose of haloperidol (0.025 mg/kg), virtually all aspects of the amphetamine response were attenuated, and this effect was enhanced by ascorbate. In haloperidol-pretreated rats, ascorbate significantly lowered sniffing and forepaw shuffling throughout the amphetamine response. These results suggest that ascorbate antagonizes dopaminergic transmission by a central mechanism.

Amphetamine↗

PubMed1988

Atypical antipsychotic drugs block selective components of amphetamine-induced stereotypy.

Individual items of behavior produced by 1.0 or 5.0 mg/kg d-amphetamine were monitored in rats pretreated 15 minutes earlier with vehicle or with behaviorally relevant doses of haloperidol (0.1 or 0.25 mg/kg), clozapine (1.0 or 5.0 mg/kg), or thioridazine (1.0 or 5.0 mg/kg). Unlike haloperidol, the atypical antipsychotics failed to block all components of either the low- or high-dose response to amphetamine. These drugs, however, did block selective items of amphetamine-induced stereotyped behavior. Clozapine significantly attenuated the sniffing produced by 1.0 mg/kg d-amphetamine as well as the oral behavior (licking and/or biting) produced by 5.0 mg/kg d-amphetamine. Thioridazine, at a dose of 5.0 mg/kg, also reduced oral behavior and selectively blocked repetitive head bobbing. Taken together, these results suggest that although atypical antipsychotic drugs exert some common effects on the amphetamine behavioral response, these drugs do not influence all amphetamine-induced behaviors equally.

Animals↗