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Biomedical subjects

G V Rebec

Publications and source records attributed to G V Rebec.

At least 109 records · Page 6Linked to original sources
PubMed1983

Shift from inhibition to excitation in the neostriatum but not in the nucleus accumbens following long-term amphetamine.

Neuronal responses to 1.0 or 5.0 mg/kg D-amphetamine were recorded simultaneously in the neostriatum and nucleus accumbens of rats pretreated twice daily with these doses or with saline for 6 consecutive days. In all groups, the number of neurons responding to a challenge injection of either dose of amphetamine with an overall excitation or inhibition was not significantly different. During the first 30-60 min of the drug response, however, neurons in the neostriatum of amphetamine-pretreated rats responded with a significant increase in firing rate compared to saline controls. In the nucleus accumbens, on the other hand, tolerance developed to the inhibition produced by 1.0 mg/kg D-amphetamine, whereas the responses produced by 5.0 mg/kg were not significantly altered by long-term treatment. Liquid chromatography with electrochemical detection revealed that pretreatment with 5.0 mg/kg D-amphetamine produced a slight, but significant, reduction of dopamine and norepinephrine levels in the neostriatum. Catecholamine levels were not significantly altered in the nucleus accumbens by either dose. These electrophysiological and neurochemical changes are discussed in relation to the known involvement of these sites in the dose-dependent behavioral alterations that accompany repeated amphetamine injections.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Dopaminergic and neostriatal neurons: dose-dependent changes in sensitivity to amphetamine following long-term treatment.

Rats were pretreated with saline, 1.0 or 5.0 mg/kg of (+)-amphetamine twice daily for 6 consecutive days. Single unit recording in the substantia nigra pars compacta (SNC) and the neostriatum, on the following day, revealed a differential shift in the intravenous dose of the drug required to produce at least a 50% change in neuronal activity (ED50) depending on the pretreatment dose. In the substantia nigra pars compacta, pretreatment with the small dose significantly reduced the ED50, compared to saline controls, whereas in rats pretreated with the large dose, the ED50 was significantly increased. In the neostriatum, control rats responded to increasing incremental doses of (+)-amphetamine with either an inhibition followed by an excitation, or an excitation. Following pretreatment with 1.0 mg/kg, neurons responded with either a depression or an excitation, whereas only amphetamine-induced excitations were recorded in the neostriatum following pretreatment with 5.0 mg/kg. The complex changes in firing rate produced by repeated exposure to amphetamine were dose-dependent in both sites and cannot be simply explained by a decrease in the sensitivity of dopamine neurons to this drug.

Action Potentials↗
PubMed1983

Tolerance to amphetamine-induced inhibition of neuronal activity in the central amygdaloid nucleus.

Rats were pretreated twice daily for 5 consecutive days with saline or 2.5 mg/kg d-amphetamine. Approximately 12 hr after the last injection, neuronal activity was recorded bilaterally from the central amygdaloid nucleus (CAN) and the animals were challenged every 2 min with 0.2 mg/kg d-amphetamine or with increasing incremental doses of apomorphine. In saline controls, all CAN neurons were inhibited by the 5th amphetamine injection and two-thirds were suppressed by 0.64 mg/kg apomorphine. In amphetamine-pretreated animals, on the other hand, the majority of CAN neurons failed to respond even by the 10th amphetamine injection and less than one-third were inhibited by apomorphine even at a dose of 2.56 mg/kg. These results indicate that tolerance develops to the inhibitory effects of d-amphetamine in the CAN and that this effect is mediated, at least in part, by a decrease in the sensitivity of postsynaptic dopamine receptors.

Amygdala↗
PubMed1983

Cataleptogenic potency of the antipsychotic drugs is inversely correlated with neuronal activity in the amygdaloid complex of the rat.

At doses known to elicit catalepsy in rats, haloperidol (1.0 and 2.0 mg/kg) and pimozide (4.0 mg/kg), injected intraperitoneally, failed to alter the spontaneous activity of neurons in the amygdaloid complex of locally anesthetized, immobilized rats. In contrast, clozapine and thioridazine, which are devoid of cataleptic effects even at high doses (10.0 and 20.0 mg/kg), caused a dramatic and prolonged increase in firing rate, whereas chlorpromazine, which produces relatively mild catalepsy at doses of 5.0 and 10.0 mg/kg, produced an intermediate response. These results, which were obtained throughout the amygdaloid complex, indicate that the cataleptogenic potency of the antipsychotic drugs is inversely correlated with their ability to accelerate neuronal activity. This finding is discussed in relation to the known mechanisms of action of these drugs on various neurotransmitter systems in the amygdaloid complex.

Action Potentials↗
PubMed1983

Reciprocal changes in the firing rate of neostriatal and dorsal raphe neurons following local infusions or systemic injections of D-amphetamine: evidence for neostriatal heterogeneity.

A local infusion of d-amphetamine (d-AMPH) into the dorsal raphe nucleus (DRN) inhibited neuronal activity in this site and produced a mirror-image excitation in the ventrolateral, but not dorsomedial, neostriatum. This effect, which was mimicked by 5-methoxy-N,N-dimethyltryptamine, a serotonin autoreceptor agonist, was not altered by pretreatment with alpha-methyl-p-tyrosine. Similar regional differences in neostriatal activity were obtained following an electrolytic lesion of the DRN or an intraperitoneal injection of d-AMPH. In fact, whereas 1.0 mg/kg of d-AMPH accelerated ventrolateral activity and inhibited dorsomedial neurons, 7.5 mg/kg produced the opposite effect. At both doses, however, DRN activity was inversely related to firing rate in the ventrolateral, but not dorsomedial, neostriatum. These results indicate that only certain regions of the neostriatum are responsive to changes in DRN activity and that these regions respond differently to systemic injections of d-AMPH than other neostriatal sites.

Animals↗
PubMed1982

Dorsal raphe neurons: self-inhibition by an amphetamine-induced release of endogenous serotonin.

A direct infusion of amphetamine into the dorsal raphe nucleus of the rat inhibited the activity of serotonergic neurons in this site. An intravenous injection of 5-methoxy-N,N-dimethyltryptamine, a serotonin autoreceptor agonist, mimicked this effect. The amphetamine-induced depression of firing rate was blocked by a subsequent injection of methiothepin, a putative serotonin autoreceptor antagonist, but not by pretreatment with a-methyl-p-tyrosine which depletes brain catecholamines. Amphetamine infusions into the surrounding periaqueductal gray or brainstem reticular formation failed to change dorsal raphe activity. The results of these studies indicate that endogenous serotonin, which can be released by a direct infusion of amphetamine, suppresses neuronal activity in the dorsal raphe nucleus by a process of self-inhibition.

Animals↗
PubMed1982

Differential subsensitivity of dopaminergic and neostriatal neurons to apomorphine with long-term treatment.

The apomorphine-induced inhibition of dopaminergic neurons in the substantia nigra of the rat was significantly attenuated following 2 daily injections of 0.05, 0.5 or 2.0 mg/kg apomorphine for 5 consecutive days. In fact, many of these neurons responded with an increase in firing rate which was never observed in control animals. Neostriatal neurons, on the other hand, decreased their sensitivity to apomorphine only after long-term treatment with 0.5 or 2.0 mg/kg. Multiple injections of the low dose actually potentiated the apomorphine-induced inhibition in the neostriatum. These results, which are consistent with the differential sensitivity of dopaminergic and neostriatal neurons to acute apomorphine, suggest that the subsensitivity of pre- and postsynaptic dopamine receptors produced by long-term apomorphine treatment is dose-dependent.

Animals↗
PubMed1982

Differential sensitivity to amphetamine following long-term treatment with clozapine or haloperidol.

When rats were pretreated for 8 consecutive days with 2.0 mg/kg haloperidol, injection of 2.5 or 5.0 mg/kg d-amphetamine 2 or 6 days later resulted in a larger increase in oral behaviors and a more prolonged period of focused sterotypy than in saline-pretreated controls. This increased sensitivity to amphetamine is consistent with the effects of a chronic haloperidol-induced increase in dopamine receptor sensitivity. In contrast, long-term treatment with either d-amphetamine or clozapine produced complex changes in the multiphasic behavioral response to amphetamine, which cannot be explained solely by a shift in the sensitivity of dopamine receptors.

Amphetamine↗
PubMed1981

Apparent serotonergic modulation of the dose-dependent biphasic response of neostriatal neurons produced by D-amphetamine.

Previous reports indicate that amphetamine produces a dose-dependent shift to the firing rate of neurons in the anterior neostriatum that parallels the shift in behavior from locomotion to focused stereotypy. To determine if para-chlorophenylalanine (PCPA), which alters the pattern of the behavioral response to amphetamine, also changes the pattern of the neuronal response to the drug, a dose-response analysis was performed on amphetamine-induced changes in unit activity in the anterior neostriatum of rats pretreated 48 h previously with 300 mg/kg PCPA or vehicle. An intraperitoneal injection of 1.0 mg/kg D-amphetamine, which inhibited neostriatal activity in vehicle controls, produced in PCPA-pretreated animals a prolonged excitation. In contrast, the pronounced increase in firing rate produced by 7.5 mg/kg D-amphetamine in control rats was significantly reduced following PCPA pretreatment. Liquid chromatography with electrochemical detection revealed that compared to controls, PCPA produced a significant reduction of serotonin, but not dopamine or norepinephrine, in the telencephalon. The differential effects of PCPA on the action of low and high doses of D-amphetamine in the anterior neostriatum may explain the differential influence of serotonergic systems on amphetamine-induced locomotion add stereotypy.

Animals↗
PubMed1981

Differential actions of classical and atypical antipsychotic drugs on spontaneous neuronal activity in the amygdaloid complex.

Classical antipsychotic drugs such as haloperidol produce akinesia and catalepsy, whereas clozapine and related atypical antipsychotics fail to elicit these behaviors even at relatively high doses. Despite these behavioral differences, a cataleptic dose of haloperidol (2.0 mg/kg) produces changes in neuronal activity in the neostriatum and nucleus accumbens comparable to those produced by a non-cataleptic dose of clozapine (20.0 mg/kg). To further elucidate the brain mechanisms underlying the differential behavioral response to these drugs, an electrophysiological analysis was extended to neurons in the rat amygdaloid complex. Whereas an intraperitoneal injection of 2.0 mg/kg haloperidol generally failed to alter the firing rate of amygdaloid neurons, 20.0 mg/kg clozapine typically produced a prolonged increase in activity. Similarly, clozapine, but not haloperidol, reversed the depression of firing rate produced by 1.0 mg/kg d-amphetamine. The results suggest that neurons in the amygdaloid complex are more responsive to antipsychotic drugs devoid of extrapyramidal side effects than to antipsychotics which elicit parkinsonian-like motor dysfunctions.

Amygdala↗
PubMed1980

Apparent tolerance to some aspects of amphetamine stereotypy with long-term treatment.

Previous reports have demonstrated that long-term amphetamine treatment results in a progressive augmentation of locomotion and focused stereotypy in the rat. A series of experiments were conducted to determine whether an increase in dopamine receptor sensitivity is the primary mechanism underlying the behavioral alterations associated with multiple amphetamine injections. Detailed observations of the focused stereotyped behaviors produced by amphetamine revealed that although some components were enhanced with long-term treatment, others were reduced. Thus, whereas repeated administration of 2.5 mg/kg d-amphetamine produced a progressive increase in repetitive head and limb movements, long-term treatment with 5.5 mg/kg d-amphetamine resulted in a reduction of licking and biting behaviors (oral stereotypies). These results, which suggest that different mechanisms mediate the various components of focused stereotypy, argue against the supersensitivity hypothesis. In fact, the apparent tolerance that develops to oral stereotypies may reflect a decrease in dopamine receptor sensitivity since repeated amphetamine administration also reduces the oral stereotypies produced by 0.5 or 2.0 mg/kg apomorphine, a direct acting dopamine agonist. Thus, the behavioral alterations produced by repeated amphetamine injections cannot be explained solely by an increase in receptor sensitivity.

Animals↗
PubMed1979

Enhanced responsiveness to intraventricular infusion of amphetamine following its repeated systemic administration.

Previous studies have demonstrated that long-term administration of d-amphetamine produces a progressive augmentation of behavior. In the present experiment, rats receiving repeated systemic injections responded to an intraventricular infusion of d-amphetamine with an augmented increase in locomotor activity. These results indicate that central mechanisms, rather than peripheral dispositional factors, subserve the enhanced behavioral response to repeated amphetamine administration.

Animals↗
PubMed1979

"Classical" and "atypical" antipsychotic drugs: differential antagonism of amphetamine- and apomorphine-induced alterations of spontaneous neuronal activity in the neostriatum and nucleus accumbens.

The ability of clozapine and haloperidol to antagonize the depression of firing rate produced by d-amphetamine and apomorphine in the neostriatum and nucleus accumbens was tested in immobilized, locally anesthetized rats. In the neostriatum, an intraperitoneal injection of 2.5 mg/kg d-amphetamine or 1.0 mg/kg apomorphine produced a prolonged inhibition of neuronal activity that was reversed by a subjsequent injection of either 20 mg/kg clozapine or 2.0 mg/kg haloperidol. An analysis of the onset and magnitude of the blockade revealed that clozapine was more effective than haloperidol in reversing the amphetamine response but that both antipsychotic drugs produced a comparable blockade of the apomorphine-induced depression. Similar results were obtained in the nucleus accumbens. The data indicate that although clozapine acts equieffectively in the neostriatum and nucleus accumbens, this atypical antipsychotic drug, aside from blocking postsynaptic dopamine receptors, may exert at least some of its effects by preventing dopamine release.

Amphetamine↗
PubMed1978

Dose-dependent biphasic alterations in the spontaneous activity of neurons in the rat neostriatum produced by d-amphetamine and methylphenidate.

A dose-response analysis was performed on D-amphetamine- and methylphenidate-induced changes in neuronal activity in the neostriatum of immobilized, phenidate-induced changes in neuronal activity in the neostriatum of immobilized, locally anesthetized rats. Whereas a marked depression of firing rate characterized the response to intraperitoneal injections of 2.5 mg/kg D-amphetamine or 10 mg/kg methylphenidate, increasing the dose (5.0--7.5 mg/kg D-amphetamine and 20--25 mg/kg methylphenidate) shifted this response pattern to a prolonged increase in activity. Both stimulant-induced increases and decreases in neostriatal activity are reversed by 2.0 mg/kg haloperidol. In contrast to the response of neostriatal neurons, the firing rate in the substantia nigra pars compacta was inhibited by both stimulants, even at doses that increased the activity of neurons in the neostriatum. The possible mechanisms underlying these drug-induced changes in firing rate are discussed along with the behavioral implications of a stimulant-induced dose-dependent shift in neostriatal unit activity.

Animals↗