Biomedical subjects

D S Segal

Publications and source records attributed to D S Segal.

At least 19 recordsLinked to original sources

PubMed1992

Amphetamine-induced changes in behavior and caudate extracellular acetylcholine.

In vivo microdialysis was used to study the effects of amphetamine on caudate extracellular acetylcholine and to compare these effects to the drug-induced behavioral response profile. Consistent with an inhibitory dopamine/acetylcholine interaction, the dopamine receptor agonist, apomorphine, decreased acetylcholine concentrations, while the dopamine receptor antagonist, haloperidol, increased acetylcholine. In contrast, an intermediate dose of amphetamine (1.75 mg/kg), did not significantly alter acetylcholine levels. Furthermore, a higher dose of amphetamine (5.0 mg/kg) promoted a two-fold increase in acetylcholine levels, and the increase paralleled the appearance of oral stereotypies in these animals. These results suggest that the effects of amphetamine on caudate acetylcholine, which may be implicated in the appearance of stereotyped behaviors, are not strictly dependent on caudate dopamine receptor activation.

Acetylcholine↗

PubMed1992

Repeated cocaine administration induces behavioral sensitization and corresponding decreased extracellular dopamine responses in caudate and accumbens.

Behavioral and brain regional dopamine responses to cocaine (10 mg/kg) were concurrently monitored using in vivo microdialysis in freely-moving rats pretreated with 4 daily injections of saline or cocaine (10 mg/kg). Repeated cocaine produced a behavioral sensitization characterized by a downward oriented locomotor activation profile. In contrast, both caudate and nucleus accumbens dopamine responses were significantly diminished in the drug-pretreated group. These results, obtained following two days of drug withdrawal, differ from previous reports of an enhanced dopamine response after longer withdrawal intervals. While the duration of withdrawal may play an important role in the quantitative features of the dopamine response to subsequent stimulant administration, these results suggest that an enhanced dopamine response may not be required for the expression of behavioral sensitization. A compensatory increase in the dopamine uptake carrier, resulting from chronic cocaine-induced uptake blockade, is discussed as a possible mechanism underlying the reduced dopamine response.

Animals↗

PubMed1992

Dissociation between in vivo hippocampal norepinephrine response and behavioral/neuroendocrine responses to noise stress in rats.

The behavioral and extracellular hippocampal norepinephrine responses to audiogenic stress were concomitantly characterized in freely moving rats using in vivo microdialysis. Noise stimulation produced a rapid, but short-lived increase in norepinephrine release from the hippocampus during the first 20 min of noise presentation that declined to baseline levels for the duration of the noise stimulation and following noise offset. In contrast, the behavioral response persisted throughout the duration of the noise stimulation. In a separate group of similarly treated animals, neuroendocrine indices of stress were monitored during exposure to noise. Consistent with the behavioral response, corticosterone and adrenocorticotropic hormone remained elevated for the duration of noise presentation. These findings support a dissociation between the hippocampal norepinephrine response and the behavioral and neuroendocrine response patterns and suggest that other systems may be involved in the regulation of behavioral responsiveness to aversive stimuli.

Animals↗

PubMed1992

In vivo microdialysis reveals a diminished amphetamine-induced DA response corresponding to behavioral sensitization produced by repeated amphetamine pretreatment.

In vivo microdialysis procedures were used to assess the effects of repeated amphetamine administration on behavior and regional brain DA dynamics in freely moving rats. Pretreatment with amphetamine (2.5 or 3.0 mg/kg) for 4-6 days did not alter baseline DA or its metabolites in caudate or accumbens 48 h or 6 days after the last injection. However, whereas this dosage regimen revealed a profound behavioral sensitization in response to challenge with amphetamine (2.5 mg/kg), including a more rapid onset and intensification of stereotypy, the DA response was significantly diminished in both brain regions. In addition, the ratio of caudate to accumbens DA, either before or after amphetamine challenge, was not altered by the pretreatment regimen. These results are consistent with our previous suggestion that there is a dissociation between the DA and behavioral responses to amphetamine, and therefore that other neurotransmitter systems and/or mechanisms significantly contribute to the amphetamine response profile. Furthermore, DA effects may represent only one, albeit critical, aspect in a time-dependent sequence of changes underlying stimulant sensitization.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Regional norepinephrine response to amphetamine using dialysis: comparison with caudate dopamine.

The response of extracellular norepinephrine to the acute administration of amphetamine was assessed, using dialysis, in prefrontal cortex and hippocampus in awake, behaving rats. Norepinephrine exhibited a pronounced and rapid dose- and time-dependent increase in response to 0.5 and 2.5 mg/kg amphetamine, which corresponded closely to the time course of the behavioral profile. These results are consistent in with a possible role for norepinephrine in the behavioral response to amphetamine.

Amphetamine↗

PubMed1992

Clorgyline-induced increases in presynaptic DA: changes in the behavioral and neurochemical effects of amphetamine using in vivo microdialysis.

Microdialysis was used in behaving rats to further characterize the behavioral and regional dopamine (DA) response to the monoamine oxidase (MAO) inhibitor clorgyline and determine how MAO inhibition affects amphetamine (AMPH)-induced changes in behavioral and extracellular DA dynamics. Although clorgyline (4.0 mg/kg) did not significantly alter behavior, it produced prolonged increases in caudate and accumbens extracellular DA and 3MT and corresponding decreases in homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Clorgyline pretreatment altered the behavioral response to both low (0.25 mg/kg) and moderate (2.5 mg/kg) doses of AMPH, which was characterized by a shift to more intense forms of stereotype and corresponding decreases in locomotion. The caudate and accumbens DA response to AMPH (0.25 mg/kg) was also significantly augmented, consistent with an increase in AMPH-releasable cytoplasmic DA. Thus, the potentiated DA response in clorgyline-pretreated animals may be responsible for the changes in the stereotypy profile. Possible implications of these observations for the augmented behavioral response observed with repeated AMPH administration are discussed.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Deprenyl alters behavior and caudate dopamine through an amphetamine-like action.

In vivo microdialysis was used to concurrently measure the behavioral and caudate dopamine (DA) responses to the alleged irreversible type B monoamine oxidase inhibitor deprenyl. The effects were contrasted to those of the type A monoamine oxidase inhibitor, clorgyline. Consistent with its effects as an irreversible monoamine oxidase inhibitor, clorgyline produced an increase in DA concentration that remained elevated for at least 6 h. In contrast, the deprenyl-induced elevation in DA concentration occurred more rapidly, achieved a higher peak response, and then returned to baseline within 2 h following drug administration. The two drugs also produced distinctive changes in DA metabolite levels. Whereas the pattern of clorgyline-induced effects were consistent with irreversible monoamine oxidase inhibition, deprenyl produced an amphetamine-like response profile. Further, deprenyl but not clorgyline significantly increased locomotor activity. These results suggest that deprenyl does not augment caudate DA levels through monoamine oxidase inhibition. Rather, the pattern of its effects on caudate DA dynamics and behavior supports previous evidence that deprenyl produces its effects through its metabolism to amphetamine-like substances.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Effects of frequency and pattern of medial forebrain bundle stimulation on caudate dialysate dopamine and serotonin.

In vivo microdialysis was employed to detect changes in extracellular dopamine and serotonin in the rat caudate in response to electrical stimulation of the medial forebrain bundle. Extracellular dopamine concentrations increased linearly as a function of the frequency (4-33 Hz) of evenly spaced stimuli in both the presence and absence of cocaine added to the dialysate. Because dopamine neurons are known to fire in single-spike and burst patterns, stimulation pulses were also delivered in a bursting pattern. The response of extracellular dopamine was augmented in both the presence and absence of cocaine when the same number of stimuli were delivered in bursts as compared to an evenly spaced pattern. Serotonin, which was only assessed in the presence of cocaine, similarly increased linearly with frequency, but, in contrast to the dopamine response, levels of serotonin were not augmented by stimuli presented in bursts. These results suggest that microdialysis can be used to detect physiological changes in synaptic transmitter concentrations.

Animals↗

PubMed1992

Differential effects of amphetamine and dopamine uptake blockers (cocaine, nomifensine) on caudate and accumbens dialysate dopamine and 3-methoxytyramine.

Evidence suggests that some amphetamine-like stimulants may enhance accumbens dialysate dopamine to the greater extent than caudate dopamine. To test our hypothesis that the difference in transmitter response may derive, in part, from the degree to which released dopamine in the two regions is metabolized to 3-methoxytyramine, we compared the effects of amphetamine with the uptake blockers, nomifensine and cocaine, on caudate and accumbens dialysate concentrations of dopamine, its acid metabolites and 3-methoxytyramine. The percentage increases in accumbens dopamine were significantly greater than in caudate only after the uptake blockers. All three drugs promoted dose-dependent increases in dialysate 3-methoxytyramine which, although temporally delayed, generally paralleled the increases in dopamine. However, after the administration of uptake blockers, the ratio of dialysate 3-methoxytyramine to dopamine was greater in caudate than in accumbens. In addition, the acid metabolite patterns were the same in the two regions after amphetamine, but were qualitatively different after the uptake blockers. These results indicate that the relative degree of metabolism of released dopamine to 3-methoxytyramine in caudate and accumbens may contribute to the regional differences in dopamine response to uptake blockers.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Amphetamine, cocaine, and fencamfamine: relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics.

Using in vivo microdialysis, the caudate and nucleus accumbens dopamine (DA) responses to the psychomotor stimulants amphetamine (AMPH), cocaine (COC), and fencamfamine (FCF) were evaluated in rats concurrent with characterization of their behavioral response profiles. Doses of each stimulant that produced either enhanced locomotion or a prolonged period of intense focused stereotypies were examined to evaluate the quantitative relationships between stimulant-induced behaviors and changes in DA dynamics and to test the hypothesis that a balance between mesostriatal and mesolimbic DA activity contributes to the appearance of specific stimulant-induced behaviors. Although 10 mg/kg COC and 1.7 mg/kg FCF promoted levels of locomotor activity substantially greater than 0.5 mg/kg AMPH, the magnitude of the DA increases in both caudate and accumbens were markedly less than was obtained following AMPH. Thus, stimulant-induced locomotion appears to be dissociated from the quantitative DA response in both brain regions. This behavioral/DA dissociation was also apparent at higher doses of AMPH (2.5 mg/kg), COC (40 mg/kg), and FCF (6 mg/kg), doses that promoted a behavioral pattern that included a prolonged period of intense stereotypy. Indeed, the regional DA responses to these high doses of COC and FCF were substantially less than the response to 0.5 mg/kg AMPH. Furthermore, there were no differences in the ratio of the caudate and accumbens DA responses as a function of dose for any of the three drugs. Thus, the balance between the regional DA activation does not appear to regulate the expression of the behavioral response. Additionally, the effects of these stimulants on regional DA metabolite concentrations were compared. The results indicate that AMPH promoted an identical pattern of effects on caudate and accumbens DA metabolites, suggesting that similar mechanisms govern the dynamics of DA in response to AMPH in both brain regions. In contrast, the DA uptake blockers promoted some region-specific effects on DA metabolites that may be due to regional differences in the DA metabolism and rates of impulse flow.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

In vivo measures of monoamines during amphetamine-induced behaviors in rats.

1. Using a removable in vivo microdialysis probe, and remote sample collection, the temporal and dose-related behavioral and monoamine response to amphetamine (AMPH) were examined in freely-moving rats. Extracellular dopamine, serotonin and their metabolites were monitored concomitant with detailed characterization of the locomotor and stereotypy profiles. Consistent with previous results, AMPH (0.5-5.0 mg/kg) induced a rapid dose-dependent increase in dopamine concentration and decrease in the concentrations of the dopamine metabolites. Dopamine and metabolites exhibited contrasting temporal and dose-related patterns, suggesting that the decline in dopamine metabolites is functionally dissociated from the AMPH-enhanced dopamine release, and that metabolite levels do not provide an accurate index of functional dopaminergic activity. 2. Dose response comparisons revealed a significant relationship between AMPH-induced increases in behavioral perseveration and the magnitude and duration of the dopamine release. However, the temporal patterns of the neurotransmitter response and individual components of stereotypy were not parallel, suggesting that the presence of stereotypies is not associated simply with quantitative differences in striatal dopamine release. 3. Consistent with this interpretation, we found that a variety of manipulations including reserpine, apomorphine, and chronic amphetamine pretreatment, produced a dissociation between the alterations in the behavioral and dopaminergic responses to amphetamine. The behavioral response to amphetamine may be influenced by the interaction between levels of dopamine and serotonin, by the state of their respective receptors, and by the relative contributions of additional dopaminergic systems.

Amphetamine↗

PubMed1990

Apomorphine does not alter amphetamine-induced dopamine release measured in striatal dialysates.

Amphetamine facilitates the release of dopamine from nerve terminals, but the mechanisms underlying this effect have not been fully delineated. The present experiments were designed to test the extent to which amphetamine-induced dopamine release is dependent on impulse flow and autoreceptor function in dopaminergic neurons. Rats were pretreated with a low dose of apomorphine (0.05 mg/kg) to inhibit dopamine neuronal activity, and the striatal dopaminergic response to amphetamine (0.5 mg/kg) was assessed by in vivo dialysis in freely moving animals. Consistent with previous results, apomorphine alone substantially decreased, whereas amphetamine increased, striatal dialysate dopamine concentrations. However, whereas apomorphine pretreatment decreased the locomotor response to amphetamine, the amphetamine-induced increase in dialysate dopamine was unaffected. These results indicate that amphetamine-facilitated dopamine release is independent of neuronal firing and autoreceptor regulation, consistent with the putative accelerative exchange-diffusion mechanism of amphetamine-induced dopamine release. Other possible mechanisms underlying the inhibitory effects of apomorphine on amphetamine locomotor activation are discussed.

Amphetamine↗

PubMed1990

Repeated amphetamine and fencamfamine: sensitization and reciprocal cross-sensitization.

The repeated administration of amphetamine and related dopamine agonists results in an augmented or sensitized behavioral response to subsequent administration of these drugs. In addition to reflecting central nervous system plasticity, this altered response profile may also represent an animal model for stimulant-induced psychosis in humans. Therefore, considerable interest has been focused on determining the mechanisms underlying the sensitization process. One approach involves comparing and contrasting the effects of various stimulants possessing different molecular mechanisms of action. In this regard, some evidence suggests that fencamfamine and amphetamine interact with pharmacologically distinguishable dopamine pools. Therefore, we compared the behavioral response profiles to the repeated administration of behaviorally comparable doses of amphetamine and fencamfamine, and examined the pattern of cross-interaction between the two stimulants. Fencamfamine produced an amphetamine-like pattern of behavioral augmentation, and both drugs exhibited identical patterns of cross-sensitization. These results lend further support to the sensitization model of stimulant psychosis. Possible dopaminergic mechanisms underlying the sensitization are discussed.

Amphetamine↗

PubMed1990

Effects of long-term administration of haloperidol on electrophysiologic properties of rat mesencephalic neurons.

Haloperidol (1.5-1.7 mg/kg/day) was administered to rats via their drinking water for periods of either 4 weeks or 13 to 14 months, after which the animals were withdrawn from the neuroleptic for 1 or 2 weeks, respectively. Rats given haloperidol for 13 to 14 months exhibited significantly more perioral dyskinesias than controls. Single-unit extracellular recordings were obtained from the substantia nigra and ventral tegmental area in subjects under urethane anesthesia. After 1 month and after 1 year of treatment, a significant decrease in the mean firing rate of substantia nigra pars reticulata neurons was found. Subtle changes in the response of pars reticulata neurons to striatal stimulation were seen after extended haloperidol intake. No consistent effects of haloperidol administration for 4 weeks or 13 to 14 months were found for either the number of spontaneously active dopamine neurons or their firing rates. Histopathologic assessment of tissue from dorsomedial, dorsolateral and ventrolateral sectors of the striatum revealed no significant effect of long-term haloperidol treatment on neuronal cell counts. The results are discussed with reference to neuroleptic-induced tardive dyskinesias.

Animals↗

PubMed1989

Reserpine enhances amphetamine stereotypies without increasing amphetamine-induced changes in striatal dialysate dopamine.

Indirect evidence suggests that amphetamine (AMPH) releases dopamine (DA) from an extravesicular, cytoplasmic pool. Disruption of vesicular DA storage by reserpine has been hypothesized to increase the concentration of extravesicular DA available for release by AMPH, which is consistent with the observation that reserpine does not prevent but augments the behavioral response to AMPH. In order to more directly test this hypothesis, the in vivo microdialysis technique was used to concurrently examine the behavioral and striatal dopaminergic response to AMPH (1.25 or 2.5 mg/kg) 24 h following reserpine pretreatment (2.5 mg/kg). Reserpine decreased tissue levels of DA by approximately 90% and reduced baseline dialysate DA concentrations by approximately 80%. Reserpine augmented the behavioural effects of AMPH, particularly increasing the occurrence and intensity of stereotypies. In contrast, reserpine did not alter the amount or duration of AMPH-induced DA release. This observation confirms that DA release by AMPH does not depend on vesicular stores but is inconsistent with the hypothesis that augmentation or behaviour by reserpine results from increased striatal DA release.

Amphetamines↗

PubMed1989

Audiogenic stress response: behavioral characteristics and underlying monoamine mechanisms.

Behavioral characterization of the audiogenic stress response in rats revealed an intensity related multiphasic pattern including an initial, transient activation followed by prolonged periods of response suppression during the remainder of the noise exposure and excitation after noise offset. These observations emphasize the need to consider the temporal proximity between exposure to a stressor and either behavioral characterization and/or determinations of neurochemical changes relevant to the stress response. In a second series of studies, the effect of the NE alpha 2 agonist clonidine and the NE alpha 2 antagonist yohimbine were evaluated on the different components of the audiogenic stress response. The effects of intracerebroventricular xylamine-induced depletion of NE were also examined. The results seem to indicate that CNS noradrenergic systems may not be specifically implicated in regulating the responsiveness to noise stimulation but instead may subserve a more general role in adjusting baseline levels of motoric output in response to environmental conditions.

Adrenergic Fibers↗

PubMed1989

Individual behavioral and neuroendocrine differences in responsiveness to audiogenic stress.

A relatively wide range of individual differences in neuroendocrine, immune and behavioral components of the audiogenic stress response has been found. In this study, an analysis of the association between the physiological and behavioral measures revealed that the degree of noise-induced suppression of both general activity and ingestive behaviors was significantly correlated with activation of adrenal steroid secretion following both acute and repeated noise exposures. Splenic natural killer cytotoxicity was not correlated with the behavioral measures of the stress response. Characterization of individual behavioral response profiles may be needed to evaluate accurately the neuroendocrine effects of stress.

Animals↗

PubMed1989

Antidromically identified striatonigral projection neurons in the chronically implanted behaving rat: relations of cell firing to amphetamine-induced behaviors.

The effects of systematically administered amphetamine (0.25-5.0 mg/kg, sc) on neostriatal neurons recorded in chronically implanted behaving rats were studied. Projection neurons, identified by antidromic activation from the substantia nigra, fired very infrequently during most predrug behaviors (e.g., median rate, 0.02 spikes per second during locomotion; 17 of 18 fired less than 1 spike per second during all rated behaviors). Nonantidromic cells also tended to fire slowly (median rate, 0.02 spikes per second during locomotion; 20 of 24 cells fired less than 1 spike per second). Cells of both type showed up to 10-fold variations in firing rate across behaviors. For most neurons, amphetamine caused a reduction in the firing rate during related pre- and postdrug behaviors. For instance, the firing rate of 28 of 42 neurons was reduced during the initial amphetamine-induced locomotion as compared with the rate during predrug locomotion. Moreover, with the higher doses of amphetamine, there was a further reduction in firing rate corresponding to the transition from locomotion to stereotypies. In contrast to previous studies, which suggest that amphetamine generally increases neostriatal firing rate in behaving animals, these results suggest that amphetamine inhibits the numerous slowly firing neostriatal neurons, many of which were identified as projection neurons. Thus amphetamine alters the magnitude and pattern of neostriatal control of its neural targets.

Action Potentials↗