Biomedical subjects

R Kuczenski

Publications and source records attributed to R Kuczenski.

At least 37 records · Page 2Linked to original sources

PubMed1997

Behavioral sensitization and extracellular dopamine responses to amphetamine after various treatments.

The repeated administration of amphetamine (AMPH) results in a pattern of behavioral changes which includes an augmentation of some behaviors, generally referred to as behavioral sensitization. Some investigators have suggested that an increased dopamine (DA) response to AMPH challenge may underlie behavioral sensitization, while others have reported behavioral sensitization in the absence of an enhanced DA response. Because temporal and dosage parameters of the AMPH pretreatment regimen have been suggested to play a role in the appearance of an enhanced DA response, we utilized a variety of AMPH pretreatment regimens to assess the relationship between pretreatment dose of AMPH, duration of withdrawal and the DA response in caudate-putamen and nucleus accumbens to a subsequent AMPH challenge. Under our experimental conditions, behavioral sensitization was observed after each of these treatments in the absence of an enhanced DA response in either brain region.

Amphetamine↗

PubMed1997

Behavioral alterations induced by an escalating dose-binge pattern of cocaine administration.

Stimulant-induced psychosis and addiction are most commonly associated with a pattern of repeated high dose 'binge' exposures, preceded by progressively escalating doses (ED). We have recently reported that an ED/multiple binge treatment with amphetamine or methamphetamine results in a unique behavioral profile, characterized by a differential change in the relative expression of locomotion and stereotypy and the emergence of a bursting pattern of ambulation. To examine the generality of this behavioral profile, a similar regimen (ED, 2-15 mg/kg; binges, 15 mg/kg x 5 hourly injections x 15 days) was used to characterize the response to cocaine. Our results show that the primary characteristics of the behavioral profile previously found with the amphetamines were also apparent with cocaine. That is, the locomotor response was significantly greater, and was characterized by a bursting pattern. These observations lend further support to the notion that the progressive behavioral changes and the underlying neurochemical alterations produced by this treatment may be implicated in the addiction and psychosis which is associated with high dose stimulant abuse.

Animals↗

PubMed1997

Quantification of dopamine D1 and D2 receptor mRNA levels associated with the development of behavioral sensitization in amphetamine treated rats.

We hypothesized that changes in expression of dopamine (DA) D1 and D2 receptor genes in caudate/putamen (CP) would correlate with the development of behavioral changes in amphetamine treated rats. In order to test this hypothesis, we measured DA D1 and D2 receptor mRNA in CP, as well as locomotor behavior, in individual rats following amphetamine treatment. D1 and D2 mRNA levels were similar in caudate/putamen of rats treated with acute amphetamine, chronic amphetamine or saline injection. We found no correlation between D1 or D2 mRNA levels in caudate/putamen and the behavioral response to either acute or chronic amphetamine. These results suggest that behavioral sensitization to amphetamine is not mediated through transcriptional regulation of D1 or D2 mRNA levels in caudate/putamen.

Amphetamine↗

PubMed1997

Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine.

Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.

Amphetamine↗

PubMed1997

Repeated binge exposures to amphetamine and methamphetamine: behavioral and neurochemical characterization.

Stimulant psychosis and addiction are most commonly associated with repeated, high-dose binges or runs, typically preceded by a more intermittent pattern of stimulant abuse. We previously reported that rats exposed to an escalating dose-run pattern of amphetamine administration exhibited changes in their behavioral response profile that differed both qualitatively and quantitatively from the response to either acute or intermittent daily treatment. To determine the generality of these effects and characterize further the nature of the behavioral and neurochemical changes of this treatment, rats received single daily injections of amphetamine (2.5 or 4.0 mg/kg s.c.) or equimolar doses of methamphetamine, followed by multiple runs (four daily injections at 2-hr intervals) with the pretreatment dose. This treatment resulted in a unique behavioral profile, including a profound increase in the relative expression of locomotion vs. stereotypy. The markedly enhanced poststereotypy locomotor activation was characterized by repeated "burst"-like episodes of ambulation. The number of runs required for the emergence of this behavior was dose dependent and was similar for the two drugs except that with methamphetamine, there also was a marked prolongation of the poststereotypy locomotor response during run exposures. During runs, both drugs produced a decline in the caudate but not the nucleus accumbens microdialysate dopamine response, whereas only methamphetamine produced a decline in the serotonin response that was apparent in both regions. The possible relationship between these behavioral and neurochemical changes and their implications for high dose patterns of stimulant abuse are discussed.

Amphetamine↗

PubMed1997

Extracellular dopamine and amphetamine after systemic amphetamine administration: comparison to the behavioral response.

To further delineate amphetamine-dopamine pharmacokinetic-pharmacodynamic relationships, we examined extracellular levels of dopamine and amphetamine in caudate-putamen after the s.c. administration of 8 mg/kg amphetamine. In a parallel group of animals, we also assessed caudate-putamen tissue levels of the drug. Extracellular concentrations of the transmitter and the drug exhibited similar temporal profiles, each achieving maximum concentrations within 30 min of drug administration. Tissue levels of amphetamine exhibited a similar, although slightly earlier time to maximum levels. The concentrations of amphetamine and dopamine in the extracellular fluid and amphetamine in tissue rapidly declined with similar rates of elimination. In contrast to the temporal profiles for both dopamine and amphetamine, stereotyped behaviors achieved maximum intensity at about 60 min. In addition, although transmitter and drug declined almost 10-fold from maximum values over the 4-hr interval after amphetamine administration, stereotyped behaviors persisted for at least 3 hr before abating. The results of these studies confirm our previous observation that the temporal profiles for stereotyped behaviors and extracellular dopamine are dissociated, and also extend this dissociation to extracellular amphetamine. In addition, although there was a close correspondence between dopamine and amphetamine within each experimental animal, individual animals exhibited a broad range of maximal dopamine responses, suggesting a differential responsiveness to amphetamine.

Amphetamine↗

PubMed1996

Amphetamine-induced changes in nigrostriatal terminal excitability are modified following repeated amphetamine pretreatment.

To investigate neural mechanisms associated with behavioral sensitization to amphetamine, we studied the effect of an intrastriatal infusion of amphetamine on nigrostriatal axon terminal electrical excitability in rats following withdrawal from repeated systemic treatment. Rats were injected with amphetamine 2.5 mg/kg s.c. or saline daily for 4 days. Either 24 h or 14 days after the last injection, extracellular recordings were obtained from dopaminergic neurons of the substantia nigra, in a blind design in which the experimenter did not know the pretreatment regime. In order to assess the electrical excitability of the nigrostriatal axonal field, neurons were activated antidromically by stimulating their terminal fields in the striatum. As previously reported, striatal infusion of amphetamine (1 microM/0.3 microliter) in control animals resulted in a significant reduction in excitability as indicated by an increase in striatal stimulus current necessary to evoke antidromic activity. In contrast, intrastriatal amphetamine administration to amphetamine-pretreated animals did not decrease excitability. Spontaneous firing rates and patterns of cell discharge did not differ between saline- and amphetamine-treated animals. The chronic amphetamine-induced change in the effect of an acute intrastriatal amphetamine infusion on nigrostriatal terminal excitability may be due to enduring alterations in the amphetamine-induced release of dopamine and other striatal neurotransmitters or to changes in the sensitivity of presynaptic hetero- and/or autoreceptors on the dopaminergic axons.

Amphetamine↗

PubMed1995

Regional quantification of dopamine transporter mRNA in rat brain using a ribonuclease protection assay.

We describe the regional distribution of dopamine transporter (DAT) mRNA in selected regions of rat brain using a highly sensitive and specific nuclease protection assay. This method determines the absolute quantity of mRNA expressed in the brain regions surveyed. DAT mRNA level varied widely between brain regions, and was detected only in cell body regions of the major dopaminergic pathways. Highest expression was seen in substantia nigra/ventral tegmentum (SN/VTA). Lower but detectable expression of a protected mRNA of the expected size was observed within hypothalamus. Expression could not be detected by this method in other brain regions studied. Our results indicate that this method is sufficiently sensitive to allow study of mRNA expression in individual animals.

Amino Acid Isomerases↗

PubMed1995

Regional quantification of D1, D2, and D3 dopamine receptor mRNA in rat brain using a ribonuclease protection assay.

We describe ribonuclease protection assays for dopamine D1, D2, and D3 receptors, and regional quantitation of mRNA levels for these receptors in rat brain. Both D1 and D2 mRNA levels were highest in caudate putamen, where they were found in approximately equal levels. Of the brain regions examined, D3 mRNA was most abundant in hippocampus, hypothalamus, and nucleus accumbens. Levels of D3 mRNA were significantly lower than values for D1 and D2 mRNA in all brain regions studied. Variability was observed between animals for expression of both D1 and D2 mRNA in caudate putamen, with a significant correlation between D1 and D2 mRNA levels in neostriatum (r = 0.942, P < 0.001). This suggests a functional interaction between D1 and D2 receptor mRNA levels in this brain region. Our results are generally consistent with regional distributions previously reported using other methods. These results suggest that DA D2 receptors function both as an auto and as a postsynaptic receptor, while D1 receptors are restricted to a postsynaptic function. Our results demonstrate the utility of this method in studying possible relationships between individual animal variation in regional mRNA expression and behavioral response to pharmacological and other experimental treatments.

Animals↗

PubMed1995

Does dizocilpine (MK-801) selectively block the enhanced responsiveness to repeated amphetamine administration?

In order to examine the hypothesis that N-methyl-D-aspartate (NMDA) receptors are selectively involved in the development of stimulant sensitization, we characterized the interaction between acute and chronic dizocilpine (MK-801) + amphetamine using a detailed behavioral analysis, including concurrent assessment of the locomotor and stereotype components of the stimulant response and continuous monitoring of all the various phases of the emergent sensitization. The results showed that MK-801 (0.125 mg/kg) significantly affected the acute response to amphetamine (0.5, 1.75, 4.0 mg/kg), increasing or decreasing locomotor activity depending on dose. Repeated administration of MK-801 + amphetamine resulted in a suppression of stereotyped behaviors and a potentiated locomotor sensitization. These findings suggest that rather than blocking the development of sensitization, MK-801 pretreatment may produce a unique behavioral augmentation that is apparent during coadministration and that persists up to 48 hr in the response to amphetamine challenge.

Amphetamine↗

PubMed1995

Effects of reserpine on extracellular caudate dopamine and hippocampus norepinephrine responses to amphetamine and cocaine: mechanistic and behavioral considerations.

Following reserpine pretreatment to disrupt vesicular stores of dopamine and norepinephrine, in vivo microdialysis was used in behaving rats to evaluate the role of vesicles in the neurochemical and behavioral responses to amphetamine and cocaine. Reserpine (2.5 mg/kg, 24 hr) completely prevented the hippocampus norepinephrine responses to 20 mg/kg of cocaine and to 0.5, 1.25 and 5.0 mg/kg of amphetamine. Likewise, reserpine almost completely abolished the caudate putamen dopamine response to cocaine. In contrast, the effect of reserpine on the amphetamine-induced dopamine response varied as a function of amphetamine dose. Although the dopamine response to 1.25 mg/kg of amphetamine was unchanged by reserpine pretreatment, the dopamine responses to both the lowest (0.5 mg/kg) and highest (5.0 mg/kg) doses of amphetamine were significantly attenuated by about 65% and 50%, respectively. These results indicate that the norepinephrine response to amphetamine is dependent on vesicular stores of transmitter at all doses of the drug. However, although amphetamine can release dopamine from a reserpine-resistant (non-vesicular) pool, it also appears that this response partially depends on vesicular stores, especially at low and high doses of drug. Concomitant behavioral assessments revealed that the behavioral responses to cocaine and the lowest dose of amphetamine, like the dopamine responses, were significantly suppressed by reserpine pretreatment. In contrast, at the intermediate dose of amphetamine, stereotypies were significantly enhanced. These altered behavioral profiles are discussed in terms of a balance between increases in both dopamine and norepinephrine produced by amphetamine.

Amphetamine↗

PubMed1995

Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine.

Microdialysis in behaving animals was used to concomitantly characterize the dopamine and 5-HT responses in the caudate and the norepinephrine response in the hippocampus to the D- and L-isomers of amphetamine and methamphetamine. Doses of all four drugs which promoted similar stereotypy responses produced a D-amphetamine-like response profile of dopamine and dopamine metabolites, suggesting that all these drugs interact with dopamine systems to facilitate the release of transmitter. However, in contrast to the similar behavioral profiles, the magnitude of the dopamine responses diverged significantly. In addition, all four drugs increased extracellular norepinephrine and 5-HT, but the relative responses differed markedly from dopamine and from each other. The contrasting structure-activity relationships for these drugs likely reflect their differential potency at the various neuronal uptake transporters in promoting either transmitter release, and/or uptake blockade. In addition, the interaction of each drug at the vesicular transporters, as well as the availability of a cytoplasmic pool of transmitter likely also contribute to the neurotransmitter response. Because of the particularly divergent transmitter response profiles exhibited by L-methamphetamine, its behavioral and neurotransmitter effects were characterized over a more extended range of doses. Although the duration of the increase in extracellular dopamine was clearly proportional to dose, the dose-dependent increases in the magnitude of the dopamine response did not parallel the behavioral profiles. The results of these studies indicate that, while the dopamine, norepinephrine and 5-HT responses to these drugs probably contribute to the expression of stimulant-induced behaviors, simple relationships between the neurotransmitter responses and the behavioral profiles were not evident.

Amphetamine↗

PubMed1994

Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment.

Microdialysis in behaving animals was used to characterize the hippocampus (HP) and prefrontal cortex (PFC) norepinephrine (NE) responses to amphetamine (AMPH) and cocaine (COC). NE exhibited regionally similar dose- and time-dependent increases to each drug. However, peak NE concentrations were approximately 2-fold greater at behaviorally similar doses of AMPH compared with COC. To examine the role of noradrenergic impulse flow in the mechanism(s) by which these stimulants enhance extracellular NE, groups of animals were pretreated with the alpha 2 autoreceptor agonist, clonidine (CLON), prior to stimulant administration. CLON (50 micrograms/kg) administration completely blocked the NE response to both 20 and 30 mg/kg COC. By contrast, CLON decreased the NE response to 0.5 mg/kg AMPH by 75%, but became progressively less effective on the response as the dose was increased to 1.75 and 5.0 mg/kg. CLON also had no effect on the caudate dopamine responses to either AMPH or COC, consistent with the presumed specificity of this drug for alpha 2 receptors and suggesting the absence of any significant pharmacokinetic interactions. These results indicate that COC acts an uptake blocker at NE-containing neurons and suggest that AMPH increases extracellular NE through two consequences of its interaction with the neuronal transport carrier: (1) reuptake blockade which predominates at lower doses; and (2) release which becomes more prevalent at higher doses. Behavioral analyses revealed effects of CLON which varied as a function of stimulant and dose.

Amphetamine↗

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↗