Caudate-putamen and nucleus accumbens extracellular acetylcholine responses to methamphetamine binges.

Exposure of experimental animals to an escalating dose, multiple binge pattern of methamphetamine administration results in the progressive emergence of a unique behavioral profile, which includes a significant decrease in the duration of the stereotypy phase as well as a profound increase and qualitative change in the locomotor activation. This behavioral profile is associated with a selective decrease in the caudate-putamen but not nucleus accumbens extracellular dopamine response. Since the acetylcholine interneurons in these regions are partly under the control of the mesostriatal and mesoaccumbens dopamine inputs, changes in the activation of these interneurons should parallel the regionally differential dopamine responses during multiple binge treatment. Therefore, we characterized the caudate-putamen and nucleus accumbens extracellular acetylcholine responses to escalating-dose, multiple binge methamphetamine administration. An acute methamphetamine binge decreased acetylcholine levels in caudate-putamen, but had no effect on levels in nucleus accumbens. Furthermore, corresponding to the selective decrease in the dopamine response, the caudate-putamen but not nucleus accumbens extracellular acetylcholine response exhibited tolerance with repeated binge exposures; i.e. the decrease in acetylcholine associated with the acute methamphetamine binge was attenuated with multiple binge exposure. These results are consistent with our hypothesis and suggest that the regionally differential acetylcholine responses reflect one functional consequence of the escalating-dose, multiple binge stimulant treatment.

Relevance of pharmacokinetic parameters in animal models of methamphetamine abuse.

Although the behavioral consequences of methamphetamine (METH) abuse have been extensively documented, a more precise and thorough understanding of underlying neurobiological mechanisms still requires the use of animal models. To study these biochemical processes in experimental animals requires consideration for the broad range of human METH abuse patterns and the many factors that have been identified to profoundly influence the behavioral and neurochemical effects of exposure to METH-like stimulants. One potentially critical issue relates to pharmacokinetic differences between the species. In this review, METH plasma pharmacokinetic profiles after single and multiple dose intravenous METH administration are compared for the rat and human. Significant differences in elimination half-life between the two species (t1/2: rat-70 min, human-12 h) result in markedly dissimilar profiles of METH exposure. However, the plasma profile of a human METH binge pattern can be approximated in the rat by increasing METH dose frequency. Consideration of METH pharmacokinetics in animal models should permit a closer simulation of the temporal profile of METH exposure in the human CNS and should provide further insight into the mechanisms contributing to the addiciton and psychopathology associated with METH abuse.

Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine.

The prescribed use of methylphenidate (Ritalin) in the treatment of attention deficit hyperactivity disorder has risen dramatically in recent years. The relative roles of dopamine, norepinephrine, and serotonin in the therapeutic action of these drugs was assessed by comparing the responses of extracellular nucleus accumbens dopamine and serotonin and hippocampus norepinephrine to the acute administration of low methylphenidate and amphetamine doses. The comparative neurochemical profiles in response to methylphenidate and amphetamine suggest that the norepinephrine effects may play an important role in the therapeutic effects of low doses of psychostimulants. In addition, to assess possible long-term consequences of prolonged exposure to this drug, we examined whether changes in the locomotor response occurred with repeated administration of these stimulant doses. Threshold doses of methylphenidate (0.5-1.0 mg/kg) or amphetamine (0.1-0.25 mg/kg) were administered twice daily, and then animals were tested in response to 2.5 mg/kg methylphenidate or 0.5 mg/kg amphetamine. Our results provide evidence that low-dose stimulant administration can result in the development of behavioral sensitization, which is evident in the subsequent behavioral response to the drug. The relevance of these data to the therapeutic uses of these drugs is discussed within the context of the many variables that can affect the behavioral and neurochemical responses to stimulants.

Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach.

We have used methamphetamine treatment of rats as an animal model for psychotic mania. Specific brain regions were analyzed comprehensively for changes in gene expression using oligonucleotide GeneChip microarrays. The data was cross-matched against human genomic loci associated with either bipolar disorder or schizophrenia. Using this convergent approach, we have identified several novel candidate genes (e.g., signal transduction molecules, transcription factors, metabolic enzymes) that may be involved in the pathogenesis of mood disorders and psychosis. Furthermore, for one of these genes, G protein-coupled receptor kinase 3 (GRK3), we found by Western blot analysis evidence for decreased protein levels in a subset of patient lymphoblastoid cell lines that correlated with disease severity. Finally, the classification of these candidate genes into two prototypical categories, psychogenes and psychosis-suppressor genes, is described.

Differential regional zif268 messenger RNA expression in an escalating dose/binge model of amphetamine-induced psychosis.

Amphetamine-induced psychosis is most often associated with a high-dose multiple binge pattern of stimulant abuse. To simulate these conditions in rats, we used an escalating dose/binge administration paradigm. Animals were pretreated with escalating doses of amphetamine (1.0-8.0mg/kg) over four days, then exposed to nine daily binges (8.0mg/kg every 2h; four injections/day). Other animals received either multiple injections of saline, saline followed by acute amphetamine (8.0mg/kg) or single daily injections of amphetamine (8.0mg/kg) in parallel with the escalating dose/binge treatment. One hour after the last injection, all animals were decapitated and regional brain activation patterns were assessed using in situ hybridization with antisense probes for zif268. Acute amphetamine resulted in a significant elevation of zif268 messenger RNA in both the nucleus accumbens and dorsal striatum. However, whereas after single daily amphetamine treatment this index was no longer elevated above control levels in the dorsal striatum, multiple binge exposures were required for the nucleus accumbens to return to baseline. Agranular insular cortex and medial olfactory tubercle zif268 messenger RNA expression was also markedly increased after acute amphetamine treatment but, unlike the nucleus accumbens and dorsal striatum, this increase was not significantly attenuated by either single daily injection or multiple binge treatment. Zif268 messenger RNA expression in the lateral nucleus of the amygdala also remained elevated above baseline after binge treatment. The possible relationships of these changes in zif268 messenger RNA regional expression patterns to the development of psychosis in high-dose stimulant abusers are discussed.

Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate.

RATIONALE: We have previously shown that during the acute response to amphetamine, a stimulant that released dopamine, behavioral sensitivity to the drug undergoes dynamic changes, as evident in the altered behavioral profile expressed to the subsequent administration of a low dose of the drug. OBJECTIVE: The present studies were designed to determine if these dynamic changes in sensitivity occur with amphetamine-like stimulants that act primarily by blocking dopamine uptake. METHODS: Groups of animals were primed with 40 mg/kg cocaine or 30 mg/kg methylphenidate, then during the acute response, a low, locomotor-stimulant dose of amphetamine (1.5 mg/kg) was administered to probe for changes in sensitivity. Conversely, to determine whether the manifestation of the increased responsivity is idiosyncratic to amphetamine, animals were also primed with amphetamine (4 mg/kg), then probed with low doses of cocaine (10 and 20 mg/kg) or methylphenidate (10 mg/kg). Parallel microdialysis studies were performed to assess the caudate-put-amen and nucleus accumbens extracellular dopamine responses. RESULTS: Priming with the uptake blockers each resulted in a stereotypy response to the subsequent low-dose amphetamine probe. Likewise, after priming with amphetamine, the uptake blockers each induced a pronounced stereotypy response. In each case, these changes in behavioral responsivity were expressed in the absence of corresponding changes in the probe-induced regional dopamine responses. CONCLUSIONS: Dynamic changes in behavioral sensitivity during the response to acute stimulant administration are a characteristic common to both dopamine releasers and uptake blockers. These rapid changes in sensitivity may contribute to the behaviors associated with binge patterns of drug abuse.

Escalating dose-binge treatment with methylphenidate: role of serotonin in the emergent behavioral profile.

Our previous studies indicate that exposure of rats to an escalating-dose, multibinge pattern of amphetamine or methamphetamine administration results in a unique emergent behavioral profile and concomitant regionally specific dopamine response patterns in the nucleus accumbens and caudate-putamen. In the present study, we explored the generality of these effects by using an escalating-dose, multibinge treatment with methylphenidate (MP), a stimulant that, unlike the amphetamines, produces no increase in serotonin transmission. Furthermore, MP exerts many of its effects through dopamine uptake blockade, in contrast to the amphetamines that primarily release dopamine. The results showed that MP administered according to an escalating-dose, multibinge regimen produced the expression of the emergent behavioral profile. This pattern of behavior was also evident in these animals in response to 2.5 mg/kg acute amphetamine after the last MP binge exposure. Consistent with previous evidence, neither acute nor multibinge MP treatment produced a significant serotonin response. In contrast, a regionally specific dopamine response alteration was observed during the course of this treatment. Caudate-putamen dopamine exhibited a pattern of increasing response during an acute MP binge but pronounced tolerance developed to this effect after multiple binges. By contrast, the nucleus accumbens dopamine response did not significantly change during the acute binge and exhibited a slight incremental pattern to the injections of the final binge. These findings, along with the effects of other stimulants, are discussed in terms of a possible role for serotonin and for the differential changes in the caudate-putamen and nucleus accumbens dopamine responses in the emergent behavioral profile. The similarity between the effects of MP and the amphetamines provides further support for the multibinge-induced behavioral profile as a possible animal model for stimulant-induced psychosis.

Escalating dose-binge stimulant exposure: relationship between emergent behavioral profile and differential caudate-putamen and nucleus accumbens dopamine responses.

Previous studies showed that treatment with high doses of amphetamine (8.0 mg/kg) administered according to an escalating dose-binge regimen, produced a unique behavioral profile that included a decrease in the duration of stereotypy and a pronounced increase in ambulation, characterized by a repeated bursting pattern of locomotion. This treatment regimen also resulted in differential dopamine response profiles in the caudate-putamen and nucleus accumbens: the dopamine response in the caudate-putamen exhibited a progressive within and between binge decline in peak levels, whereas the dopamine response in the nucleus accumbens was not significantly altered. The present study was designed to determine if this behavioral/dopamine response relationship was obtained under two additional conditions: first, in response to a relatively low dose amphetamine challenge (2.5 mg/kg) after withdrawal from escalating dose-binge treatment with either amphetamine or methamphetamine (6.0 mg/kg), and, second, during a lower dose (2.5 mg/kg amphetamine) escalating dose-binge regimen. Both the emergent behavioral profile and the regional differences in the dopamine response patterns were obtained under each set of conditions. These effects may be significantly implicated in the induction of stimulant psychosis, since the psychotogenic effects of amphetamine-like stimulants are most commonly associated with frequent, relatively high dose binge exposures.

Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D1 and D2 dopamine receptors.

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate-putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D1 and D2 dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D1 and D2 dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment ('priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D1 and D2 receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D1/D2 agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5-1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D1 and D2 dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.

Caudate-putamen dopamine and stereotypy response profiles after intravenous and subcutaneous amphetamine.

We compared the behavioral and caudate-putamen extracellular dopamine responses following intravenous (3.6 mg/kg) and subcutaneous (8 mg/kg) amphetamine administration using 2-min microdialysate sampling intervals, and doses of the drug selected to achieve comparable maximal brain concentrations. Following intravenous amphetamine, dopamine peaked within the first 2 min, then declined with a first-order decay rate of 0.018+/-0.007 min(-1). Following subcutaneous amphetamine, dopamine achieved maximum concentrations at 9 min and remained near peak levels for about 30 min before declining with a first-order decay rate of 0.019+/-0.008 min(-1). Maximal brain amphetamine levels and peak dopamine concentrations were equivalent following either route of drug administration. In contrast to the short latency to maximal extracellular dopamine, the onset of oral stereotypies was delayed until about 30 min following both routes of drug administration. Furthermore, in contrast to the behavioral response to amphetamine, apomorphine administration resulted in the rapid appearance of oral stereotypies within 5-10 min after drug administration. These results suggest that although caudate-putamen dopamine receptor activation may be a critical factor in the expression of focused oral stereotypies, other effects of amphetamine may interfere with the ability of animals to exhibit these behaviors.

Sensitization of amphetamine-induced stereotyped behaviors during the acute response.

The quantitative and qualitative features of the behavioral response to amphetamine-like stimulants in rats can be dissociated from the dopamine response. This dissociation is particularly evident in the temporal profiles of the extracellular dopamine and stereotypy responses to higher doses of amphetamine. One possible mechanism contributing to this temporal dissociation is that during the acute response to amphetamine, dopamine receptor mechanisms are enhanced such that stereotyped behaviors can be supported by synaptic concentrations of dopamine which are not sufficient to initiate these behaviors. To further explore the dynamics of stimulant sensitivity during the acute response, we examined the behavioral and extracellular dopamine responses to a low, nonstereotypy-producing dose of amphetamine (0.5 mg/kg) at various times after an acute, priming injection of 4.0 mg/kg when stereotypies had subsided and extracellular dopamine was approaching predrug baseline levels. The low-dose challenge produced intense stereotypies although the regional dopamine responses were not significantly different from control animals. Blockade of the expression of stereotypies during the priming response by the D2 antagonist haloperidol or the D1 antagonist SCH 23390 prevented the expression of an enhanced stereotypy response to the challenge injection. Our results suggest that an exposure to amphetamine results in a rapid sensitization of the stereotypy response which does not involve changes in the extracellular dopamine response but requires activation of dopamine receptors. Such a mechanism may be significantly implicated during binge patterns of stimulant abuse and may also play a role in the sensitization associated with repeated amphetamine administration.

l-methamphetamine pharmacokinetics and pharmacodynamics for assessment of in vivo deprenyl-derived l-methamphetamine.

This study evaluated whether the caudate-putamen dopamine response that has been observed after deprenyl administration could be attributed exclusively to metabolically generated l-methamphetamine (l-MeAmp). Brain and plasma levels of deprenyl and l-MeAmp were measured after deprenyl (10 mg/kg s.c.) from 10 to 60 min in conscious rats. Peak caudate-putamen levels were observed for deprenyl (15 nmol/g) at 10 min and for l-MeAmp (3 nmol/g) at 30 min. In a parallel study, l-MeAmp metabolism was evaluated. After l-MeAmp (20 mg/kg s.c.), metabolite levels remained low relative to those of the parent compound: l-amphetamine, approximately 5 to 12%; and para-hydroxy-l-methamphetamine (OH-MeAmp), approximately 0.25%. Accordingly, l-MeAmp was considered to be the primary pharmacologically active deprenyl metabolite. A pharmacokinetic-pharmacodynamic analysis was then used to relate these pharmacokinetic data to the results of previous microdialysis studies in which increases in extracellular dopamine were measured in the caudate-putamen after l-MeAmp (3-18 mg/kg) and after deprenyl (10 mg/kg). Dopamine response-area under curve versus dose plots were generated and used to show that an administered dose of 4 mg/kg l-MeAmp would be necessary to effect a dopamine response-area under curve comparable to that observed after the deprenyl dose. However, the present pharmacokinetic results indicated that l-MeAmp brain levels after deprenyl corresponded to those that would be obtained from 0.4 mg/kg l-MeAmp (i.e., one tenth of the required dose). Collectively, these results suggest that the acute increases in extracellular dopamine observed after deprenyl are not due uniquely to metabolically generated l-MeAmp but also to other actions of deprenyl at the dopamine terminal.

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.

Dopamine transporter mRNA is up-regulated in the substantia nigra and the ventral tegmental area of amphetamine-sensitized rats.

Converging evidence supports a significant role for dopamine (DA) in the development of behavioral sensitization and it has been suggested that changes in either DA transporter (DAT) or D2 autoreceptors contribute to the effects of stimulant treatment. To determine if alterations in DAT or D2 autoreceptor mRNA are long-lasting and parallel the time course of amphetamine (AMPH)-induced behavioral sensitization we performed the following experiment. Two groups of rats were used for mRNA analysis by in situ hybridization. They were given either single daily injections of saline or AMPH (2.5 mg/kg) for 5 days and sacrificed 7 days later. Two groups pretreated in a similar manner were used to test for behavioral sensitization. Pretreatment with AMPH which resulted in a sensitization response profile after AMPH challenge also produced a significant up-regulation of DAT mRNA in both the ventral tegmental area (VTA) (P = 0.01) and substantia nigra (SN) (P < 0.05) compared to the saline controls, whereas there were no significant group differences in D2 mRNA in either the SN or the VTA. The possible role of these changes in behavioral sensitization is discussed.

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.

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.

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.

Follow-on formula in the prevention of iron deficiency: a multicentre study.

Six-month-old infants were recruited at 21 centres in the UK and Ireland and randomly assigned to receive matching iron-fortified (12.3 mg/l iron) or non-fortified (1.4 mg/l iron) formula for 9 months. Infants already receiving cow's milk continued this feed. Haematological indices and iron status were evaluated at age 6 months, 9-10 months and 15 months. Four hundred and six infants entered and 302 completed the study. There were no differences between the groups for increases in weight, head circumference or length. Significant differences between the groups were observed at 15 months for haemoglobin, serum ferritin, serum iron and total iron binding capacity. Haemoglobin levels were < 110 g/l in 33% of infants fed cow's milk compared with 13% and 11% in those receiving non-iron-fortified and iron-fortified formula respectively. The corresponding figures for serum ferritin < 10 microg/l were 43%, 22% and 6%. Follow-on formula provides an acceptable vehicle for preventing iron deficiency in this vulnerable group.

An escalating dose/multiple high-dose binge pattern of amphetamine administration results in differential changes in the extracellular dopamine response profiles in caudate-putamen and nucleus accumbens.

Amphetamine (AMPH)-induced psychosis is most frequently associated with a chronic high-dose "binge" or "run" pattern of stimulant abuse, generally preceded by a period of gradually escalating doses of the drug. We showed previously that animals subjected to such a regimen of AMPH administration developed, over multiple daily binges, a unique pattern of behavioral response that included a decrease in stereotypy and a pronounced increase in locomotion. Because of the involvement of mesolimbic and mesostriatal dopamine (DA) pathways in locomotion and stereotypy, respectively, we hypothesized that a persistent shift in the relative magnitude of caudate-putamen (CP) and nucleus accumbens (NAC) DA transmission may contribute to this altered behavioral profile. To test this hypothesis, we examined CP and NAC extracellular DA in response to multiple high-dose AMPH binges. Our results revealed that with multiple binges the CP DA response but not the NAC response developed a profound tolerance/tachyphylaxis to the drug-induced increase in extracellular transmitter. These differential regional response alterations seem to correspond to the shift in the relative expression of stereotypy and locomotion. We hypothesize that changes in DA synthesis, perhaps mediated by regionally specific adaptations in DA autoreceptor function, contribute to the differential extracellular transmitter response profiles, and suggest that these neurochemical changes may have important implications for the mechanisms underlying the addictive and psychotogenic properties of AMPH.

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.