Effects of high amphetamine dose on mood and cerebral glucose metabolism in normal volunteers using positron emission tomography (PET)

Psychiatry Research: Neuroimaging Section 83 Ž1998. 149]162

Effects of high amphetamine dose on mood and cerebral glucose metabolism in normal volunteers using positron emission tomography Ž PET. Franz X. Vollenweider aU , Ralph P. Maguire b , Klaus L. Leenders b , Karoline Mathys c , Jules Angst a a

Research Department, Psychiatric Uni¨ ersity Hospital Zurich, Box 68, CH-8029 Zurich, Switzerland ¨ ¨ b PET Department, Paul Scherrer Institute, CH-5232 Villigen, Switzerland c Institute of Pharmacy, Uni¨ ersity of Bern, CH-3012 Bern, Switzerland Received 25 July 1996; accepted 26 May 1998

Abstract The effects of high euphorigenic doses of D-amphetamine Ž0.9]1.0 mgrkg p.o.. on regional cerebral glucose metabolism ŽrCMRglu. and psychological measures were investigated in 10 healthy human volunteers using a within-subject design and wF-18x-fluorodeoxyglucose positron emission tomography ŽFDG-PET. and a variety of psychological assessments. At the dose tested, D-amphetamine produced a mania-like syndrome concomitantly with a widespread increase in absolute cerebral metabolism, which was significant in the anterior cingulate cortex, caudate nucleus, putamen, and thalamus. An exploratory analysis revealed that: Ž1. certain aspects of this mania-like syndrome correlated positively with the metabolic changes seen in the frontal cortex, caudate nucleus and putamen; and Ž2. some of the amphetamine-induced changes in CMRglu correlated with D-amphetamine plasma levels. The present findings of cortical and subcortical increases in cerebral metabolism after D-amphetamine application in humans accord with previous studies in animals, demonstrating that relatively high doses of D-amphetamine Žpresumably at least 1 mgrkg. are needed to increase cerebral glucose metabolism. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Emotion; Arousal; Anterior cingulate; Basal ganglia; Thalamus; Prepsychotic state; Healthy human volunteers

U

Corresponding author. Tel.: q41 1 3842604; fax: q41 1 3843396; e-mail: [email protected]

0925-4927r98r$ - see front matter Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0925-4927Ž98.00033-X

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1. Introduction Amphetamine is a central nervous system ŽCNS. stimulant well-known for its mood and behavioral activating effects, at clinically relevant doses, in healthy human volunteers ŽSilverstone et al., 1983; Zacny et al., 1992.. Sustained amphetamine administration in normal subjects produced a psychosis that uniquely resembled the paranoid form of schizophrenia ŽAngrist and Gershon, 1970; Griffith et al., 1972.. Amphetamine, usually tested at non-psychotogenic doses, can also provoke or lead to an exacerbation of psychotic symptoms in schizophrenic patients ŽLieberman et al., 1990.. Amphetamine is thought to produce its mood activating and psychotogenic effects by increasing presynaptic dopamine release and by inhibiting dopamine reuptake ŽSnyder, 1973.. Animal studies suggest, however, that norepinephrine and serotonin might also contribute to the psychological effects of amphetamine ŽGroves and Rebec, 1976; Sloviter et al., 1978.. The psychological effects of amphetamine are dose-dependent in both normal subjects and psychiatric patients ŽLieberman et al., 1990.. Previous studies of the psychopathology of amphetamine-induced psychosis in healthy human volunteers indicate that amphetamine, at relatively low doses Ž5]10 mg, p.o.., produces alertness, elation, mild euphoria, enhanced self-confidence, and behavioral activation ŽGriffith et al., 1972; Silverstone et al., 1983.. With increasing dose Ž50]100 mg, p.o.., normal subjects developed an exaggerated euphoric or dysphoric state characterized by suspiciousness, cognitive impairment, grandiosity, blunting of affect, illusions, compulsive behavior, and activation or retardation of psychomotor drive. To induce a florid amphetamine psychosis, however, sustained amphetamine administration was necessary, usually in cumulative doses of 100 mgrday over a period of 3]4 days ŽGriffith et al., 1972.. Thus the study of a florid amphetamine psychosis is hampered by a long induction phase and limited by ethical constraints. Studies into acute high prepsychotic doses of amphetamine using wF-18x-fluorodeoxyglucose positron emission tomography ŽFDGPET. may, however, prove useful to elucidate the

functional organization of the brain in euphoria and prepsychotic states. Most brain imaging studies of the effects of amphetamine in normal subjects found no changes or only a non-significant trend towards a diffuse reduction of whole brain glucose metabolism ŽCMRglu. or cerebral blood flow ŽCBF. ŽMathew and Wilson, 1985; Kahn et al., 1989; de Wit et al., 1991.. One PET study in normal subjects reported small, but significant decreases of CMRglu in the frontal and temporal cortices and striatum in response to amphetamine which were negatively correlated with the amphetamine plasma level ŽWolkin et al., 1987.. A non-significant global reduction in CBF ŽWolkin et al., 1987; Daniel et al., 1991. and a significant decrease in CMRglu in the left temporal cortex were also found in amphetamine challenge studies in schizophrenic patients ŽWolkin et al., 1987, 1994.. These findings appear surprising and contrast with the results obtained with amphetamine in animal studies. In animals, amphetamine consistently increased cerebral glucose metabolism or blood flow, particularly in terminal fields of dopaminergic pathways ŽMcCulloch and Harper, 1977; Berntman et al., 1978; Wechsler et al., 1979; Orzi et al., 1983.. The discrepancy between animal and human studies may be attributable to interspecies differences andror the much higher doses of amphetamine given to animals Žapprox. 2]20 times higher than in human studies.. Indeed, a number of animal studies strongly suggest that the threshold dose to increase cortical CMRglu in animals is approx. 1]1.5 mgrkg of amphetamine ŽMcCulloch and Harper, 1977; Neuser and Hoffmeister, 1977; Eison et al., 1981; Porrino et al., 1983., while all of the human studies that found no increase in cortical CMRglu or CBF in normal subjects had investigated considerably lower doses ranging from approx. 0.07 to 0.5 mgrkg ŽMathew and Wilson, 1985; Wolkin et al., 1987; Kahn et al., 1989; de Wit et al., 1991.. In the present FDG-PET study we investigated the acute effect of a high dose of amphetamine on cerebral glucose metabolism and its relation to psychological effects in normal volunteers. Based on the dose]response relationship in metabolic animal studies and the clinical effects in human

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studies, we hypothesized that a high dose of approx. 1.0 mgrkg amphetamine may increase CMRglu in dopaminergic projections sites such as the frontal cortex, anterior cingulate, and basal ganglia, in concert with a prepsychotic state. 2. Methods The study was approved by the Ethics Committee of the Psychiatric University Hospital Zurich ¨ ŽPUK.. All subjects were examined at the Research Department of the PUK, the MRI Center of the University Hospital of Zurich, and the PET ¨ Department of the Paul Scherrer Institute Villigen ŽPSI.. 2.1. Subjects and experimental design Ten healthy volunteers Žmale s five, female s five. between 28 and 44 years of age Žmean " S.D.s 34.0" 5.8. were recruited from university and hospital staff. Written consent was obtained prior to participation. The subjects were screened by psychiatric interview to exclude those with personal or family Žfirst-degree relatives. histories of major psychiatric disorders or histories of illicit drug abuse. Subjects were healthy according to physical examination, electrocardiogram, MRI, blood and urine analysis. Subjects were free to withdraw from the study at any time. In order to reduce risks and anxiety, and to train subjects to lie still for approx. 50 min under the influence of amphetamine, subjects received a preliminary drug exposure in a recreational environment at the PUK. Subsequently, each of the subjects was scanned on two occasions and 10 subjects were scanned overall. 2.2. Substance D-Amphetamine was obtained through the University Hospital Pharmacy, Zurich, Switzerland, ¨ and prepared as capsules Ž1 and 5 mg..

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conditions using the inventory of the ‘Association for Methodology and Documentation in Psychiatry’ ŽAMDP. ŽArbeitsgemeinschaft fur ¨ Methodik und Dokumentation in der Psychiatrie AMDP, 1981.. From the AMDP inventory two total scores for ‘manic-depression’ and ‘schizophrenia’, as well as subscale scores for apathy, mania, somatic and retarded depression, paranoia, hypochondria, psycho-organic Žthought disorder. and neurological deficits, hallucinatory-disintegration, and vegetative reactions, were derived. The ‘Altered States of Consciousness Questionnaire’ ŽAPZ. was applied as a self-assessment inventory to evaluate amphetamine effects as changes from the pre-drug condition ŽDittrich, 1994, 1996.. The APZ questionnaire yields three dimensions Žfactors. composed of several item clusters measuring shifts in mood and changes in the experience of the selfrego and the environment in altered states of consciousness ŽASC.. The first subscale, OSE Ž‘oceanic boundlessness’., measures derealization and depersonalization phenomena associated with a positive basic mood ranging from heightened feelings to sublime happiness and alterations in the sense of time and space. The second subscale, VUS Ž‘visionary restructuralization’ ., assesses illusions and hallucinations, and synaesthetic phenomena, as well as changes in the meaning and interpretation of various percepts. The third subscale, AIA Ž‘dread of ego-dissolution’., measures thought disorder, anxious]ego]disintegration, loss of control over body and thought, and derealization phenomena associated with arousal and anxiety. The APZ Questionnaire has been validated extensively and used to investigate drug- and non-drug-induced ASC, while the three APZ dimensions } OSE, VUS, and AIA } have been shown to be altered consistently in a manner that is independent of the particular treatment, disorder, or condition that led to the ASC ŽDittrich et al., 1985; Dittrich, 1994.. 2.4. PET studies

2.3. Psychometric scales All subjects were examined by an experienced psychiatrist to obtain scores in baseline and drug

Each subject received a baseline and an amphetamine PET scan, in a randomized order, and at monthly intervals. Upon arriving at the Paul

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Scherrer Institute ŽPSI. PET Department Ž11:00 h., fasting subjects ingested capsules containing amphetamine Ž1 or 5 mgrcapsule.. Injection of FDG began 90 min after ingestion, to coincide with the peak effects of the drug ŽSilverstone et al., 1983.. Human studies suggest that relatively high doses of amphetamine Ž50]100 mg, p.o.. are necessary to produce reliable stimulant effects and mania-like Žprepsychotic. symptoms in normal volunteers ŽGriffith et al., 1972.. Thus, in the present study a high dose of approx. 0.9]1.0 mgrkg amphetamine was used to assure arousal and mood altering effects over a period of 60]120 min. Subjects had their eyes closed and ears plugged during PET scanning. Subjects were examined immediately after PET scanning using the AMDP rating scales. Subjects also completed the APZ questionnaire after the drug effects had completely subsided. FDG-PET scans were performed using a CTI ŽSiemens 933r04-16. tomograph. The scanner simultaneously measures seven contiguous planes Žwidth, 8 mm. with an in-plane transaxial resolution of 8 mm Žfull-width half-maximum. after image reconstruction. Before tracer administration, a transmission scan was performed using an external germanium-68rgallium-68 ring source with the field of view parallel to and from 20 to 76 mm above the orbitomeatal line ŽOM line. and in a second position displacing the field of view 40 mm in the cranial direction. A time series of acquisition Ž3 = 1 min, 10 = 3 min, and 3 = 5 min duration., was performed during the first 48 min after tracer infusion } dynamic scan. This acquisition protocol was immediately followed by one 5-min measurement in the second position, 60]116 mm above the OM line } static scan. A 3-min infusion of FDG was begun at the start of the dynamic scan. The mean administered FDG dose was 177.6 MBq Žmin s 107.3, max s 244.2.. Twenty-three arterial blood samples were collected from an indwelling radial artery catheter ŽTeflon, 0.8 mm. for determination of blood plasma radioactivity, glucose concentration, and drug levels. A urethane foam head holder was made for each subject to fix the subject’s head parallel to the OM line, and to allow repeated

PET experiments in virtually the same head position. During the dynamic and static scans, seven planes were recorded simultaneously but, because two planes overlapped after axial displacement, only 12 planes were recorded independently. Using the measured data from the last time point of the dynamic measurements and from the static measurement, a contiguous set of 12 planes was performed representing uptake in a volume with an axial field of view of 96 mm. The autoradiographic method described by Rhodes et al. Ž1983. was used to form parametric images of rCMRglu for each of the planes independently on a pixelby-pixel basis. The images were transformed into the standard stereotaxic space described by Talairach and Tournoux Ž1988. using a combination of linear and non-linear transformations included in the Statistical Parametric Mapping ŽSPM. algorithm ŽFriston et al., 1989, 1991.. Feature localization is determined by intercomparison of the image volume with a set of standard templates ŽFig. 1, Table 1.. After spatial standardization, a set of regions of interest ŽROIs; 32 in each hemisphere, approx. 5.6 to 5.6 mm or 5.6 to 10.4 mm. using the Talairach coordinate system were placed symmetrically in cortical and subcortical regions with high dopaminergic projections ŽFig. 1.. The coordinates, according to Talairach, of the following ROIs were determined and collapsed into the following seven regions Ž n s number of adjacent planes.: frontomedial Ž n s 10. and frontolateral cortex Ž n s 10.; anterior Ž n s 2. and posterior Ž n s 2. cingulate cortex; caudate nucleus Ž n s 3.; putamen Ž n s 2.; and thalamus Ž n s 3. ŽTable 1.. For each plane one total image ROI was determined. The ROIs were determined either on the last frame of the dynamic sequence Ž45min after tracer injection. or in the static image obtained in the second head position. For each time frame, the ROI value was determined, decay-corrected, and expressed in becquerels per milliliter. Regional glucose utilization was expressed as glucose metabolic rate in micromoles per 100 grams per minute. The average whole brain glucose

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Fig. 1. Template for the location of regions of interest used in the analysis of metabolic images: FRM, frontomedial cortex; FRL, frontolateral cortex; GCA, cingulate anterior; GCP, cingulate posterior; CAU, caudate nucleus; THA, thalamus.

Table 1 Talairach coordinates of the left-hemispheric regions of interests ŽROIs. FRM

FRL

GCA

GCP

CAU

PUT

THA

Ž xryrz . y4r44r40 y4r45r35 y4r45r32 y5r48r28 y5r53r12 y5r56r8 y5r58r4 y5r59ry 1 y5r58ry4 y6r50ry8

Ž xryrz . y27r40r40 y27r40r35 y30r46r32 y31r47r28 y33r52r12 y34r53r8 y34r57r4 y34r57ry1 y34r56ry4 y35r56ry8

Ž xryrz .

Ž xryrz .

Ž xryrz .

Ž xryrz .

Ž xryrz .

y4r5r35 y4r23r32

y4ry34r35 y4ry34r32 y11r10r12 y10r15r8 y8r15r4

y21ry1r8 y20ry2r4

y10ry13r12 y10ry18r8 y10ry16r4

Note. The Talairach coordinates Ž xryrz . indicate the center of ROIs. ROIs were placed symmetrically in both hemispheres. In each hemisphere, ROIs in adjacent planes were collapsed into frontomedial ŽFRM., frontolateral ŽFRL., anterior cingulate ŽGCA., posterior cingulate ŽGCP., caudate nucleus ŽCAU., putamen ŽPUT., and thalamic ŽTHA. regions.

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metabolic rate was calculated as the mean of three total image ROIs which cut through the basal ganglia. Changes in absolute metabolism from a baseline to an amphetamine scan were assessed as percent difference from baseline.

parisons were made, the results should be regarded as exploratory rather than confirmatory. 3. Results 3.1. Clinical response to amphetamine

2.5. Plasma amphetamine assay Plasma amphetamine levels were measured using an HPLC-DAD method with a sensitivity of 2.5 ngrml for amphetamine ŽMathys and Brenneisen, 1992.. During PET scanning the volunteer’s plasma was collected using the cannula in the radial artery after 0, 10, 30, 48 and 54 min. All plasma samples were stored at y208C until analysis. 2.6. Statistical analysis In this study, each subject served as his or her own control to minimize the effect of interindividual variation in metabolic rates and psychopathology scores. The significance of the effects of amphetamine on absolute CMRglu was tested with univariate analyses of variance ŽANOVA. using STATISTICArw, Version 5.1 ŽStatSoft, 1995.. A three-way ANOVA with treatment Žbaseline, amphetamine., hemisphere Žleft, right., and brain regions ŽROIs. as repeated measures was used to explore laterality effects of amphetamine on cerebral metabolism. The Greenhouse]Geisser adjustment was applied to correct for repeated measurement. When significant main effects or interactions were revealed in the ANOVA, post-hoc comparisons were done with Tukey’s tests. The significance levels of the main factors are cited in the text and those for Tukey’s post-hoc tests of individual measures are given in the figures. The Wilcoxon matched pairs test was used to evaluate differences in psychopathology scores between baseline and amphetamine conditions. The Spearman correlation coefficient was used to evaluate correlations between changes in absolute metabolic rates of glucose, psychopathology scores, and amphetamine plasma levels. Statistically significant P values were considered to be those less than 0.05. Since no correction for the number of com-

Amphetamine produced significant changes in mood, arousal, and small-to-moderate derealization and depersonalization phenomena. The psychic and stimulant effects began approx. 30 min after amphetamine administration, peaked between 60 and 90 min after ingestion, and lasted for 8]12 h. Thus, the PET investigation, which occurred from 90 to 140 min after drug administration, was done during the period of peak drug effects. The plasma levels of amphetamine ranged from 43.5 to 131.2 ngrml Žmean " S.D.s 93.2" 34.6 ngrml. between subjects. Intraindividual amphetamine plasma levels, however, remained within the same range of magnitude during PET scanning. Amphetamine produced typically stimulant-like effects as indicated by the small but significant increase in the overall syndrome score for ‘manic-depression’ Ž P- 0.05, Fig. 2.. Item-based analysis of the manic-depression syndrome scale revealed that this increase was mainly based on items relating to excessive elation, euphoria, accelerated thinking, and internal tension, although some of the subjects Žthree of nine. felt dysphoric and depressed. As seen in Fig. 2, amphetamine markedly increased the AMDP subscale sores for mania Ž P - 0.01., thought disorder Žpsychoorganic syndrome, P- 0.01., somatic depression Ž0.01. and vegetative side effects Ž P- 0.01., while the subscale scores for apathy Ž P- 0.05., retarded depression Ž P- 0.05., and hypochondria Ž P- 0.05. were only slightly increased. At the high dose used, amphetamine also produced small-to-moderate derealization and depersonalization phenomena, as indicated by significant increases in the OSE, VUS and AIA scores of the APZ rating scale ŽFig. 3.. The increase in the OSE score was due to a prominent increase in the ‘positive basic mood’ items and moderate increases in the ‘derealization’, ‘depersonalization’, and ‘alterations in the sense of time and

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Fig. 2. Mean AMDP subscale and syndrome scores Ž"S.D.. of normal subjects under baseline and amphetamine conditions during PET scanning. AMDP subscale scores: apat, apathy; hall, hallucinatory disintegration; host, hostility; mania; s-dep, somatic depression; para, paranoia; kata, katatonia; g-dep, retarded depression; hypo, hypochondria; psych, thought disorder; veg, vegetative side effects. The AMDP syndrome scores: man-dep, manic-depression, schizo, schizophrenia. U P- 0.05, UU P - 0.01.

Fig. 3. Mean APZ Žaltered state of consciousness . scores Ž"S.D.. of normal subjects under baseline and amphetamine conditions during PET scanning. OSE, oceanic boundlessness; AIA, dread of ego dissolution; VUS, visionary restructuralization. U P- 0.05, UU P - 0.01.

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space’ item clusters. The increase in the VUS score was due to intensified vision and hearing. None of the subjects reported visual or auditory hallucinations. The increase in the AIA score was attributable to the ‘thought disorder’ and ‘loss of body control’ items. Subjects did not become paranoid or fully psychotic during the amphetamine challenge test. However, two of the subjects became quite suspicious about the experimental setting, but denied paranoid feelings. 3.2. Effects of amphetamine on cerebral metabolism The percent changes of absolute CMRglu from baseline to amphetamine PET scans for the seven ROIs examined are shown in Fig. 4. Amphetamine increased CMRglu in cortical regions by 4]11% and subcortical CMRglu by 10]16%. A three-way ANOVA with Greenhouse]Geisser adjustments revealed significant main effects of treatment Ž F1,9 s 6.3; P - 0.033., hemisphere Ž F1,9 s 8.1; P- 0.019., and region Ž F1.8,15.9 s 13.8; P- 0.00001., and a significant treatment = region

interaction Ž F2.9,26.2 s 4.91; P- 0.008.. Post-hoc analysis Žof the treatment = region interaction . with Tukey’s tests revealed that amphetamine produced significant increases in CMRglu in the anterior and posterior cingulate, caudate nucleus, putamen and thalamus when left and right ROIs were pooled ŽFig. 4.. The inspection of the left vs. the right mean regional percent changes suggested that subjects with amphetamine had slightly higher increases in absolute CMRglu in the left than in the right hemisphere ŽFig. 4.. However, these apparent laterality effects of amphetamine could neither be confirmed by a significant treatment = hemisphere interaction Ž F1,9 s 2.9; P- 0.12. nor by a triple interaction of treatment = hemisphere = region Ž F2.8,25.2 s 0.9; P- 0.45.. The failure to obtain significant interactions might be due to the small sample size and relatively large number of comparisons. Finally, a one-way ANOVA revealed that amphetamine significantly increased average whole brain metabolism approx. 7.4% Ž F1,9 s 6.07, P- 0.035..

Fig. 4. Change Ž"S.E.. of absolute metabolic rates of glucose ŽCMRglu. from baseline to amphetamine in normal subjects. See note to Fig. 1 for abbreviations of brain regions. Note: Significance of Tukey’s post-hoc comparison of metabolic values between baseline and amphetamine: U P- 0.05.

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3.3. Metabolic responses and correlations with amphetamine plasma le¨ el and psychopathology scores Although amphetamine significantly increased whole brain metabolism, the apparent metabolic stimulation was not uniform across subjects Žand brain regions.. Subjects with amphetamine plasma levels greater than 90 ngrml responded quite uniformly with substantial increases in CMRglu in cortical regions, while subjects with amphetamine plasma levels between 70 and 90 ngrml showed either slight increases or slight decreases Žin corresponding regions.. One subject, however, who displayed the lowest amphetamine plasma level Ž43.5 ngrml. consistently showed decreases in these cortical regions. More uniform increases in CMRglu after amphetamine Žin 9 of 10 subjects. were found in the caudate nucleus and putamen. An exploratory analysis using Spearman rank-order correlations indicated that this ‘biphasic’ metabolic response to amphetamine correlated significantly in several brain regions with the amphetamine plasma level ŽTable 2.. As seen in Table 2, Spearman rank-order correlations also

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revealed that the amphetamine-induced changes in the OSE, apathy and manic-depression scores showed positive correlations with regional changes in absolute metabolism. 4. Discussion Two major conclusions can be drawn from the present investigation. First, a high dose of amphetamine Ž0.9]1.0 mgrkg. produced a mania-like syndrome, including moderate derealization and depersonalization phenomena. Second, amphetamine increased cerebral glucose metabolism in cortical and subcortical regions in humans in a plasma level-dependent fashion, as expected from previous animal studies. In the present study, amphetamine produced typical stimulant-like effects comparable to those seen after lower doses of amphetamine Ž20]30 mg. ŽSilverstone et al., 1983; Heishman and Henningfield, 1991.. However, the high dose of amphetamine tested in this study additionally produced moderate derealization and depersonalization phenomena including visual, tactile and auditory illusions, first signs of loss of body and

Table 2 Correlations of metabolic changes with amphetamine plasma level or psychopathology scores Brain regions

FRM FRL GCA GCP CAU PUT THA

Left Right Left Right Left Right Left Right Left Right Left Right Left Right

Amph levels ŽSpearman R .

OSE a ŽSpearman R .

Apathy b ŽSpearman R .

Man-Dep b ŽSpearman R .

0.70U 0.59 0.58 0.62U 0.44 0.18 0.38 0.95UU 0.54 0.56 0.64U 0.55 0.48 0.07

0.56 0.81UU 0.72U 0.71U 0.29 0.18 0.67U 0.28 0.61 0.51 0.59 0.67UU 0.34 0.35

0.49 0.36 0.56 0.57 0.44 y0.40 0.43 0.36 0.43 0.64U 0.28 0.64U 0.57 0.28

0.22 0.17 0.26 0.21 y0.07 y0.28 0.01 0.40 0.63U 0.19 0.63U 0.45 0.07 y0.10

a

For APZ rating. For AMDP rating. Significant correlations are indicated by b

U

P- 0.05; UU P- 0.01; UUU P- 0.001.

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thought control, and, in some subjects, ideas of reference. Thus, the present data indicate that a single high dose of amphetamine can produce a mania-like state that contrasts in some respects with the more activating and euphoric reactions seen after small-to-moderate doses of amphetamine. This finding is consistent with previous observations that cumulative administration of small doses of amphetamine Ž5 and 10 mg, p.o.. up to 50 mg lead to a prepsychotic phase similar to that seen in the present study, but that larger doses were necessary to precipitate a florid amphetamine psychosis ŽGriffith et al., 1972.. In the present human study, amphetamine significantly increased whole brain glucose metabolism, but differentially affected absolute CMRglu in selected cortical and subcortical regions. The most prominent and robust increases in CMRglu were found in the caudate nucleus, putamen, thalamus, and left cingulate anterior cortex. This observation is consistent with previous findings in animal studies demonstrating that comparable doses of amphetamine stimulated CMRglu with greatest effect in dopaminergic projection sites. For example, amphetamine Ž0.2]0.5 mgrkg. selectively increased CMRglu in the nucleus accumbens in rats, while cortical activation was not seen until a dose of 1.0 mgrkg was administered ŽPorrino et al., 1983.. Neuser and Hoffmeister Ž1977. reported that 1.25 mgrkg of amphetamine was the minimal effective dose to increase both cortical and subcortical glucose metabolism in rats. Eison et al. Ž1981. found that 1.5 mgrkg of amphetamine selectively increased CMRglu in the caudate nucleus and thalamus in rats. Amphetamine, at 1.25 mgrkg, also produced substantial increases in both cerebral metabolic rates of glucose and oxygen in baboons ŽMcCulloch and Harper, 1977.. Finally, at least two studies in rats found that higher doses of amphetamine Ž5 mgrkg. than those used in the present study not only increased CMRglu or CBF in thebasal ganglia, but also in cortical and limbic regions ŽWechsler et al., 1979; Orzi et al., 1983.. Thus, the effects of high doses of amphetamine on CMRglu observed in this study with humans are consistent with those seen in animal studies. Amphetamine produced only relatively small

and non-significant mean increases in CMRglu in the prefrontal cortex, with the exception of the left anterior cingulate. This finding may be explained by the fact that although great care was taken to test subjects at or near the peak uptake of amphetamine, amphetamine plasma levels differed across subjects. Indeed, an exploratory correlation analysis indicated that amphetamine increased CMRglu in a plasma-level-dependent fashion, at least in some of the cortical regions examined. For example, subjects with the highest amphetamine plasma levels Ž90]131 ngrml. showed increases in CMRglu ofapprox. 18% in the frontomedial cortex. On the other hand, subjects with plasma levels between 70 and 90 ngrml showed smaller increases or even decreases in CMRglu of approx. 5%, while subjects at plasma levels lower than 70 ngrml consistently showed decreases. Increases, as well as decreases, in CMRglu were also seen after relatively small doses of amphetamine Ž5 and 10 mg, p.o.. in an FDG-PET study in normal human volunteers Žde Wit et al., 1991.. The decreases found in our subjects with plasma levels up to 90 ngrml are consistent with findings from previous amphetamine challenge studies in normal volunteers. A non-significant diffuse reduction of cerebral glucose metabolism or blood flow was reported in three studies in normal subjects after 10 mg, 15 mg or 0.3 mgrkg of amphetamine ŽKahn et al., 1989; Mathew and Wilson, 1989; de Wit et al., 1991.. Furthermore, Wolkin et al. Ž1987. found small decreases Žup to 7.6%. in frontal and temporal glucose metabolism after amphetamine Ž0.5 mgrkg, p.o.. in an FDG-PET study in normal subjects with plasma amphetamine levels ranging from 30 to 75 ngrml. It is noteworthy that these decreases were of the same magnitude as those seen in the present study and occurred at very similar plasma levels. The present finding of an increase in cortical metabolism seen in subjects with high amphetamine plasma levels is in accordance with a number of metabolic animal studies ŽMcCulloch and Harper, 1977; Neuser and Hoffmeister, 1977; Wechsler et al., 1979; Orzi et al., 1983. and a human study reporting a substantial increase in cortical CBF with emphasis in the left frontal cortex in a case of amphetamine intoxica-

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tion ŽBerglund and Risberg, 1980.. Taken together, the present findings and these data strongly suggest that high doses of amphetamine stimulate cortical metabolism in a dose-dependent manner, as expected from animal studies. Moreover, it appears that the threshold dose of amphetamine to increase CMRglu in humans is similar to that seen in animal studies and might be at least 1.0 mgrkg. Previous studies in rats demonstrated that amphetamine increased dopamine release in a dose-dependent manner in the striatum and nucleus accumbens ŽSharp et al., 1987.. Thus, it is conceivable that the metabolic changes seen after amphetamine may be due to the amphetamine-induced presynaptic release of dopamine. Likewise, it has been assumed that the psychological effects of amphetamine in humans are due to indirect dopamine D 2 receptor agonism, based largely on the clinical efficacy of D 2 antagonists in treating amphetamine-induced psychosis, as well as mechanistic studies in animals ŽNurnberger et al., 1982; Swerdlow et al., 1990.. Also in concert with a dopamine hypothesis is the observation that the dopamine agonists apomorphine and piribedil increased prefrontal and anterior cingulate ŽGrasby et al., 1993., as well as global, CBF ŽGuell et al., 1982. in normal human subjects. Hence, it is somewhat surprising that low and high doses of amphetamine appear to have opposite effects on CMRglu in humans. A possible explanation may be that higher doses of amphetamine might lead to a different release profile of dopamine andror involve different dopamine receptor subtypes or other neurotransmitter systems. Indeed, there is evidence that amphetamine, particularly at high doses, also stimulates the release of norepinephrine and serotonin ŽGroves and Rebec, 1976; Sloviter et al., 1978.. Thus, the widespread metabolic activation after higher doses of amphetamine may reflect the integrated downstream effects of dopamine and other neurotransmitters rather than the effects of dopamine alone. Nevertheless, in the absence of mechanistic studies, no firm conclusions can be drawn regarding the mediation of the observed amphetamine effects in humans. Considerably more research is needed to clarify the mechanisms and sites of action under-

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lying the effect of amphetamine on cerebral metabolism in humans. Based on animal studies, it has been suggested that the anterior cingulate may relate to attention, emotion, and integrative cognitive functions, while the posterior cingulate may mediate motor and sensory functions ŽVogt et al., 1992.. Indeed, direct electrical stimulation of the anterior cingulate in humans yielded a spectrum of affective changes and psychosensory phenomena, including fear, euphoria, confusion and hallucinations ŽDevinsky and Luciano, 1993.. A circumscribed activation of the anterior cingulate and basal forebrain, as well as an increase in global CBF, was reported in procaine-induced euphoria in healthy normal subjects ŽKetter et al., 1996.. The opposite, decreased activity or blunted activation of the anterior cingulate was reported in depressed patients in most, but not all, studies ŽGeorge, 1993; Ketter et al., 1996; Ebmeier et al., 1997; George et al., 1997.. Thus, it appears that the concomitant activation of the left anterior cingulate and induction of affective arousal and mania-like symptoms in our amphetamine subjects is consistent with a modulatory role of the anterior cingulate in the expression of mood and arousal. The failure of a significant correlation between anterior cingulate activation and manialike symptom scores in the present study may be explained by the fact that not a single region, but rather a neuronal network involving the anterior cingulate and associated paralimbic structures, the frontal cortex and the basal ganglia, is implicated in mood regulation and affective behavior ŽKetter et al., 1996.. The limbic cortico]striato] thalamo]cortical ŽCSTC. feedback loop has been suggested to provide an anatomical substrate implicated in mood and psychotic disorders ŽCarlsson and Carlsson, 1990; Ketter et al., 1996.. Specifically, it is thought that dysfunction of anterior cingulate, caudate-putamen and thalamus may lead to a disruption of CSTC feedback loops which in turn may lead to a sensory overload of the cortex and arousal ŽSiegel et al., 1993; Vollenweider, 1994; Ketter et al., 1996.. This view is consistent with the widespread increase in global metabolism and the activation of the anterior cingulate and basal ganglia observed in our am-

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phetamine subjects. A global increase in cortical glucose metabolism ŽBaxter et al., 1985. and CBF ŽMukherjee et al., 1984. was also found in acute mania and in hypomanic states in rapid-cycling bipolar patients, respectively. The involvement of the basal ganglia in the expression of mood is supported by the present finding of significant correlations between caudate-putamen activation and mania-depression in the left and between caudate]putamen activation and apathy in the right hemisphere. The correlation between left cingulate posterior activation and derealization and depersonalization phenomena measured by the OSE score may add further evidence for a functional subdivision of anterior vs. posterior cingulate cortex. Finally, the positive correlation between amphetamine-induced derealization and depersonalization ŽOSE. and the dose-dependent activation of the frontal cortex is consistent with our recent findings noted in the ketamine and psilocybin models of psychosis ŽVollenweider et al., 1997, 1997.. Also, recent brain imaging studies suggested that increased frontomedial and anterior cingulate metabolism may relate to some positive psychotic symptoms, such as grandiosity, disorganization and thought disorder in acutely ill schizophrenic and non-schizophrenic patients ŽLiddle et al., 1992; Ebmeier et al., 1995; Lahti et al., 1995; Sabri et al., 1997.. In view of the substantial interindividual differences in cortical activation and the small sample size, it should be emphasized that the present correlational analysis is regarded as exploratory rather than confirmatory. The present data indicate that high doses of amphetamine activate limbic cortico]striato] thalamic pathways with some emphasis in the left hemisphere and that dysfunction in these regions may be associated with mania-like and psychotic responses. Together with other reports, our data also indicate that catecholaminergic, presumably dopaminergic hyperactivity may underlie the functional changes seen after amphetamine administration. In this respect, it is of interest that acute administration of the D 2 antagonist haloperidol in healthy volunteers time-dependently reduced glucose metabolism in the very

same brain regions ŽBartlett et al., 1994, 1996. that were noted to be activated by amphetamine in this study. Thus, studies of amphetamine in combination with specific dopamine receptor antagonists may prove valuable to further elucidate functional changes associated with emotional experiences in health and affective disorders. Acknowledgements We gratefully acknowledge the use of the SPM image analysis system which has been made available to us courtesy of Prof. R.S.J. Frackowiak. We also are grateful to the Department of Radiopharmacy of the PSI through which the radiotracer FDG was obtained. We especially thank Prof. R. Brenneisen, Institute of Pharmacy, University of Bern, for the amphetamine blood level analysis, and Dr. M.F.I. Vollenweider-Scherpenhuyzen, Institute of Anesthesiology, University Hospital Zurich, and Dr. Kirsten Krebs Thomson, ¨ Department of Psychiatry, UCSD, for critical comments on the manuscript. This study was financially supported in part by the Swiss National Science Foundation Ž32-28746.90.. References Angrist, B.M., Gershon, S., 1970. The phenomenology of experimentally induced amphetamine psychosis } preliminary observations. Biological Psychiatry 2, 95]107. Arbeitsgemeinschaft fur ¨ Methodik und Dokumentation in der Psychiatrie AMDP, 1981. Das AMDP-System. Manual zur Dokumentation psychiatrischer Befunde. Springer-Verlag, Berlin. Bartlett, E.J., Brodie, J.D., Simkowitz, P., Dewey, S.L., Rusinek, H., Wolf, A., Fowler, J.S., Volkow, N.D., Smith, G., Wolkin, A., Cancro, R., 1994. Effects of haloperidol challenge on regional cerebral glucose utilisation in normal human subjects. American Journal of Psychiatry 151, 681]686. Bartlett, E.J., Brodie, J.D., Simkowitz, P., Dewey, S.L., Rusinek, H., Volkow, N.D., Wolf, A.P., Smith, G., Wolkin, A., Cancro, R., 1996. Time-dependent effects of a haloperidol challenge on energy metabolism in the normal human brain. Psychiatry Research 60, 91]99. Baxter, L., Phelps, M., Mazziotta, J., Schwartz, J., Gerner, R., Selin, C., Sumida, R., 1985. Cerebral metabolic rates for glucose in mood disorders. Archives of General Psychiatry 42, 441]447.

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