Journal of Neurochemistry. 1979, Vol. 32. pp. 15-22. Pergamon Press. Printed in Great Britain.

EFFECTS OF d- AND |-AMPHETAMINE
ON LOCAL CEREBRAL GLUCOSE
UTILIZATION IN THE CONSCIOUS RAT!

L. R. WecuHSLER, H. E. Savakt and L. SOKOLOFF
Laboratory of Cerebral Metabolism, National Institute of Mental Health,

United States Public Health Service, Department of Health, Education, and Welfare,
Bethesda, MD 20014, U.S.A.

(Received 23 May 1978. Accepted 3 June 1978)

Abstract—Amphetamine, a potent sympathomimetic amine, has powerful stimulant actions in the cen-
tral nervous system. These actions are believed to be related to the influence of amphetamine on
release and uptake of catecholamine neurotransmitters. The ['*C]deoxyglucose method makes it poss-
ible to study changes in cerebral metabolic rate in different areas of gray and white matter. Because
of the close relationship between metabolic rate and functional activity, this method may be used
to identify specific structures in the brain in which functional activity is altered. The [’*C]deoxyglucose
method was used to explore for changes in metabolic rate produced by d- and l-amphetamine (5 mg/kg)
in forty gray and four white matter structures in normal conscious rats. d-Amphetamine produced
increases in local cerebral glucose utilization in a number of components of the extrapyramidal motor
system, as well as in some other structures known to contain dopamine-producing and/or dopaminocep-
tive cells. The largest increases after d-amphetamine administration occurred in the subthalamic nucleus
and the zona reticulata of the substantia nigra. /-Amphetamine produced increases in some but not
all of these same structures, and these were generally smaller than those observed with d-amphetamine.
Decreases in local cerebral glucose utilization after either d- or l-amphetamine administration were
found in the habenula and the suprachiasmatic nuclei of the hypothalamus. The effects in the supra-
chiasmatic nuclei may reflect their normal diurnal rhythm in metabolic rate. These results indicate
that amphetamines may influence behavior through effects on specific regions of the brain. Only some

of these regions have previously been studied as possible sites of action of amphetamine.

AMPHETAMINE, a potent sympathomimetic amine, pro-
duces marked behavioral changes in man and animals
and, when administered in large doses, can induce
a schizophrenia-like psychotic state in man (ANGRIST
& GERSHON, 1970; GrirFiTH et al., 1970). Its behav-
ioral effects are generally believed to result from its
actions on the release and re-uptake of neurotrans-
mitters at catecholaminergic synapses in the CNS
(SNYDER et al., 1972). Amphetamine, for example, has
been found to decrease uptake of [*H]dopamine in
the corpus striatum (TAYLOR & SNYDER, 1971) and
to depress spontaneous firing rates of dopamine-pro-
ducing cells in the substantia nigra, possibly by acti-
vation of a feedback pathway (BUNNEY et al., 1975).
Such evidence has implicated dopaminergic pathways
as sites of action of amphetamine, but there is also
evidence to indicate similar effects in noradrenergic
systems (COYLE & SNYDER, 1969; BUNNEY et al., 1975).
Snyder and coworkers (TAYLor & Snyper, 1970,
1971; SNYDER, 1974) have suggested that the dopa-
minergic and noradrenergic actions of amphetamine
might be distinguished by comparison of the relative

 

‘ Preliminary reports of portions of this work were pre-
sented at the 7th Annual Meeting of the Society for Neuro-
sciences, November 1977, Anaheim, CA (WECHSLER et al.,
1977). :

15

potencies of its d- and J/-isomers in any given effect.
He has presented evidence that d-amphetamine is
7-10 times more potent than /-amphetamine at nor-
adrenergic synapses but only 2~3 times more potent
at dopaminergic sites (SNYDER, 1974). These relative
potencies have not been uniformly confirmed; in fact,
nearly opposite relative potencies have been observed
(FERRIS et al., 1972; HARRIS & BALDESSARINI, 1973;
HEIKKILA et al., 1975).

Although a number of dopaminergic pathways
have been identified in the CNS (MELTZER & STAHL,
1976), the nigrostriatal and mesolimbic dopamine-
pathways have been most thoroughly examined as
possible sites of action of amphetamine. Some of the
drug’s behavioral effects, particularly the stereotyped
behavior, have been associated with effects in the
nigrostriatal pathway (TAYLOR & SNYDER, 1971; BUN-
NEY et al., 1975; ReBEC & Groves, 1975). Effects in
the mesolimbic system are believed to be involved
in amphetamine-induced psychosis, and, in fact,
because of similarities between amphetamine-psy-
chosis and schizophrenia, abnormalities in the meso-
limbic system have been suspected in schizophrenic
states (SNYDER et al., 1972). The effects of amphet-
amine in other dopamine-pathways, or, indeed, in
most other systems of the CNS, have not been so
thoroughly investigated.
16 L. R. Wecusier, H. E. SAvAK! and L. SOKOLOFF

The recently developed ['*C]deoxyglucose method
has made it possible to measure the rates of glucose
utilization simultaneously in all the anatomical and
functional components of the CNS (SoKotorF et al.,
1977). Because of the close coupling between energy
metabolism and functional activity, this method has
proved useful to map localized regions of the brain
with altered functional activity in various physiologi-
cal and pharmacological states (SoKOLOFF, 1977). This
technique has been applied to normal conscious rats
treated with d- or l-amphetamine. A number of struc-
tures known to be components of dopamine-path-
ways, such as the caudate nucleus and substantia
nigra, were found to have markedly increased rates
of glucose metabolism; some components of other
dopamine-pathways were unaffected; and a few
structures not previously associated with catechola-
minergic systems exhibited altered rates of glucose
utilization.

MATERIALS AND METHODS

Animals. Normal adult male Sprague-Dawley rats
weighing 350-400 g were used in all experiments. The ani-
mals were maintained on Purina Laboratory Chow and
water ad lib. until the time of the experiments.

Materials. 2-Deoxy-p-[1-'*C]glucose (spec. act., 50-
55 mCi/mmol) was purchased from New England Nuclear
Corp. (Boston, MA). Calibrated ['*C]toluene, used for
internal standardization of samples assayed by liquid scin-
tillation counting, was also obtained from New England
Nuclear Corp. (Boston, MA). The d- and /-isomers of
amphetamine sulfate were obtained from Sigma Chemical
Co. (St. Louis, MO) and Smith, Kline, and French Labora-
tories (Phila., PA), respectively.

Experimental procedures. Local cerebral glucose utiliza-
tion was measured by the ['*C]deoxyglucose method
described by SokoLorF et al. (1977). The animals were
anesthetized with halothane and N,O, and polyethylene
catheters were inserted in one femoral artery and vein.
They were then placed in a loose-fitting plaster cast and
immobilized from the abdomen to the hind-legs; the head,
forelegs, and thorax were unrestrained. At least 2h were
allowed for complete recovery from the effects of anesthe-
sia. The animals were then injected intravenously with
either physiological saline or 5 mg/kg of d- or /-ampheta-
mine sulfate in normal saline. Fifteen minutes later 50 pCi
of ['*C]deoxyglucose were administered as a pulse via the
intravenous catheter, and timed arterial blood samples
were then drawn during the following 45 min. The arterial!
blood samples were immediately centrifuged in a Beckman
Microfuge B (Beckman Instrument Co., Fullerton, CA),
and the plasma was separated and stored on ice until
further analysis. At the end of the 45min period the ani-
mals were decapitated, and the brains were removed as
rapidly as possible and frozen in Freon XII chilled to
—70°C in liquid nitrogen. The brains were then coated
with chilled embedding medium (Lipshaw Manufacturing
Co., Detroit, MI), stored at —70°C in plastic bags, even-
tually sectioned into 20 pm sections at —22°C in a cryo-
stat, and autoradiographed along with calibrated
(‘*C]methyl methacrylate standards as previously
described (SOKOLOFF et al., 1977).

The arterial plasma samples were assayed for ['*c]
deoxyglucose concentration by liquid scintillation counting
with internal standardization and for glucose concen-
tration by means of a Beckman Glucose Analyzer (Beck-
man Instrument Co., Fullerton, CA), also as previously
described (SOKOLOFF et al., 1977). Local tissue concen-
trations of '*C were determined from the autoradiographs
by densitometric analysis of the autoradiographs with a
scanning microdensitometer (Gamma Scientific Corp., San
Diego, CA) with an aperture of 100 um. Local cerebral
glucose utilization was calculated as previously described
(SOKOLOFF et al., 1977).

Statistical analyses. Local cerebral glucose utilization
was measured in 40 gray and 4 white structures in 5 con-
trol animals, 5 animals treated with d-amphetamine, and
5 treated with -amphetamine. Each structure was analyzed
for statistically significant effects of the drugs by the
procedure of DUNNETT (1955; 1964). This procedure is
specifically designed for multiple comparisons with a single
control group and is a more rigorous test for statistical
significance than Student’s ¢ test.

RESULTS

Behavior

The control animals were all awake and alert
throughout the experimental period. Both d- and
l-amphetamine produced gross behavioral changes
that were readily apparent in all animals receiving
either drug. Despite restraint of the pelvis and lower
limbs, animals treated with either isomer exhibited
increased side-to-side and front-to-back movements
and sniffing and exploratory behavior that began
quickly after administration of the drug and persisted
throughout the experimental period. The effects of
d-amphetamine were always more prominent than
those of /-amphetamine, and animals treated with
d-amphetamine maintained their level of stimulation
throughout the experiment whereas the behavioral
effects of the /-isomer tended to abate somewhat
toward the end of the experimental period.

Effects of d-amphetamine on local cerebral glucose uti-
lization

d-Amphetamine stimulated glucose utilization in a
number, though by no means all, of the gray struc-
tures of the brain examined (Table 1). Most of the
structures thus affected are known sites of dopamine-
producing or dopamine-receptive cells, and the most
prominent effects were in components of the extrapyr-
amidal motor system. The greatest percent increases
were observed in the zona reticulata of the substantia
nigra (+87°%%) and the subthalamic nucleus (+ 67%).
The effects in these two structures were so pro-
nounced that they could be visualized directly in the
autoradiographs (Fig. 1). Other components of the
extrapyramidal system also significantly affected were
the zona compacta of the substantia nigra, the cau-
date nucleus, the globus pallidus, and the red nucleus.
Statistically significant increases were also observed
in the visual cortex, ventral nucleus of the thalamus,
and area A,3, a hypothalamic brain structure demon-
17

 

Fic. 1. Autoradiographic visualization of the effects of d-amphetamine on local cerebral glucose utiliza-

tion in components of the extrapyramidal motor system. A and B, comparable sections from control

(A) and drug-treated (B) animals at the level of the substantia nigra (S.N.). C and D, comparable

sections from control (C) and amphetamine-treated (D) animals at the level of the subthalamic nucleus
(Subt. N.).
18

 

Fic. 2. Autoradiographic visualization of effects of d-amphetamine on local glucose utilization in area
A, of the hypothalamus. A and B, comparable sections from control (A) and amphetamine-treated
(B) animals.
Effects of amphetamines on brain glucose metabolism

19

TABLE {. EFFECTS OF d-AMPHETAMINE AND /-AMPHETAMINE ON LOCAL CEREBRAL GLUCOSE UTILIZATION IN THE CONSCIOUS

RATT

 

Control

d-Amphetamine

!-Amphetamine

 

Visual cortex
Auditory cortex
Parietal cortex
Sensory—motor cortex
Olfactory cortex
Frontal cortex
Prefrontal cortex

Thalamus—Lateral nucleus
Ventral nucleus
Habenula
Dorsomedial nucleus

Medial geniculate

Lateral geniculate

Hypothalamus
Suprachiasmatic nucleus
Mamillary body

Lateral olfactory nucleus$

Ais

Hippocampus—Ammon’s horn
Dentate Gyrus .

Amygdala

Septal nucleus

Caudate nucleus

Nucleus accumbens

Globus pallidus

Subthalamic nucleus

Substantia nigra—zona reticulata
Zona Compacta

Red nucleus

Vestibular nucleus
Cochlear nucleus
Superior olivary nucleus
Lateral lemniscus
Inferior colliculus

Dorsal tegmental nucleus
Superior colliculus
Pontine gray

Cerebellar flocculus
Cerebellar hemispheres
Cerebellar nuclei

Corpus callosum
Genu of corpus callosum
Internal capsule
Cerebellar white

Gray matter

102 + 8 135 + 11* 105 + 8
160 + 11 162 + 6 141 +6
109 +9 125 + 10 116+4
118 +8 139 +9 1lt4
100 + 6 93 +5 94 +3
109 + 10 130 + 8 105+ 4
146 + 10 166 +7 154+4
97 + 5 114+8 117+6
8547 108 + 6* 96 +4
118 + 10 TL + 5** 82 + 2**
92 +6 11+8 106 + 6
116 +5 119 +4 116+4
719 +5 88 +5 8444
5445 5643 5243
94+ 4 75 + 4** 67 + 1**
117 +8 134 +5 142 + 5*
92 + 6 95 +5 99 + 6
+4 914 4** 8144
79 +5 7342 8146
60 +4 5543 6747
46 +3 46 +3 4442
56 +3 55+2 54 +3
109 + 5 132 + 8* 127 + 3*
16 +5 80 + 3 78 +3
5343 64 + 2* 65 + 3*
89 + 6 149 + 10** 107 + 2
58 +2 105 + 4** 7244
6544 88 + 6** 7243
16 +5 94 + 5* 8642
121411 137 +5 130+ 4
139 + 6 126 + 1 14145
144 +4 143 +4 147 + 6
107 + 3 96 +5 98 +3
193 + 10 169 +5 150 + 8**
109 + 5 11247 122 +6
80 +5 89 +3 +1
5844 65 +3 60 +1
124 + 10 146 + 15 153 + 10
55 +43 68 + 6 6442
102 +4 105 +8 110 +3
White matter
23 +3 2442 2341
2942 30 +2 26+2
2141 2442 19+2
2+1 3142 3142

 

+ All values are the means + S.E. of the mean for five animals.
* Significant difference from the control at the P < 0.05 level.
** Significant difference from the control at the P < 0.01 level.
$It was not possible to correlate precisely this area on autoradiographs with a specific structure in the rat brain.
It is, however, most likely the lateral olfactory nucleus.

strated by UNGERSTEDT (1971) to contain dopamine-
producing cells. The effects in area A,, were also
visible in the autoradiographs (Fig. 2). d-Ampheta-
mine may also have stimulated glucose utilization in
the frontal and sensory-motor cortex, but the in-
creases observed in these structures were barely short
of statistical significance at the P < 0.05 level.
Several structures known to contain dopaminergic
synapses and dopamine-receptive cells did not appear
to be affected by d-amphetamine. The nucleus

N.C. 32/1 B

accumbens was clearly visible in the autoradiographs
of both the control and experimental animals, but
its glucose consumption was unchanged. The olfac-
tory tubercle, central amygdaloid nucleus, and area
Aio of the ventral tegmentum, the site of origin of
the mesolimbic dopamine pathway, could not be
identified in the autoradiographs, presumably because
their rates of glucose utilization were not sufficiently
different from those of the tissues surrounding them.

Two gray structures exhibited reduced rates of glu-
20 L. R. WECHSLER, H. E. SAVAKI and L. SOKOLOFF

cose utilization. These were the suprachiasmatic nu-
cleus and the habenula. Neither of these areas are
known to be part of any dopamine pathway. No
changes were observed in any of the white structures
(Table 1).

Effects of |-amphetamine on local cerebral glucose utili-
zation

The effects of /-amphetamine resembled those of
d-amphetamine, but they were less pronounced, and
fewer structures were affected (Table 1). Of the struc-
tures of the extrapyramidal system that were clearly
affected by d-amphetamine, only the caudate nucleus
and globus pallidus exhibited a statistically significant
increase in glucose utilization in response to /-amphe-
tamine. In these structures the effects of the two
isomers were quantitatively similar. There also
appeared to be increases in glucose utilization in the
substantia nigra and subthalamic nucleus, but these
were less than those seen with d-amphetamine and
short of statistical significance. Glucose utilization
was reduced in the habenula and suprachiasmatic
nuclei to the same degree as observed with d-amphet-
amine, and it was also depressed in the inferior colli-
culus. There were no effects in the cerebral cortical
regions nor in any of the white structures.

DISCUSSION

The results of the present studies demonstrate that
d-amphetamine in doses that produce characteristic
stereotyped behavior and increased locomotor ac-
tivity stimulates glucose utilization in specific regions
of the brain. The effects are clearly selective and are
restricted to a limited number of specific regions,
most of which are known to be components of major
dopaminergic pathways in the brain. Essentially all
the structures of the extrapyramidal motor pathway
were stimulated. These include the zona compacta
and zona reticulata of the substantia nigra, caudate
nucleus, globus pallidus, subthalamic nucleus, and red
nucleus. The effects in the zona compacta and caudate
nucleus are fully consistent with the well-established
evidence that the nigrostriatal pathway is a dopa-
minergic system and a site of action of dopamine
agonists like amphetamine (TAYLOR & SNYDER, 1971;
BUNNEY et al, 1975; ReBec & Groves, 1975).
Although less conclusive, there is also evidence that
the globus pallidus contains significant quantities of
dopamine (VEERSTEEG et al., 1976) and dopamine
receptors (BuRT et al., 1976) and is, therefore, a poten-
tial site for actions of dopamine agonists.

Less expected were the effects in the zona reticulata
and the subthalamic nucleus, the most pronounced
of any seen in the brain. These structures have not
generally been considered components of dopaminer-
gic systems. The zona reticulata, however, has
recently been shown to be the site of termination of
a feedback pathway from the caudate nucleus to the
substantia nigra (BUNNEY & AGHAJANIAN, 1976), and

a dopamine-sensitive adenylate cyclase, present not
in the dopamine-cell bodies of the zona compacta but
presumably in cells of the zona reticulata, has recently
been found in the substantia nigra (GALE et al., 1977).
Similarly, significant quantities of dopamine (VEER-
STEEG et al., 1976) and dopamine-sensitive adenylate
cyclase (WOLFSON et al. 1977) have recently been
found in the subthalamic nucleus. The present results
obtained with amphetamine provide additional evi-
dence that these two structures function in some still
undefined dopaminergic systems. It should be noted,
however, that the ['*C]deoxyglucose method
measures only glucose utilization, and because of the
close coupling between energy metabolism and func-
tional activity, it serves as a marker for altered func-
tional activity (SOKOLOFF, 1977). It is conceivable that
some of the structures with increased utilization were
not activated directly by amphetamine action but in-
directly because they were part of a neural pathway
activated elsewhere by the drug.

BROWN & WOLFSON (1978) have recently reported
similar studies with ['*C]deoxyglucose on the effects
of another dopamine agonist, apomorphine. Although
they employed only the autoradiographic aspects of
the method without full quantification, they were able
to demonstrate in the autoradiographs increased rela-
tive densities for the same components of the extra-
pyramidal system shown in the present studies to
have increased rates of glucose utilization in response
to d-amphetamine. These effects were prevented by
prior treatment of the animals with the dopamine-
blocking agent, haloperidol, which by itself had unde-
tectable effects except, perhaps, to increase autoradio-
graphic density in the region of the zona compacta
(BROWN & WOLFSON, 1978). The congruence of the
effects with two different dopamine agonists and the
prevention of effects with a dopamine-blocking drug
strongly indicate that the effects in the components
of the extrapyramidal motor system are consequences
of the dopamine-agonistic actions of the drugs.

Not all dopaminergic pathways were stimulated by
amphetamine. None of the components of the dopa-
minergic mesolimbic system appeared to be affected.
Ajo, the site of origin of this pathway, could not be
visualized in the autoradiographs of the ventral teg-
mentum from both control and drug-treated animals,
and the nucleus accumbens, one of its projection
areas, exhibited no change in glucose utilization.
WOLFSON & BROWN (1978) also failed to observe any
effects of apomorphine in the mesolimbic system.

Glucose utilization was inhibited by amphetamine
in two structures of the brain, the suprachiasmatic
nuclei and the habenula, and both the d- and
l-isomers had essentially equal effects. The changes
in metabolism in the suprachiasmatic nuclei were
probably unrelated to the actions of amphetamine.
These nuclei have recently been found to exhibit a
diurnal rhythm in their rate of glucose utilization
(SCHWARTZ & GAINER, 1977), and the changes seen
in the present studies may reflect differences in the
Effects of amphetamines on brain glucose metabolism 21

time of day between the control and experimental
studies. The habenula, however, exhibits no such
rhythm, and the basis of the inhibition of its glucose
utilization by both d- and /-amphetamine is unclear.

The effects of d-amphetamine were clearly more
pronounced and more diffuse than those of the
l-isomer at the dose used in the present studies. The
results are, therefore, in agreement with those of
SNYDER (1974) that indicate greater potency of the
d-isomer at both noradrenergic and dopaminergic
sites. He has suggested that the adrenergic and dopa-
minergic actions of the drug could be differentiated
on the basis of their different relative potencies in
these two types of systems (SNYDER, 1974). However,
inasmuch as the effects of d-amphetamine were con-
fined, with relatively few exceptions, to dopaminergic
systems and /-amphetamine was largely without sti-
mulatory effect, there does not appear to be any basis
from the present results on which to exercise such
discrimination.

NauHorskI & ROGERS (1973) have reported that
d-amphetamine exerts in the conscious mouse a tem-
porally biphasic effect, first an inhibition followed by
a stimulation, on the glycolytic flux in the brain as
a whole. In the rat, lightly anesthetized with 70%
N,0-30% O, and immobilized with a neuromuscular
blocking agent, CARLSSON et al. (1975) observed an
approx 40% increase in overall cerebral O, consump-
tion following amphetamine administration. MCCUL-
LOCH & HARPER (1977) observed similar stimulatory
effects of d-amphetamine in the anesthetized baboon.
In order to compare the local values of energy meta-
bolism obtained in the present studies with the aver-
age values in the brain as a whole obtained pre-
viously, it would be necessary to obtain a mean of
the local values weighted by the relative weights of
the individual structures. Such weighting factors are
presently unavailable for the rat brain. The present
studies demonstrate that the effects of amphetamine
are not generalized but selective in specific regions
of the brain. It seems unlikely from the number and
size of the structures affected and the magnitude of
the effects that the average glucose utilization of the
brain as a whole could have been very greatly
affected. Indeed, comparison of the simple arithmetic
means of all the gray structures indicates no signifi-
cant differences in average gray matter glucose utiliza-
tion between the control animals and either of the
two amphetamine-treated groups. The present results
are, therefore, more in agreement with those of pre-
vious studies in conscious man which failed to
demonstrate any significant effects of amphetamine
on average cerebral oxygen consumption (ABREU et
al., 1949; SHENKIN, 1951).

Acknowledgements—The authors wish to express their
thanks and appreciation to KAREN PETTIGREW for her
advice and assistance in the statistical analyses, JANE JEHLE,
Gwen Brown, and SUZANNE Cook for their technical
assistance, and RUTH Bower for her assistance in the
preparation of the manuscript.

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