Departments of 1Psychiatry, 2Neurology and Neurological Surgery, 3Radiology, and 4Anatomy and Neurobiology, Washington University School of Medicine; and 5The Mallinckrodt Institute of Radiology, St. Louis, Missouri 63110
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ABSTRACT |
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Black, Kevin J., Tamara Hershey, Mokhtar H. Gado, and Joel S. Perlmutter. Dopamine D1 Agonist Activates Temporal Lobe Structures in Primates. J. Neurophysiol. 84: 549-557, 2000. Changes in the function of dopamine D1-influenced neuronal pathways may be important to the pathophysiology of several human diseases. We recently developed methods for averaging functional imaging data across nonhuman primate subjects; in this study, we apply this method for the first time to map brain responses to experimental dopamine agonists in vivo. Here we report the use of positron emission tomography (PET) in seven normal baboons to measure the regional cerebral blood flow (rCBF) responses produced by an acute dose of the dopamine D1 full agonist SKF82958. The most significant rCBF increases were in bilateral temporal lobe, including amygdala and superior temporal sulcus (6-17%, P < 0.001). Blood flow decreased in thalamus, pallidum, and pons (4-7%, P = 0.001). Furthermore the rCBF responses were dose-dependent and had a half-life of ~30 min, similar to that reported for the drug's antiparkinsonian effects. Absolute whole-brain blood flow did not change, suggesting that these local changes in rCBF reflect neuronal rather than direct vascular effects of the agonist. The prominent temporal lobe response to a D1 agonist supports and extends our recent observations that levodopa produces prominent amygdala activation both in humans and in other primates. We speculate that levodopa may exert its known effects on mood in humans through increased amygdala activity, mediated in part by D1 receptors.
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INTRODUCTION |
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Dopamine D1-like receptors
(D1 and D5) may be
important in several human diseases, including movement disorders
(Young and Penney 1993), drug abuse (Self et al.
1996
), major depression (Gambarana et al. 1995
),
and schizophrenia (Okubo et al. 1997
). In addition,
D1 receptors regulate working memory function in primates (Williams and Goldman-Rakic 1995
) and are
thought to be important in the control of normal movement and
appetitive behavior (Jackson and Westlind-Danielsson
1994
). D1 receptors are distributed
anatomically so as to permit this wide functional range. They are most
densely located in striatum (preferentially on striatonigral projection
neurons) and substantia nigra but at lower levels are widely
distributed in cortex, where they substantially outnumber
D2 receptors (Bergson et al. 1995
;
Gerfen et al. 1995
; Levey et al. 1993
;
Surmeier et al. 1996
; Waszczak et al.
1998
). Dopaminergic cortical afferents appear to terminate on
dendrites of pyramidal neurons so as to potentially alter projection
neuron responses to excitatory inputs (Goldman-Rakic et al.
1989
, 1990
, 1992
).
Abnormal function of D1-influenced neuronal
pathways could arise from alterations in D1
receptors. However, other changes, such as in co-modulators or second
messengers, can produce functionally important changes in these
pathways without altering receptor binding (Goulet et al.
1996; LaHoste and Marshall 1992
; Morelli et al. 1990
). Ideally one would like to probe the overall
function of D1-influenced neuronal pathways in
vivo. One approach is to administer a receptor-specific agonist and
evaluate its acute effects on regional cerebral blood flow (rCBF) or
metabolism as an index of a regional change in neural activity.
The utility of this approach has been demonstrated by
studies examining regional metabolic responses to an acute dose of
various dopaminergic drugs (Ingvar et al. 1983;
Kelly and McCulloch 1987
; McCulloch 1982
,
1984
; Pizzolato et al. 1987
; Sharkey et
al. 1991
; Trugman and Wooten 1986
;
Trugman et al. 1991
), including the partial D1 agonist SKF38393 (Engber et al.
1993
; Morelli et al. 1993
; Palacios and
Wiederhold 1985
; Trugman and James 1992
, 1993
;
Trugman and Wooten 1987
; Trugman et al.
1989
). Most of these studies used the ex vivo
[14C]2-deoxyglucose (2DG) autoradiographic
technique in normal or 6-hydroxydopamine (6OHDA)-lesioned rats. These
studies have revealed substantial information about the rodent brain's
functional response to dopaminergic lesions or treatment (Orzi
et al. 1993
; Trugman 1995
; Wooten and
Trugman 1989
). Notably, this method is sensitive to functional
changes that cannot be detected by measuring receptor binding alone
(McCulloch 1982
, 1984
; McCulloch and Teasdale
1979
; Trugman and James 1992
).
We have extended these studies to the living primate brain by assessing
the acute effects of various dopamimetics on rCBF using
H215O and positron emission
tomography (PET) in humans and nonhuman primates (Black et al.
1996b, 1997a
; Hershey et al. 1997
, 1998
; Perlmutter 1995
; Perlmutter et al. 1993
).
Regional blood flow is a useful marker as it can be measured frequently
and quantitatively, and alterations in rCBF have been shown to reflect
regional metabolic changes in the presence of dopaminergic drugs
(Azuma et al. 1988
; McCulloch and Harper
1977
; McCulloch et al. 1982a
). Many
other investigators have also studied drug effects with PET, though not
with D1 agonists (see selected references in
Black et al. 1997a
; Perlmutter 1997
).
We recently developed and validated methods for averaging functional
imaging studies in nonhuman primates into a common atlas space
(Black et al. 1996a, 1997b
). Such methods enhance
signal-to-noise properties for identification of brain responses in
either physiological or pharmacological activation studies (Fox
et al. 1988
; Raichle et al. 1991
). Image
averaging across subjects also allows one to deal with anatomic and
functional variability and to map physiologic neuronal responses
without a priori knowledge of the sites of action in the brain. Similar
methods have long been available for humans (Fox et al.
1985
) and were widely adopted due to these advantages. Their
availability in other species now permits us to perform experiments
such as mapping brain responses to an experimental drug not available
for human use.
In this report, we describe the effects of the dopamine
D1 full agonist SKF82958 (Andersen and
Jansen 1990; Bergman et al. 1996
) on rCBF in
normal nonhuman primates. The goal of the study was to define which
brain regions are most influenced by D1 agonists in the normal primate brain. To our knowledge, this is the first autoradiographic study in primates of D1 agonist
effects, and the first study to analyze functional imaging data in a
group of different nonhuman subjects using stereotaxy and recent
statistical developments.
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METHODS |
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PET image acquisition
All PET studies were performed on a Siemens 953B scanner in
two-dimensional (2D) wobble mode. This scanner records data
simultaneously for 31 slices with a center-to-center slice separation
of 3.4 mm (Mazoyer et al. 1991; Spinks et al.
1993
). For each study, we acquired a transmission scan for
individual attenuation correction with rotating rod sources of activity
containing 68Ge/68Ga. PET
images were reconstructed to an initial transverse full width
half-maximum (FWHM) resolution of 5.4 mm using a ramp filter (final
image resolution was 8 mm; see following text). CBF was measured using
arterial sampling and a 40-s emission scan following the intravenous
bolus injection of ~10 ml of saline containing 30-50 mCi of
15O-labeled water, a method previously validated
in baboons (Herscovitch et al. 1983
; Raichle et
al. 1983
; Videen et al. 1987
).
Scan protocol
With the prior approval of the Washington University Animal
Studies Committee, we performed eight PET studies in five normal baboons sedated with 70% inhaled N2O. Each study included
multiple measurements of rCBF; a total of 89 measurements was included in these studies. No physiologic PET scans were obtained until the
animal had been ventilated with 70% N2O for 3 h. Six of
the studies involved triplicate quantitative measurements of rCBF under
each of four conditions: at baseline and from ~15 to 45 min after
each of three successive intravenous doses of the D1 agonist SKF82958 (1, 10, and 100 µg/kg). In the remaining two studies, the 100 µg/kg dose was administered immediately after completion of the baseline scans.
SKF82958 is considered to be a selective D1 full agonist,
though there is some debate (Andersen and Jansen 1990;
Bergman et al. 1996
; Gilmore et al. 1995
;
Ruskin et al. 1998
). The 100 µg/kg intravenous dose
corresponds to published data showing antiparkinsonian or other
behavioral effects in primates using intramuscular doses of 75-234
µg/kg (Bergman et al. 1996
; Domino and Ni
1998
) or subcutaneous doses of 100-1,000 µg/kg
(Blanchet et al. 1994
; Goulet et al. 1996
; Kuno 1997
; Rupniak et al.
1992
). The intravenous route we used would be expected to
produce higher peak levels than similar intramuscular or subcutaneous
doses. We did not test higher doses since we found that either the 10 or 100 µg/kg doses sometimes produced 10-20 mmHg changes in systolic
BP for ~2-5 min after injection.
We performed additional control PET studies, one in each of three
baboons, involving 48 additional rCBF measurements. These studies
followed the same protocol, except that no dopamine agonist was
injected. Further details of animal preparation and experimental setup
are given elsewhere (Black et al. 1997a).
Absolute CBF
Absolute global (whole-brain) blood flow was quantified in a
subset of scans using published methods (Black et al.
1997a; Herscovitch et al. 1983
; Raichle
et al. 1983
; Videen et al. 1987
).
Statistical methods
For regional analysis of the PET data, we used normalized PET
counts, which are linearly related to blood flow (Fox and Mintun 1989). This is the most common approach to analysis of PET
[15O]water studies. We took the additional step
of quantifying absolute brain blood flow to confirm that this method is
appropriate (see RESULTS and DISCUSSION). If
absolute global flow does not change, the absolute and normalized
regional values are redundant. In addition, the absolute rCBF values
are noisier since they include several additional measurement steps.
Normalized PET images were transformed to a common atlas space and
resampled to 1-mm cubic voxels (Black et al. 1996a,
1997b
; Davis and Huffman 1968
). After this step
(which also adds spatial filtering via registration error and
interpolation), a three-dimensional (3D) Gaussian filter with 6.0 mm
FWHM kernel was applied using a freely available software package
(SPM96 with random effects kit) (Friston et al. 1996
;
Holmes and Friston 1998
). The final image resolution was
estimated by SPM96 as ~8 mm.
The primary comparison was between baseline scans and scans after 100 µg/kg SKF82958. Voxels in atlas space were included in the
statistical analysis if the voxel intensity in each image was 80% of
the mean intensity in that image. This resulted in a search volume of
187 ml, which is appropriate given a baboon atlas brain volume of
~165 ml (unpublished data). As images were already intensity
normalized, no further global normalization was performed in SPM96. At
each included voxel, SPM96 computed a random effects statistic
corresponding roughly to a paired t-test and transformed
this statistic to a Z score. An initial magnitude threshold
of Z
2 was applied, and SPM96 computed the
probability that each region of contiguous voxels attaining this
magnitude would have occurred by chance given the size in voxels of the activated region. Regional activations were considered significant with
a corrected probability of P < 0.05. This strategy has
been validated using simulations (Friston et al. 1994
,
1996
). Representative peaks within each region, separated by
8 mm, were reported by SPM96, and the most significant peaks (i.e.,
those for which P < 0.05 after voxelwise correction
for multiple comparisons based on Z-score magnitude only)
are given in Table 1. Points lying outside the brain were ignored. Amplitude and time-course data for
selected peaks were computed based on an 8-mm-diam spherical VOI
centered on the peak coordinate reported by SPM96.
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Calculation of half-life of PET responses
For the most prominent activations, a half-life of the PET
response was computed as follows. The rCBF response in each scan, expressed as a percentage change from the average baseline rCBF from
that study, was plotted against the elapsed time from the administration of 100 µg/kg SKF82958 to the beginning of the scan (Fig. 2A). A two-parameter exponential decay model,
rCBF = A× 2-time/B, was
fit to the data using SSPS for Windows 7.5.1 (SPSS, Chicago, IL),
giving the half-life B and an estimate r of
goodness of fit.
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RESULTS |
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Regional activations
Two areas of significant changes in rCBF were observed following 100 µg/kg SKF82958 (see Table 1 and Fig. 1). The D1 agonist activated a diffuse area of temporal cortex bilaterally (corrected P < 0.001), extending into amygdala and hippocampus but also involving a large area of lateral temporal lobe along the superior temporal sulcus (STS). A significant decrease in rCBF was observed in the brain stem/basal ganglia (corrected P = 0.001) with the most significant decreases centered on the globus pallidus and thalamus.
|
Time course of activations
By plotting relative change in rCBF against time, we observed that
the rCBF changes generally followed a pharmacologically sensible time
course, reaching a peak early and then falling over time (Fig.
2A). Assuming linear kinetics,
one can also compute a half-life t1/2 for
the individual rCBF responses by fitting a first-order exponential
curve to the data. For some regions, this plot was noisy, with
r < 0.5, and consequently estimates of
t1/2 were unreliable. For regions in which
r 0.5 (such as R. and L. superior temporal gyrus and
L. amygdala), the t1/2 of the PET response
was between 26 and 35 min (Fig. 2A). This corresponds well
to a 35- to 60-min duration of antiparkinsonian effect of subcutaneous
SKF82958 in cynomulgus monkeys, which presumably reflects striatal
action of the drug (Blanchet et al. 1994
).
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Dose-response curve
A dose-response curve for the most significant PET response is shown in Fig. 2B. Recall that peak locations were obtained independent of the PET responses to 1 or 10 µg/kg SKF82958.
Control experiments
Since the order of scans could not be randomized (i.e., baseline
scans always preceded drug), the significant rCBF changes described
above could be due either to the D1 agonist or to
unknown factors associated with the passage of time from the pre- to
postdrug scans. Evidence against the latter interpretation includes the following. First, the two studies that proceeded directly from baseline
scans to post-100 µg/kg SKF82958 scans produced mean rCBF responses
of right STS, +13.6%; thalamus 4.1%, left amygdala, +7.5%. These
are nearly identical to the PET responses in the remaining studies in
which the post-100 µg/kg SKF82958 scans followed the baseline scans
by 1.5-4 h. Second, the rCBF changes after the highest dose tended to
peak early and then decline over time (see Fig. 2A), whereas
the opposite would be expected if the changes were nonspecific.
Finally, in three control studies in which no dopamine agonist was
administered, the average change in rCBF over a similar time interval
was: right STS, +5.0%, thalamus,
3.7%, and left amygdala, +1.2%,
noticeably smaller than the responses observed after 100 µg/kg SKF82958.
Absolute global blood flow
There was no significant change in absolute global cerebral blood
flow with 100 µg/kg SKF82958. Expressed as ml × 102 × g
1 × min
1, global blood flow
at baseline was 67.5 ± 15.7 (mean ± SD, n = 17 scans), and after 100 µg/kg SKF82958 was unchanged at 67.2 ± 19.1 (n = 20).
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DISCUSSION |
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The most significant change in rCBF following administration of a dopamine D1 agonist in primates was a diffuse activation of bilateral temporal lobes, including increases in amygdala and superior temporal sulcus. The increases were dose dependent and were not due to a "priming" effect of the preceding smaller doses or to passage of time between baseline and postdrug scans. A time-response curve could be extracted from the data, allowing us to estimate the t1/2 of the drug's effects on rCBF.
Bilateral temporal lobe activation
The largest responses were observed in both lateral and medial
temporal lobe bilaterally. It may appear surprising that the D1 agonist produced such a prominent activation
in the amygdala, but this supports and extends observations we have
made in other primate studies. Most rodent pharmacologic activation
studies with dopaminergic agents have focused on changes in subcortical structures, especially in the lentiform nuclei, substantia nigra, or
lateral habenula (McCulloch 1982, 1984
; Orzi et
al. 1993
; Trugman 1995
; Wooten and
Trugman 1989
). Although no prior reports have focused on
amygdala activation by dopaminergic agents, we have recently discovered
that the amygdala is a major site of increased blood flow following
levodopa administration in each of four primate groups: normal humans,
chronically treated patients with Parkinson's disease (PD), an awake
monkey, and sedated baboons (Hershey et al. 1997
, 1998
).
This finding is also consistent with the data of McCulloch et
al. (1982)
, which demonstrate a dose-dependent metabolic
increase in the anterior amygdala (among numerous other regions) after
administration of the nonselective dopamine agonist apomorphine to
normal rats. Our results with SKF82958 may indicate that the effect of
these nonspecific dopaminergic agents in the amygdala is mediated at
least in part by D1 receptors.
This observation begs the question, which D1
receptors? The question is important because regional alterations of
blood flow following administration of dopamimetics do not correspond
well with the local density of dopamine receptors (McCulloch
1982, 1984
). Rather, a regional metabolic change appears to
derive from changes in the firing rate of axons terminating in the
region (Ackermann et al. 1984
; Eidelberg et al.
1997
; Schwartz et al. 1979
). Thus a metabolic
change in a given area, after administration of a dopamine agonist, may
be mediated either by distant dopamine receptors that modulate firing
of afferents or by local receptors, such as presynaptic receptors or
receptors on local interneurons.
Increased amygdala rCBF following SKF82958 may reflect increased local
neuronal activity following stimulation of D1
receptors in the amygdala (Levey et al. 1993).
Alternatively, positive feedback in amygdala-cortical-striatal neuronal
pathways may be stimulated by D1 effects at any
of these three sites, which might increase neuronal activity in all
three areas (Price et al. 1996
).
What might be the functional relevance of the prominent amygdala
response to a D1 agonist? There is substantial
evidence for the amygdala's role in emotion, including the finding of
abnormal amygdala rCBF at rest in patients with major depression
(Drevets and Raichle 1994; Drevets et al.
1992
; Price et al. 1996
). In our PET studies
with PD patients, the amygdala response to levodopa was more pronounced
in a patient group with longstanding disease and chronic treatment
(Hershey et al. 1998
), although none of those subjects
had evidence of depression when studied. It is tempting to speculate
that an increase in the amygdala's response to individual doses of
levodopa may relate to the observation that some patients with
long-standing, chronically treated PD develop levodopa dose-responsive
depression and hypomania (Damásio et al. 1971
;
Goodwin 1990
; Hardie et al. 1984
;
Keshavan et al. 1986
; Lees 1989
;
Maricle et al. 1995a
,b
, 1998
; Nissenbaum et al. 1987
; Riley and Lang 1993
). If these mood
fluctuations prove to be primarily mediated by D1
receptors, this may suggest alternative treatment strategies for PD
patients with these disabling symptoms.
The specific mechanism producing the D1
agonist-mediated response in STS is unclear. Previous rat studies do
not provide many clues. Lateral temporal cortex appears to contain
higher levels of D5 mRNA in primates than in
rodents, but primate lateral temporal cortex expresses
D1-like receptor protein at relatively low levels (Jackson and Westlind-Danielsson 1994; Levey et
al. 1993
). Thus the large response observed here may not be
attributable exclusively to effects on local cortical
D1 receptors. Alternatively, the blood flow
response may reflect increased firing of afferents projecting to STS.
The specific D1-influenced projections that may
mediate this response are not obvious. The receptor-rich basal ganglia
project to inferotemporal cortex but not substantially to STS
(Middleton and Strick 1996
). Thalamic afferents to STS arise primarily from the medial pulvinar nucleus, although there is
some sparse innervation from the dopamine-influenced mediodorsal and
ventroposterolateral nuclei (Yeterian and Pandya 1989
).
Many investigators consider the STS a sensory convergence area,
receiving unimodal as well as polymodal and highly processed sensory
afferents from lateral and ventral temporal lobe, amygdala, thalamus,
and cortical sensory regions (Pandya and Seltzer 1982
;
Seltzer and Pandya 1994
). One could speculate that the
attention-enhancing effects of stimulants, which require
D1 receptors for at least some physiological
effects (Moratalla et al. 1996
), occur in part via
indirect dopaminergic modulation of the higher-order, polymodal sensory
processing attributed to STS. Consistent with this speculation Fletcher et al. (1996)
reported that the nonspecific
dopamine agonist apomorphine modulates a rCBF response in the STS to
verbal tasks in patients with schizophrenia.
Decreases in rCBF
The rCBF decreases in thalamus and pons are new findings. No
significant effect on thalamic metabolism was seen in normal rats
(Trugman and James 1993). However, a metabolic decrease
in thalamus is consistent with activation via D1
receptors of striato-(internal)pallidal GABAergic neurons, causing a
decrease in firing of pallidal afferents to thalamus (Young and
Penney 1993
). Rodent studies did not provide data for pons
(Palacios and Wiederhold 1985
; Trugman and James 1993
).
The statistically most significant decrease, however, was centered in
globus pallidus, pars externa (GPe). With the image resolution
available with PET, we cannot tell whether this reflects a single
response in GPe or two responses in flanking structures, such as
putamen and globus pallidus, pars interna (GPi). SKF38393 had no
significant net effect on GP 2DG metabolism in awake, normal rats
(Engber et al. 1993; Trugman and James
1993
), but responses in 6OHDA-lesioned animals were mixed
(Wooten and Trugman 1989
).
Differences from ex vivo rodent studies
Ex vivo 2DG studies in normal rats using acute doses of the
D1 partial agonist SKF38393 have shown marked
(22%) increases in metabolic activity in the substantia nigra pars
reticulata (SNpr) and similar increases in the entopeduncular nucleus
(EP), the rat homologue of the primate GPi. Metabolic decreases were seen in the lateral habenula (Trugman and James 1993).
These responses are sensitive to functional status including induction
of parkinsonism or treatment with dopaminergic agents (Engber et
al. 1993
; Morelli et al. 1993
; Trugman
1995
; Trugman and James 1992
, 1993
;
Trugman and Wooten 1987
; Trugman et al.
1989
; Wooten and Trugman 1989
).
In comparing these results with our data, there were interesting differences, most notably the prominence of the temporal lobe response in our primate model and the absence of increases in GPi and midbrain regions. There are several possible, nonexclusive, explanations for these differences.
Some of the differences between our data and the rodent 2DG results may be attributable to differences in technique. First, we measure blood flow rather than glucose metabolism so quantitative differences may be expected. Second, partial volume averaging (due to the lower resolution of PET compared with film autoradiography) reduces the peak magnitude of our signal. For instance, the GPi is small relative to the resolution of PET, and rCBF changes in this nucleus could be overshadowed by changes in nearby structures. Parenthetically, most human brain mapping PET studies have been done at image resolutions that raise similar issues, and rCBF increases of 6-17% are generally considered quite substantial. Third, we studied normal animals; in rodent studies, the responses to DA agonists are much smaller in magnitude in normal animals than in lesioned animals. Fourth, the limited number of available subjects may have decreased our power to replicate some of the activations reported from ex vivo autoradiographic studies in rats.
Conceivably N2O anesthesia could account for
differences in our results, but several lines of evidence suggest this
is unlikely. Direct effects of inhaled N2O on
rCBF are irrelevant to interpreting this study since
N2O concentration remained constant throughout the study. More importantly, under N2O
anesthesia, rCBF responses to pCO2 changes or
certain behavioral or pharmacologic stimuli remain intact (Fox
et al. 1992; Yaster et al. 1994
), and in studies with the D2-like agonist quinpirole, we
demonstrated identical pallidal rCBF responses in
N2O-sedated baboons and in awake nemestrina monkeys (Perlmutter et al. 1993
). Furthermore although
the anesthetic effects of N2O appear to be
mediated through N-methyl-D-aspartate (NMDA)
receptor blockade (Jevtovic-Todorovic et al. 1998
), the NMDA antagonist MK801 does not interfere with the coupling of metabolism and blood flow (Nehls et al. 1990
) and
produces only modest effects on
D1-agonist-induced changes in behavior or
metabolism (Engber et al. 1993
). Observations such as
these contributed to our choice of N2O anesthesia
for this study.
However, it remains possible that animals sedated with
N2O have different physiologic responses to
dopamimetic agents compared with awake animals. This would not be
unprecedented since chloral hydrate, halothane, or barbiturate
anesthesia substantially alters the regional metabolic response to
dopamine agonists (Grome and McCulloch 1981, 1983
), and
nitrous oxide may affect cerebral metabolic responses to some
physiologic stimuli (Crosby et al. 1983
). In support of
this possibility, we have recently found that an acute dose of levodopa
causes decreased putaminal rCBF in sedated baboons but increased
putaminal rCBF in awake humans or an awake monkey (Hershey et
al. 1997
). Nevertheless as noted in the preceding text, there
was an rCBF increase in amygdala in all of these models, suggesting
that at least the amygdala activation reported here is not due to the
effects of nitrous oxide.
Finally, we have assumed that the rCBF changes reflect changes in
neuronal firing. Since SKF82958 had no effect on absolute global blood
flow, the alternative would be to posit that the drug directly dilated
blood vessels in some brain regions and constricted vessels in other
regions. Such effects were not typical of studies with other
dopamimetics (Azuma et al. 1988; McCulloch and
Harper 1977
). McCulloch, Kelly and Ford (1982a)
measured changes in regional blood flow and metabolism induced by
apomorphine and showed that after accounting for the drug's effects on
global blood flow, residual regional variations were attributable to changes in neuronal metabolism. Thus it is reasonable to assume that
the observed regional CBF responses faithfully reflect regional metabolic changes although we have not directly tested this assumption with SKF82958.
Despite these caveats, we believe the differences in our results in
baboons compared with those reported in rodents are likely meaningful
rather than artifactual. In the resting state regional brain metabolism
is similar in rodents and primates (Blin et al. 1991).
This suggests that different metabolic or rCBF responses to a
physiologic stimulus indicate true differences in the sensitivity of
the physiologic system probed rather than differences in baseline activity. There are well-known differences in basal ganglia anatomy and
pharmacology between rodents and primates (Jackson and
Westlind-Danielsson 1994
; Parent 1990
;
Pifl et al. 1991
), and the prominent temporal lobe
activation in primates may reflect such differences.
Spatial averaging of functional imaging data in nonhuman species
In addition to the physiological implications of this study for
dopaminergic function, its methodological implications should also be
mentioned. Among the technical advances in the development of
functional neuroimaging, one important early step was the development of methods to combine data from different subjects in a common atlas
space (Fox et al. 1985, 1988
). This allowed greater
sensitivity to low-magnitude responses and reduction in individual
anatomic variation (Fox et al. 1988
; Raichle et
al. 1991
). Although nonhuman species have been crucial to the
development of many widely used functional imaging methods
(Perlmutter et al. 1989
, 1991
; Raichle et al.
1983
; Schwartz et al. 1979
), intersubject image
averaging in a common atlas space has never been applied to functional
imaging in a nonhuman species. In part this may be attributed to the
appropriate use of humans for many studies of cognition, emotion, and
sensorimotor function. However, other species may be more appropriate
for some purposes, such as longitudinal study of lesion models of human disease (Perlmutter et al. 1997
), neuropharmacologic
investigations (Black et al. 1997a
), or drug development
(Perlmutter 1995
). In this study we provide an example
of such an application by applying an experimental drug to probe the
dopaminergic system, using intersubject averaging of baboon PET images
to increase sensitivity and reduce noise.
Atlas methods have been used for years to aid in identifying individual
regions of interest in individual animals studied with specific
radioligands (e.g., Perlmutter et al. 1989). However, for functional activation studies, investigators have resorted to using
a priori-defined regions of interest in each animal rather than
examining data from the entire brain (e.g., Black et al. 1997a
; Tsukada et al. 1997
). Tsujimoto et
al. (1997)
averaged PET data from two macaques after scanning
each animal with the canthomeatal line placed along the center plane of
the scanner, but no spatial normalization was performed to account for
differences in brain size. However, we now report the use of a
stereotactic method of spatial signal averaging across subjects in a
nonhuman functional neuroimaging study. Further refinements are likely now that high-quality three-dimensional atlases are available for the
macaque (Cannestra et al. 1997
; Martin and Bowden
1996
), and functional magnetic resonance imaging has been
demonstrated in nonhuman primates (Logothetis et al.
1999
; Stefanacci et al. 1998
). A recent
functional MRI study averaged functional responses to levodopa across
several rhesus monkeys; however, details of the stereotactic method
were not provided and the analysis was primarily region-based
(Chen et al. 1999
).
In summary, the implementation in nonhuman primates of a method for averaging PET responses across subjects allowed us to map physiologic responses to a dopamine D1 agonist in vivo. The results, including the prominence of temporal lobe responses, were not predicted by prior reports in rodents but confirm and extend our reports of the rCBF effects of levodopa in both humans and nonhuman primates.
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ACKNOWLEDGMENTS |
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We gratefully acknowledge helpful discussions with Drs. Jonathan W. Mink, Joseph L. Price, and Tom O. Videen, members of the Stastistical Parametric Mapping e-mail list, and the technical assistance of C. Collins, T. Anderson, and J. L. Carl.
This work was supported by National Institutes of Health Grants NS-01898, NS-32318, NS-31001, and MH-17104; the Charles A. Dana Foundation (The Dana Clinical Hypotheses Research Program); the American Parkinson Disease Association; the National Alliance for Research on Schizophrenia and Depression (NARSAD); the Tourette Syndrome Association; and the McDonnell Center for Higher Brain Function.
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FOOTNOTES |
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Address for reprint requests: K. J. Black, Campus Box 8134, 4940 Children's Place, St. Louis, MO 63110-1093 (E-mail: kevin{at}npg.wustl.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 July 1999; accepted in final form 15 March 2000.
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REFERENCES |
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