Cerebellar vermis involvement in cocaine-related behaviors.
ABSTRACT Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered to mediate stimulant-associated behaviors since it is low in dopamine. Yet, the primate cerebellar vermis (lobules II-III and VIII-IX) has been reported to contain axonal dopamine transporter immunoreactivity (DAT-IR). We hypothesized that DAT-IR-containing vermis areas would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands. We used BOLD fMRI to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and positron emission tomography imaging of healthy humans to determine whether the DAT-selective ligand [11C]altropane accumulated in those vermis regions. Cocaine-related cues selectively induced BOLD activation in lobules II-III and VIII-IX in cocaine users, and, at early time points after ligand administration, we found appreciable [11C]altropane accumulation in lobules VIII-IX, possibly indicating DAT presence in this region. These data suggest that parts of cerebellar vermis mediate cocaine's persisting and acute effects. In light of prior findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, we propose that the vermis be considered one of the structures involved in cocaine- and other incentive-related behaviors.
- SourceAvailable from: Marta Miquel[Show abstract] [Hide abstract]
ABSTRACT: Pavlovian conditioning tunes the motivational drive of drug-associated stimuli, fostering the probability of those environmental stimuli to promote and trigger drug seeking and taking. Interestingly, different areas in the cerebellum are involved in the formation and long-lasting storage of Pavlovian emotional memory. Very recently, we have shown that conditioned preference for an odour associated with cocaine was directly correlated with cFOS expression in cells at the dorsal region of the granule cell layer of the cerebellar vermis. The main goal of the current investigation was to further extend the description of cFOS-IR patterns in cerebellar circuitry after training mice in a cocaine-odour Pavlovian conditioning procedure, including now the major inputs (the inferior olive and pontine nuclei) and one of the output nuclei (the medial deep nucleus) of the cerebellum. The results showed that the cerebellar hallmark of preference towards an odour cue associated to cocaine is an increase in cFOS expression in the dorsal part of the granule cell layer. cFOS-IR levels expressed in the granule cell layer of mice that did not show cocaine conditioned preference did not differ from the basal levels. Remarkably, mice subjected to a random cocaine-odour pairing procedure (the unpaired group) exhibited higher cFOS-IR in the inferior olive, the pontine nuclei and in the deep medial nucleus. Therefore, our findings suggest that inputs and the output of cerebellar circuitry are enhanced when contingency between the CS + and cocaine is lacking.Physiology & Behavior 06/2014; 132:24–35. · 3.03 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cocaine addiction involves persistent deficits to unlearn previously rewarded response options, potentially due to neuroadaptations in learning-sensitive regions. Cocaine-targeted prefrontal systems have been consistently associated with reinforcement learning and reversal deficits, but more recent interspecies research has raised awareness about the contribution of the cerebellum to cocaine addiction and reversal. We aimed at investigating the link between cocaine use, reversal learning and prefrontal, insula and cerebellar gray matter in cocaine-dependent individuals (CDIs) varying on levels of cocaine exposure in comparison with healthy controls (HCs). Twenty CDIs and 21 HCs performed a probabilistic reversal learning task (PRLT) and were subsequently scanned in a 3-Tesla magnetic resonance imaging scanner. In the PRLT, subjects progressively learn to respond to one predominantly reinforced stimulus, and then must learn to respond according to the opposite, previously irrelevant, stimulus-reward pairing. Performance measures were errors after reversal (reversal cost), and probability of maintaining response after errors. Voxel-based morphometry was conducted to investigate the association between gray matter volume in the regions of interest and cocaine use and PRLT performance. Severity of cocaine use correlated with gray matter volume reduction in the left cerebellum (lobule VIII), while greater reversal cost was correlated with gray matter volume reduction in a partially overlapping cluster (lobules VIIb and VIII). Right insula/inferior frontal gyrus correlated with probability of maintaining response after errors. Severity of cocaine use detrimentally impacted reversal learning and cerebellar gray matter.Addiction Biology 04/2014; · 5.93 Impact Factor
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ABSTRACT: Recent emerging functional magnetic resonance imaging (fMRI) studies have identified many brain regions in which gambling cues or rewards elicit activation and may shed light upon the ongoing disputes regarding the diagnostic and neuroscientific issues of gambling disorder (GD). However, no studies to date have systemically reviewed fMRI studies of GD to analyze the brain areas activated by gambling-related cues and examine whether these areas were differentially activated between cases and healthy controls (HC). This study reviewed 62 candidate articles and ultimately selected 13 qualified voxel-wise whole brain analysis studies to perform a comprehensive series of meta-analyses using the effect size-signed differential mapping approach. Compared with HC, GD patients showed significant activation in right lentiform nucleus and left middle occipital gyrus. The increased activities in the lentiform nucleus compared to HC were also found in both GD subgroups that had, or had not, excluded substance use disorder comorbidity. In addition, the South Oaks Gambling Screen scores were associated with hyperactivity in right lentiform nucleus and bilateral parahippocampus, but negatively related to right middle frontal gyrus. These results suggest dysfunction within the frontostriatal cortical pathway in GD, which could contribute to our understanding of the categories and definition of GD and provide evidence for the reclassification of GD as a behavioral addiction in the DSM-5.Behavioural Brain Research 09/2014; · 3.39 Impact Factor
Cerebellar Vermis Involvement in Cocaine-Related Behaviors
Carl M Anderson1, Luis C Maas1, Blaise deB Frederick1, Jacob T Bendor2, Thomas J Spencer3, Eli Livni3,
Scott E Lukas4, Alan J Fischman3, Bertha K Madras2, Perry F Renshaw1and Marc J Kaufman*,1
1Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, USA;2Department of Psychiatry, Division of Neurochemistry,
New England Primate Research Center, Harvard Medical School, Southborough, MA, USA;3Division of Nuclear Medicine of the Department of
Radiology, Massachusetts General Hospital, Boston, MA, USA;4Behavioral Psychopharmacology Research Laboratory, Department of Psychiatry,
McLean Hospital, Harvard Medical School, Belmont, MA, USA
Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered
to mediate stimulant-associated behaviors since it is low in dopamine. Yet, the primate cerebellar vermis (lobules II–III and VIII–IX) has
been reported to contain axonal dopamine transporter immunoreactivity (DAT-IR). We hypothesized that DAT-IR-containing vermis
areas would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands.
We used BOLD fMRI to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and
positron emission tomography imaging of healthy humans to determine whether the DAT-selective ligand [11C]altropane accumulated in
those vermis regions. Cocaine-related cues selectively induced BOLD activation in lobules II–III and VIII–IX in cocaine users, and, at early
time points after ligand administration, we found appreciable [11C]altropane accumulation in lobules VIII–IX, possibly indicating DAT
presence in this region. These data suggest that parts of cerebellar vermis mediate cocaine’s persisting and acute effects. In light of prior
findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of
sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and
other cognitive tasks, we propose that the vermis be considered one of the structures involved in cocaine- and other incentive-related
Neuropsychopharmacology advance online publication, 12 October 2005; doi:10.1038/sj.npp.1300937
Keywords: cocaine; stimulants; cerebellum; vermis; dopamine transporter; craving
A common circuitry has been proposed to regulate drug-
seeking behaviors evoked by stimulant drugs, their cues,
and stress (Kalivas and McFarland, 2003). The circuitry
includes a ‘limbic subcircuit’ (ventral tegmental area,
amygdala/extended amygdala, mediodorsal thalamus, and
lateral tegmental nucleus) that channels information into a
‘motor subcircuit’ (dorsal prefrontal cortex/anterior cingu-
late and nucleus accumbens core) referred to as a ‘final
common pathway’ linking cognitive processing to beha-
vioral output (Kalivas and McFarland, 2003). Most, but not
all structures comprising these circuits exhibit relatively
high concentrations of dopamine and dopamine transpor-
ters (DAT), the latter of which is blocked by cocaine and
other stimulants, leading to the rapid synaptic dopamine
increases thought to contribute to the acute behavioral
effects of cocaine and other abused drugs.
Yet, a number of brain structures with relatively low
dopamine and DAT levels appear to mediate effects of
cocaine and other stimulants. One such region is the frontal
cortex, which is intimately connected with the circuitry
described above but is low in dopamine and DAT. By virtue
of its involvement in salience attribution and in regulating
inhibition of inappropriate behavioral responses, the frontal
cortex appears to act as a higher order locus of control over
stimulant and other drug-seeking behaviors (for review,
see Goldstein and Volkow, 2002). Another brain area, the
cerebellum, has been proposed to play a role in reinforce-
ment (Martin-Solch et al, 2001). The cerebellum, like the
frontal cortex, has relatively low concentrations of dopa-
mine and dopamine receptors, and whole cerebellar DAT
binding is very low (Kaufman et al, 1991; Fischman et al,
2001). Thus, it typically is excluded from consideration as a
region mediating drug-associated behaviors. However, as
has been noted by Cotterill (2001), ‘Muscular contraction is
the nervous system’s only externally directed product, and
the signaling routes which pass through the various brain
components must ultimately converge on the motor areas’
Online publication: 13 September 2005 at http://www.acnp.org/
Received 21 March 2005; revised 25 July 2005; accepted 2 September
*Correspondence: Dr MJ Kaufman, Brain Imaging Center, McLean
Hospital, 115 Mill Street, Belmont, MA 02478, USA, Tel: +1 617 855
3469, Fax: +1 617 855 2770, E-mail: firstname.lastname@example.org
Neuropsychopharmacology (2005), 1–9
& 2005 Nature Publishing GroupAll rights reserved 0893-133X/05 $30.00
(Cotterill, 2001). Indeed, recent data suggest that the
cerebellum plays fundamental roles in a number of
cognitive processes required for executing goal-directed
and suppressing disadvantageous behaviors, including
sensory functions (Paradiso et al, 1999), attention (Allen
et al, 1997; Bischoff-Grethe et al, 2002), conditioned
response learning (Logan and Grafton, 1995), and executive
functions (Smith and Jonides, 1997; Ernst et al, 2003;
Hu ¨lsmann et al, 2003) including response inhibition
(Mostofsky et al, 2003). Thus, the cerebellum is critically
interposed to link internal processing of exteroceptive and
interoceptive stimuli to action.
A cerebellar role in stimulant-associated behaviors is
suggested by several functional imaging studies. Cerebellar
activation in response to presentation of cues for cocaine
initially was reported by Grant et al (1996) who noted
a correlation between cerebellar activation and degree of
cocaine craving. Subsequent studies noted cerebellar
activity during cocaine craving (Kilts et al, 2001; Bonson
et al, 2002), during recall or imagery of cocaine-use
experiences (Wang et al, 1999; Kilts et al, 2001), and during
stimulant expectancy (Volkow et al, 2003). Acute adminis-
tration of or cues for other stimulants or psychoactive drugs
also has been associated with increased cerebellar activity
(Volkow et al, 1996, 1988; London et al, 1990; Ghatan et al,
1998; Sell et al, 1999; Domino et al, 2000). Two studies
reported cerebellar midline (vermis) activation by alcohol
odor cues and by stimulant expectancy (Schneider et al,
2001; Volkow et al, 2003). Such findings are intriguing in
light of reports localizing DAT immunoreactivity (DAT-IR)
and mRNA in primate cerebellar vermis (Melchitzky and
Lewis, 2000; Hurley et al, 2003). Moreover, in rodents, the
vermis is a context-dependent self-stimulation site (Ball
et al, 1974) and vermis lesions alter cortical dopamine
turnover (Snider and Snider, 1977). Together, these findings
suggest that the cerebellum and the vermis in particular
may exert some regulatory control over forebrain dopamine
To date, a role for the vermis in mediating effects of
abused drugs has not been evaluated or articulated in detail.
Accordingly, we used blood oxygen level-dependent func-
tional MRI (BOLD fMRI) to assess whether presentation of
cocaine-related audiovisual cues evokes vermis activation in
cocaine abusers. We retrospectively analyzed fMRI data
acquired as part of our previously published study noting
cocaine cue-associated anterior cingulate and left dorsolat-
eral prefrontal cortex activation (Maas et al, 1998). That
study reported no significant BOLD effect in cerebellum
(Maas et al, 1998). However, it was published prior to the
vermis DAT-IR findings of Melchitzky and Lewis (2000) and
cerebellum was analyzed as a whole structure, an approach
that would have missed small activation areas due to partial
volume effects. In our reanalysis, we hypothesized that
we would observe selective cocaine cue-associated BOLD
activation in vermis regions (lobules II–III and VIII–IX)
reportedly containing axonal DAT-IR (Melchitzky and
In addition, though DAT-IR and mRNA have been
localized in vermis (Melchitzky and Lewis, 2000; Hurley
et al, 2003), no study to date has directly characterized
vermis DAT density or distribution. While we (Kaufman
et al, 1991; Fischman et al, 2001) and others documented
low whole cerebellar DAT-binding levels in vitro and
in vivo, as noted above, global DAT-binding measure-
ments might have missed DAT-enriched zones. Thus,
we conducted an in vitro autoradiographic study in
human post-mortem cerebellar vermis tissue sections and
an in vivo positron emission tomography (PET) study
of healthy human cerebellum, using the DAT-selective
cocaine congeners [3H]2b-carbomethoxy-3b-(4-fluorophenyl)
tropane ([3H]CFT) (Kaufman et al, 1991) and [11C]2b-
nortropane ([11C]altropane) (Fischman et al, 2001), respec-
tively, to examinevermis
hypothesized that [3H]CFT and [11C]altropane would
accumulate selectively in vermis lobules II–III and VIII–IX.
MATERIALS AND METHODS
We studied 10 crack cocaine abusers (six men) with X6-
month histories of at least biweekly crack abuse (mean (SD)
age¼3677 years old), and eight comparison subjects
(three men, 3176 years old). Crack cocaine was the
preferred drug of abuse by cocaine subjects but history of
other drug use was not grounds for exclusion. Comparison
subjects reported no history of drug abuse of any form.
Subjects were screened with the Structured Clinical Inter-
view for DSM-IV Axis I Disorders. Subjects with histories of
psychotic disorder or current Axis I mood disorder were
excluded. All subjects were otherwise healthy and had no
history of neurological disorder. All subjects tested negative
for recent drug (Triage Test, Biosite Diagnostics Inc.) and
alcohol (Alco Sensor III, Intoximeters Inc.) use immediately
prior to the fMRI study.
Studies were conducted with approval from the McLean
Hospital Institutional Review Board and subjects provided
written informed consent. The cocaine cue audiovisual
presentation consisted of four contiguous 150-s alternating
segments of neutral (butterflies) and cocaine-related scenes
and sounds (Childress et al, 1999) adapted for presentation
to each subject via an MRI-compatible audiovisual system
(Maas et al, 1998), while supine in the magnet.
All fMRI data were obtained on a 1.5 Tesla General
Electric Signa scanner (Milwaukee, WI) retrofit with a whole
body resonant gradient set (Advanced NMR Systems Inc.,
Wilmington, MA). Gradient echo planar images were
acquired from 16 oblique-coronal slices, including four
to five slices containing cerebellum, with the following
parameters: 7-mm thickness, 3-mm skip, TE¼40ms,
TR¼5s, a¼901, in-plane resolution¼3.125?3.125mm2).
Matched anatomical T1-weighted images also were acquired
for region of interest (ROI) placement.
To quantify craving levels, a visual analog desire for
cocaine scale was administered prior to and after scanning,
to determine change scores, as described previously (Maas
et al, 1998). All fMRI data were motion-corrected before
analysis (Maas et al, 1997). One image slice, containing the
bulk of cerebellar lobule VIII, was selected for vermis ROI
placements. Three ROIs (Figure 1a and b) encompassing
anterior vermis (AV: lobules II–III), posterior-superior
vermis (PSV: lobules V–VI), and posterior-inferior vermis
(PIV: lobules VIII–IX) were selected to compare axonal
Cerebellar vermis and cocaine
CM Anderson et al
DAT-IR-enriched zones (AV and PIV) to the DAT-IR-poor
zone (PSV). These ROIs were identified on matched
anatomical MR images and mapped to the midcerebellar
fMRI slice by a single rater blind to subject identities. BOLD
fMRI activation was estimated as percent change in the
mean ROI intensities measured between neutral and
cocaine-cue fMRI segments and as spatial activation extent
(fraction of regional pixels exceeding an r¼0.30 activation
threshold, as noted previously (Maas et al, 1998)). We
established good inter-rater reliability for both activation
measures (Maas et al, 1998).
[11C]altropane In Vivo PET
PET with [11C]altropane was conducted in 11 healthy adults
(two women) aged 23.970.9 years old, who provided
informed consent to participate in this study. Images were
acquired using a HR+ (CTI, Knoxville, TN) PET camera.
Camera imaging parameters are in-plane and axial resolu-
tions of 4.5-mm FWHM, with 63 contiguous slices of 2.5-
mm separation. Images were acquired in 3D mode and
reconstructed using an iterative algorithm to an in-plane
resolution of 4.5-mm FWHM. Photon attenuation measure-
ments were made with68Ge rotating pin sources. For each
scan, B5mCi of [11C]altropane was injected intravenously
over 30s. Dynamic image collection started at infusion and
images were acquired in 15-s frames (initial 2min), in 1-
min frames (next 4min), and in 2-min frames (remaining
54min). All projection data were corrected for detector
response nonuniformity, dead time, random coincidences,
and scattered radiation.
The initial 11 volumes acquired immediately after
injection of the [11C]altropane bolus were summed to
create blood flow images on which ROIs were manually
traced using an in-house tool written for AVS (Advanced
Visual Systems Inc., Waltham, MA). ROIs were positioned
bilaterally on frontal cortex, thalamus, substantia nigra, and
cerebellar hemispheres. ROIs also were traced within the
highest intensity core of the putamen bilaterally on axial
slices. For vermis, three ROIs were sampled in the sagittal
plane within AV, PSV, and PIV. The complete set of ROIs
was replicated on summed volumes (14–31) to represent
position of the coronal oblique fMRI acquisition slice (A, anterior; P, posterior; L, left; R, right). The black, blue, and orange box overlays on panels a and b
represent the AV, PSV, and PIV, respectively. (b) BOLD activation map from a single cocaine subject overlaid on an oblique image. Yellow pixels represent
activation foci at the P¼9?10?12statistical significance level. (c) PIV activation time course for pixels within the PIV box on panel b; bluish gray and green
epochs indicate neutral and cocaine cue periods, respectively. (d) [11C]altropane PET time–activity curves. Shown are mean (SE) activity levels (a.u. –
arbitrary units) from 11 healthy subjects in putamen (Pu), posterior-inferior vermis (PIV), posterior-superior vermis (PSV), and substantia nigra (SN). (e)
Normalized regional [11C]altropane accumulation during the initial 6min after ligand infusion. Shown are means (SE) in various brain regions, normalized to
PSV accumulation. Posterior-inferior vermis (PIV); thalamus (TH): anterior vermis (AV); cerebellar hemispheres (CH); whole cerebellar slice (axial aspect)
(CER); frontal cortex (FC); substantia nigra (SN). Post hoc tests with Bonferroni multiple comparisons correction for significant difference from PIV: *Po0.05;
wPo0.01;zPp0.005. In all panels, regions with bilateral representations were averaged into single data values.
BOLD fMRI activation of and [11C]altropane accumulation in vermis. (a) Midsagittal vermis gross anatomy section overlaid with the approximate
Cerebellar vermis and cocaine
CM Anderson et al
Relative regional [11C]altropane accumulation levels were
calculated over the first 6min after ligand infusion as
quotients of summed activity within each ROI, divided by
PSV summed activity. The referent PSV reportedly is DAT-
IR devoid (Melchitzky and Lewis, 2000). For regions with
bilateral representations, ROI values were averaged across
hemispheres. Relative activity levels were analyzed with
ANOVA to detect a regional difference in [11C]altropane
accumulation. The putamen, which contains high DAT
levels, was excluded from all statistical analyses, so that it
did not bias our global analyses in favor of finding regional
differences in [11C]altropane accumulation. Post hoc tests
were conducted using a Bonferroni correction for multiple
[3H]CFT In Vitro Receptor Autoradiography
Cerebellar vermis tissue blocks from two healthy women
(pathologically confirmed) were obtained from the Harvard
Brain Tissue Resource Center at McLean Hospital and
stored until sectioning at ?801C. Subject age, post-mortem
index, and time interval between death and the autoradio-
graphy study were 6072.8 years, 19.377.1h, and 1.870.3
years, respectively. Autoradiography was conducted as
described (Kaufman et al, 1991). Vermis tissue blocks were
sectioned (20mm thickness) sagittally on a cryostat at
?181C. Tissue sections were thaw-mounted onto Adhesion
Superfrost Plus microscope slides (Brain Research Labora-
tories, Newton, MA) and stored at ?801C. Tissue sections
were equilibrated at 01C 12h prior to autoradiography
studies. Six sections per brain were preincubated for 20min
in Tris buffer (50mM Tris-HCl containing 100mM NaCl,
pH 7.4 at 41C), then incubated in triplicate for 2h in buffer
containing tracer (10nM) concentrations of [3H]CFT
([3H]WIN 35428, spec. act.: 81.3Ci/mmol, Dupont-New
England Nuclear, Boston, MA) to measure total binding, or
with 10nM [3H]CFT and 30mM (?)-cocaine hydrochloride
to measure nonspecific binding, washed with two 1-min
rinses in ice-cold buffer, dipped rapidly in ice-cold distilled
water, and dried with chilled desiccated air. Tissue sections
and autoradiographic standards ([3H]Microscales, Amer-
sham Biosciences Corp., Piscataway, NJ) were apposed to
autoradiographic film (Hyperfilm-[3H], Amersham Bios-
ciences Corp., Piscataway, NJ) for 10 weeks at 41C. Films
were developed at room temperature using Kodak D-19
developer (5min), rinsed in water for 30s, fixed in Kodak
Rapid Fix for 5min, and washed for 20min. Films were
dipped in Kodak Photoflo and hung to air dry. Densito-
metric data were acquired from DAT-IR-enriched lobule
VIII and DAT-IR-poor lobule VI, as well as from whole
vermis and vermis white matter, using the MCID analysis
system (St Catharines, Ont.). Densities are expressed as
regional ratios and statistical analyses were conducted using
one sample t-tests.
BOLD fMRI Studies
Cocaine but not comparison subjects reported increased
desire for cocaine following cocaine cue presentation. Mean
desire ratings increased by 2.2 (0–10 scale) arbitrary units
(SD¼2.7, t¼2.7, Po0.03). There was a group difference in
vermis BOLD activation (F1,16¼4.95, P¼0.04) with cocaine
subjects exhibiting higher mean percent increases (0.48%
magnitude difference) than comparison subjects. Within
vermis, BOLD activation magnitudes differed by region
(F2,32¼7.51, P¼0.002); post hoc Scheffe tests indicated
greater BOLD activations in AV and PIV than in PSV
(Po0.01). Mean BOLD activation spatial extent scores also
were greater (F1,16¼7.17, Po0.02) and regional differences
were identified (F2,32¼6.70, P¼0.004) in cocaine subjects;
post hoc Scheffe tests indicated greater spatial activation
extent in PIV than PSV (Po0.005). We found a marginal
association between desire rating change score and BOLD
activation increase in PIV (R¼0.713, Po0.02), though that
finding was strongly influenced by an outlier case, which,
when removed, eliminated statistical significance. Although
we did not identify sex differences on these measures, our
study was not adequately powered to test for an effect of
sex, and thus we cannot rule in or out any effects of sex.
Autoradiography and PET Imaging Studies
[3H]CFT-specific binding levels approached background
(o10pmol/g tissue equivalent) throughout vermis gray
matter (data not shown). Although [3H]CFT binding
in lobule VIII was higher than white matter levels
(108.770.4%, Po0.005, one sample t-test), it was margin-
ally lower than binding in either lobule VI (DAT-IR-poor)
or in whole vermis (95.373.7 and 93.070.4%, respectively,
Po0.02, one sample t-test).
In PET imaging studies, high [11C]altropane accumula-
tion levels were detected in putamen, as expected. At early
time points following ligand administration, time–activity
curves were suggestive of greater peak [11C]altropane
accumulation in PIV than in all other areas but putamen
(Figure 1d). There was a regional difference in normalized
ligand accumulation (F6,76¼12.2, Po0.001, excluding puta-
men). Post hoc testing with Bonferroni correction for
multiple comparisons indicated that PIV [11C]altropane
accumulation was greater than in substantia nigra, frontal
cortex, and all other cerebellar regions (Figure 1e). Tha-
lamic [11C]altropane accumulation was equivalent to that in
PIV. We were unable to detect appreciable PIV accumula-
tion using binding potential analysis (data not shown),
though that method may be less sensitive for detecting
transient ligand accumulations in regions containing low
specific binding densities.
These data document cocaine cue-induced cerebellar vermis
BOLD fMRI activation in cocaine users and selective PIV
[11C]altropane accumulation in healthy subjects at early
time points following ligand administration. Consistent
with our a priori hypotheses, BOLD activation occurred
only in AV and PIV, regions containing axonal DAT-IR
(Melchitzky and Lewis, 2000). Group differences (cocaine
users vs controls) in BOLD activation magnitudes (0.62 and
0.37% in AV and PIV, respectively) were substantially larger
than those we reported previously in the same subjects in
anterior cingulate (0.29%) and left dorsolateral prefrontal
Cerebellar vermis and cocaine
CM Anderson et al
cortex (0.20%) (Maas et al, 1998). This may indicate that
cocaine cue exposure induces greater neuronal activation in
vermis than in forebrain structures (Kim et al, 2004).
Alternatively, the larger apparent BOLD signal response in
vermis ROIs could have resulted from less partial voluming
(and less BOLD activation dilution per volume tissue) for
discrete vermis lobules.
Since we observed significant activation in vermis lobules
VIII–IX, which also are activated by smooth pursuit
oculomotor movements (Tanabe et al, 2002), and since
such movements were necessary to view the cocaine cue
program, smooth pursuit eye motion may have contributed
to BOLD responses. However, smooth pursuit eye move-
ments occurred in all subjects but lobules VIII–IX were
activated only in cocaine subjects. This suggests that
cocaine-related visual stimuli, salient only to cocaine users,
induced either new activity or a potentiated form of smooth
pursuit activation in lobules VIII–IX in cocaine abusers.
Vermis lobules VII and VIII process auditory information
(Brodal, 1980) and the combination of salient auditory and
visual cocaine-related cues may have contributed to lobule
VIII–IX activation. As there were no other overt motor
requirements in our paradigm, we interpret these findings
to suggest that salient polysensory qualities of the cue
paradigm selectively activated portions of the vermis.
It also is conceivable that the vermis BOLD activations we
identified in cocaine users represent early sensory proces-
sing of visual and auditory stimuli presented in the cocaine
cue paradigm. In this regard, neurophysiology studies in
cats noted vermis lobule VIII activation in response to
auditory–visual stimuli (Snider and Stowell, 1944). PET
blood flow studies in healthy humans documented anterior
and posterior vermis activations during early sensory
recognition of complex auditory and visual stimuli (Pen-
hune et al, 1998). These regions were proposed to be part of
a supramodal sensory timing apparatus that computes
temporal parameters of incoming sensory stimuli to
support timed motor responses (Penhune et al, 1998).
While visual and/or auditory sensory stimuli might induce
early vermis activations independent of DAT activity, the
localization of significant DAT-IR in this region in primates
implies that dopaminergic mechanisms linked with reward
could coexist and interact with such early sensory proces-
sing circuits. From these findings, we conclude that axonal
DAT-IR-enriched vermis lobules are activated by cocaine-
related cues. The vermis also is activated during stimulant
expectancy (Volkow et al, 2003) and in alcoholics during
alcohol odor cue-induced craving (Schneider et al, 2001),
implying that it may generally activate in response to drug-
associated stimuli in drug abusing cohorts.
Our PET findings suggest that at early time points after
ligand administration [11C]altropane accumulated at higher
levels in PIV than in substantia nigra, frontal lobe, and
other cerebellar areas. This finding is consistent with the
report of DAT-IR enrichment in this area (Melchitzky and
Lewis, 2000). PET time–activity curves indicated that PIV
[11C]altropane washout was more rapid than in putamen or
substantia nigra, suggesting different ligand kinetics in PIV
vs putamen and substantia nigra. It is unlikely that the
excess PIV [11C]altropane accumulation is solely the result
of blood flow differences since PET blood flow data from
healthy adults indicate mismatches between cerebellar
blood flow patterns, which are higher in cerebellar hemi-
spheres than vermis and homogenous within vermis (Ouchi
et al, 2001; Ito et al, 2003) and [11C]altropane accumulation,
which was lowest in cerebellar hemispheres and was
heterogeneous within vermis. Although it is possible that
excess [11C]altropane accumulation in PIV represented
labeling of other sites (see below), a parsimonious conclu-
sion is that DAT may be present in the DAT-IR-enriched
PIV and that this region may be a proximate site of action of
cocaine, methylphenidate, and other drugs that interact
with the dopamine transporter.
Our human post-mortem autoradiography studies were
unable to detect vermis-specific [3H]CFT binding. Thus, our
autoradiography data appear to conflict both with our own
PET imaging data and with prior DAT-IR findings
(Melchitzky and Lewis, 2000). The lower DAT affinity and
selectivity of CFT vs altropane (Madras et al, 1998), and the
lower affinity of radioreceptor ligands (nanomolar range) vs
immunohistochemical ligands (subnanomolar range), may
in part explain why we failed to detect specific [3H]CFT
autoradiography binding in vermis, when binding was
detected with other DAT-selective ligands. Two additional
factors may have contributed to our inability to detect
specific [3H]CFT binding with autoradiography: our studies
were conducted in the post-mortem state in tissues from
elderly subjects. DAT radioligand binding declines post-
mortem by up to 35% after 5 or more hours of post-mortem
time (Patel et al, 1993) and the post-mortem interval for
tissues used in this study averaged 19.3h. In addition, a
number of studies have shown that DAT radioligand-
binding density declines with age in healthy subjects (see,
for example, Kaufman and Madras, 1993; Volkow et al,
1994; van Dyck et al, 1995). The 3.5-decade age difference
between our PET and autoradiography subjects (averaging
25 and 60 years old, respectively) might have resulted in a
significant depletion of DAT activity (using an 8% per
decade decline in DAT activity, van Dyck et al, 1995).
Together, post-mortem time and aging effects could result
in significant losses of functional DAT, comparable to the
differences reported between cryopreserved human caudate
nucleus and fresh rat striatum (Eshleman et al, 2001). Thus,
if [11C]altropane accumulation in the vermis indeed reflects
DAT binding, and if vermis and striatal DAT losses are
parallel with post-mortem factors and age, then conceiva-
bly, detection of specific [3H]CFT binding to vermis DAT
would be severely compromised. This could explain our
negative autoradiography findings. Recent rodent studies
suggest that the age-associated decline in functional DAT
results not from loss of DAT protein but from reduced
functional DAT expression in the plasma membrane
(Salvatore et al, 2003). Accordingly, in healthy subjects at
any age, DAT may be easier to detect with immunohisto-
chemical than with radioreceptor methods. This also means
that a proportion of vermis DAT-IR detected in prior
studies may not represent functional DAT protein.
Interestingly, thalamic [11C]altropane accumulation was
statistically equivalent to that in PIV (Figure 1e). DAT-IR
has been reported in thalamus (Melchitzky and Lewis, 2001)
and thalamic [11C]cocaine accumulation was proposed to
reflect DAT binding (Telang et al, 1999). Moreover, a very
recent report described a significant dopaminergic innerva-
tion of the primate thalamus including a confirmation of
Cerebellar vermis and cocaine
CM Anderson et al
widespread DAT-IR localization (Sanchez-Gonzalez et al,
2005). Thus, thalamic [11C]altropane accumulation may
reflect DAT-binding sites. Clearly, additional pharmacolo-
gical studies are required in PIV and thalamus to more
precisely characterize the nature of cocaine congener
accumulation in these areas. This is important because
cocaine has comparable affinity for dopamine, norepi-
nephrine (NET), and serotonin transporters, and cocaine’s
effects may be mediated in some regions via interactions
with sites other than DAT. For example, frontal lobe
dopamine uptake occurs primarily via NET activity (Moron
et al, 2002). NET is present in cerebellum including vermis
(Ding et al, 2003). Accordingly, some cerebellar regions
containing NET might mediate effects of cocaine and its
cues. While the present data do not identify vermis
substrates activated by cocaine or its cues, they suggest
that the PIV contains elements that may mediate or
participate in both effects.
Cerebellar Connectivity to Dopamine Circuitry
Our findings suggesting that parts of the vermis mediate
effects of cocaine and its cues are consistent with prior data
documenting vermis connections to dopamine cell body
regions in the ventral tegmental area (VTA) and substantia
nigra (Snider et al, 1976). In addition, the VTA projects to
cerebellum (Ikai et al, 1992) implying the presence of a
reciprocal midbrain to cerebellum circuit. A subset of VTA
efferents to cerebellum appears to be dopaminergic (Ikai
et al, 1992) and some of those projections could be a target
for DAT-IR labeling and contain DAT-binding sites.
Interestingly, in rodents, a proportion of VTA efferents
bifurcates, sending projections both to cerebellum and
either prelimbic/anterior cingulate or piriform-entorhinal
cortex; such projections are segregated from VTA connec-
tions to subcortical (including limbic subcircuitry) struc-
tures (Ikai et al, 1994). Those bifurcating projections,
together with cerebellar efferents to VTA (Snider et al,
1976), could form a separate circuit connecting cerebellum
to frontal and temporal lobes independent of ascending
thalamic (Middleton and Strick, 2001) and descending
pontine (Schmahmann and Pandya, 1997) relays. Such
circuitry could be a basis for forebrain dopamine turnover
changes induced by vermis lesions (Snider and Snider,
1977), could account for our finding of vermis activation in
cocaine abusers by cocaine-related cues, and could explain
why the cerebellum tends to coactivate with frontal lobes
during some cognitive tasks (see below).
Reward Circuitry, The Cerebellum, and
The reward circuitry has been proposed to participate as a
shared pathway for processing drug and nondrug rewards
(Garavan et al, 2000) and aversive stimuli (Becerra et al,
2001). Vermis activation also occurs in response to nondrug
rewards or their anticipation (Rogers et al, 1999; Kunig
et al, 2000; Martin-Solch et al, 2001; Knutson et al, 2003),
painful or aversive stimuli or their anticipation (Paradiso
et al, 1999; Casey et al, 2000; Becerra et al, 2001), and
interoceptive stimuli triggered by vegetative regulatory
functions including thirst (Egan et al, 2003), hunger
(Tataranni et al, 1999), and respiratory stress (Evans et al,
2002). Together, those findings are consistent with the
suggestion that the cerebellum and the vermis process
multimodal sensory inputs to influence cortical excitability
and enhance motor sequence learning and execution
(Molinari et al, 2002).
That multimodal sensory processing function may be a
form of or closely related to selective attention, as vermis
participates both in attentional processes linked to motor
responses (Allen et al, 1997) and in response reassignment,
which involves context-dependent changes in sensorimotor
sets to facilitate motor outputs (Bischoff-Grethe et al, 2002).
These capacities may be very important in drug dependence
(and its treatment) since a ‘hyperattentive state’ with regard
to salient drug-related stimuli may underlie drug craving
and relapse (Franken, 2003). Vermis activation in response
to cocaine-related cues (present study) and in response to
alcohol odor cues (Schneider et al, 2001) may indicate that
it is involved in ‘hyperattentive states.’ This could be
significant as vermis also is involved in later stages of
voluntary movement planning (Hu ¨lsmann et al, 2003) and
thus is positioned to strongly influence behavioral output
Of course, the vermis and other cerebellar areas do not
function in isolation but rather coordinate task processing
duties with other forebrain structures via cerebello-thala-
mo-cortical (Middleton and Strick, 2001) and cortico-
1997), and perhaps also via VTA circuitry (see above).
The fronto-cerebellar interplay seems to be dynamic in
nature and normally is dominated by frontal structures
(Smith and Jonides, 1997; Gould et al, 2003), with cerebellar
structures playing a supporting role. However, in addiction
disorders, in which the frontal lobes are known to be
compromised (Goldstein and Volkow, 2002), cerebellar
(and vermis) activity appears to increase to support several
tasks involving frontal lobe function including monetary
reward response (Martin-Soelch et al, 2001), response
inhibition (Hester and Garavan, 2004), and working
memory (Desmond et al, 2003). Vermis activation also
occurs during reward tasks in Parkinson’s and in attention
deficit hyperactivity disorder patients, but not in compari-
son subjects (Ernst et al, 2003; Goerendt et al, 2004; Kunig
et al, 2000). In addition, increased cerebellar (and vermis)
activation occur to support working memory function in
frontotemporal dementia, Parkinson’s Disease, and schizo-
phrenia, (Mentis et al, 2003; Meyer-Lindenberg et al, 2001;
Rombouts et al, 2003). Thus, several domains of frontal lobe
function pertinent to addiction-related behaviors appear to
be supported by cerebellum and vermis. Along with the
present findings, these observations suggest that the vermis
plays a central role in organizing sensory inputs and
planning motor responses to rewarding and other incentive-
related stimuli, and that its role in modulating these
responses may increase when the frontal lobes are
compromised by disease or chronic drug use.
These findings must be interpreted in light of several
limitations. First, our fMRI data were acquired with older
technology and analyzed retrospectively, after learning that
Cerebellar vermis and cocaine
CM Anderson et al
DAT-IR is present in primate vermis (Melchitzky and Lewis,
2000). Thus, fMRI acquisition parameters
optimized for detecting cerebellar activations, and in
particular, for activations localized to specific vermis
lobules. For this reason, we believe that the BOLD activation
magnitudes we identified may be very conservative
estimates of localized vermis responses to cocaine-related
cues. Second, the ligand we used for PET-imaging studies,
[11C]altropane, exhibits fast washout kinetic properties.
Thus, it probably is not optimal for detecting DAT in
regions with low DAT densities. Indeed, binding potential
analysis was unable to identify DAT binding in PIV. Yet, we
found statistically significant normalized [11C]altropane
accumulation differences within vermis and cerebellum
(when referenced to the DAT-devoid PSV) that cannot be
attributed to blood flow differences (Ouchi et al, 2001; Ito
et al, 2003), suggesting the presence of DAT binding in PIV.
Third, we were unable to detect specific [3H]CFT binding in
vermis lobule VIII suggesting some discrepancy between
[3H]CFT and both DAT-IR and [11C]altropane labeling. As
noted above, this discrepancy could be related to differ-
ential kinetics and pharmacological specificity for these
ligands (Madras et al, 1998; Fischman et al, 2001) as well as
from age and post-mortem reductions in functional DAT
expression (Patel et al, 1993; Salvatore et al, 2003).
Notwithstanding these limitations, we believe the present
findings support the concept that the cerebellar vermis is
involved in mediating cocaine-related behaviors. We also
believe that these findings warrant further studies to better
characterize cerebellar and vermis roles in cocaine- and
other incentive-related behaviors and to identify vermis
substrates mediating the effects noted presently.
We thank the National Institute on Drug Abuse (DA016222
(CMA), DA16746 (CMA), DA017324 (MJK), DA009448
(PFR), DA03994 (SEL),DA014178
(MJK), DA015116 (PFR), DA14013 (BdeBF), DA00343
RR000168 (BKM) for supporting these studies, the Harvard
Brain Tissue Resource Center, supported in part by PHS
Grant MH/NS31862, for donating human post-mortem
cerebellar vermis tissue, the Whitaker Foundation, the John
and Virginia B Taplin Endowment Fund, and the Dr Ralph
and Marian C Falk Medical Research Trust. We thank Anne
Smith, RTR, Eileen Connolly, RTR, Veronica Rogers, Sarah
Daniels, and Thellea Kukes for assistance in data collection.
Portions of these data were previously published in abstract
form at the 64th and 67th Annual Scientific Meetings of the
College on Problems of Drug Dependence, Quebec City,
Quebec, June 2002 and Orlando, FL, 2005, respectively.
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