Tyrosine Hydroxylase- and Dopamine Transporter-Immunoreactive Axons in the Primate Cerebellum Evidence for a Lobular- and Laminar-Specific Dopamine Innervation

Abstract

The cerebellum seems to play a critical role in many motor and cognitive functions, including those that are disturbed in schizophrenia. Although dopamine is known to influence the motor or cognitive functions mediated by other brain regions and to play a role in the pathophysiologyThe primary function of the cerebellum has traditionally been considered to involve the control and integration of motor processes, including the coordination of goal-directed movements and the regulation of posture (Ito 1984). However, recent evidence suggests that the cerebellum may also be important in cognitive functions (Schmahmann 1991;Kim et al. 1994). For example, neuro-imaging studies have demonstrated activation in the cerebellum during word-association tasks (Petersen and Fiez 1993), as well as during mental imagery and mental counting (Ryding et al. 1993). These cognitive aspects of the cerebellum seem to involve the lateral hemispheres and the dentate nucleus (Schmahmann 1991;Petersen and Fiez 1993;Kim et al. 1994). In con- Received May 19, 1999; revised October 18, 1999; accepted October 22, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 5 Dopamine Axons in Primate Cerebellum 467 trast, the medial regions of the cerebellum, such as the vermis and fastigial nucleus, are primarily associated with motor control of the trunk and head, including smooth pursuit eye movements (Ito 1984).The cerebellum has also been implicated as a site of dysfunction in schizophrenia, a disorder characterized by certain types of motor and cognitive impairments. For example, many subjects with schizophrenia exhibit abnormalities in smooth pursuit eye movements (Holzman et al. 1973;Levy et al. 1994;Hutton and Kennard 1998). In addition, some of the cognitive deficits observed in individuals with schizophrenia, such as impairments in planning, verbal fluency, abstract thinking, and working memory, are present in patients with cerebellar lesions (Schmahmann and Sherman 1998). Furthermore, studies of schizophrenic subjects have revealed reductions in cerebellar volume (Jacobsen et al. 1997;Weinberger et al. 1980), metabolism (Volkow et al. 1992, and blood flow (Steinberg et al. 1995), especially in the vermal regions. Consistent with these observations, the size of Purkinje cells has been reported to be decreased in the vermis of subjects with schizophrenia (Tran et al. 1998).Abnormalities in dopamine (DA) neurotransmission have long been considered to be involved in the pathophysiology of schizophrenia (Carlsson et al. 1997;Davis et al. 1991;Grace 1991;Snyder 1972;), and DA is known to play a critical role in the regulation of motor and cognitive functions in both cortical and subcortical structures (Goldman-Rakic 1998; Lewis and Sesack 1997). However, whether DA directly influences motor or cognitive functions at the level of the cerebellum is unclear. Historically, the cerebellum was not thought to utilize DA as a neurotransmitter, and the DA present in the cerebellum was considered to serve only as a precursor for noradrenaline. Mo...

A Positron Emission Tomography Study Of Methylphenidate in Adults with ADHD: Alterations in Resting Blood Flow and Predicting Treatment Response

“…Therefore, the observed effect of MPH may reflect MPH effects on cerebellar noradrenergic systems, although we cannot rule out contributions owing to effects of MPH on serotonergic systems. The dopaminergic innervation of the human cerebellar vermis is variably described as being sparse to rich (see Melchitzsky and Lewis, 2000), although Volkow et al (2001) have shown using PET and [ 11 C]raclopride that MPH does not appear to increase cerebellar dopamine levels. Therefore, it is uncertain whether the effects of MPH on rCBF in the cerebellar vermis are related to effects on dopaminergic systems.…”

Cerebellar Vermis Involvement in Cocaine-Related Behaviors

“…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).…”

“…Relative regional [ 11 C]altropane accumulation levels were calculated over the first 6 min 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.…”

“…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 Lewis, 2000).…”

“…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 measurements might have missed DAT-enriched zones.…”