Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects.

Abstract

Previously we demonstrated that positron emission tomography (PET) can be used to measure changes In the concentrations of synaptic dopamine and acetylcholine. Whether induced directly or indirectly through interactions with other neurotransmitters, these studies support the use of PET for investigating the functional responsiveness ofa specific neurotransmitter to a pharmacologic challenge. In an extension of these findings to the human brain, PET studies designed to measure the responsiveness of striatal dopamine release to central cholinergic blockade were conducted in normal male volunteers using high-resolution PET and Neurotransmitter receptor studies using functional imaging techniques including positron emission tomography (PET) and single photon emission computed tomography initially examined single neurotransmitter systems in human and primate brains. For example, the first application of these techniques to neuropsychiatric disease addressed one important component of the dopamine hypothesis of schizophrenia (1, 2). However, the results were controversial and have been the subject of continued debate with respect to differences in methodology and subject characteristics (3, 4). Therefore, the need to further study mechanisms that regulate synaptic dopamine activity is supported not only by the evidence that schizophrenic patients may or may not show significant changes in dopamine receptor number (Bmax) from normal controls but by the fact that the degree of striatal D2 receptor occupancy is not indicative of response to neuroleptic treatment (5, 6). As a result, a series of PET studies using a multiple mechanistic approach, including an examination of the interactions that have been shown to exist between acetylcholine and dopamine, have demonstrated that the binding of labeled N-methylspiroperidol (NMSP) (7) and raclopride, radiotracers used in these early studies, is sensitive to changes in synaptic dopamine concentrations (8-12). Both raclopride and NMSP are used as PET imaging agents for postsynaptic dopamine D2 receptors.PET's sensitivity for detecting alterations in labeled raclopride or NMSP binding has been demonstrated by pharmacologic agents that selectively increase or decrease synaptic dopamine concentrations by neurochemically different mechanisms (8, 9). These findings suggest that this experimental approach is well suited for studies designed to investigate disease states that begin with or result from a loss in the ability to adequately regulate synaptic dopamine release. Furthermore, the potential for this experimental approach clearly extends beyond the ability to measure changes in a single neurotransmitter system after a specific pharmacologic challenge. As it is well known that neurotransmitter systems do not work in isolation, we have extended these studies to include an examination ofthe utility ofPET for noninvasively assessing neurotransmitter interactions in the human brain.Neurotransmitter interactions have been demonstrated anatomically, physiologically, and beha...

Cholinergic Neuronal Modulation Alters Dopamine D2Receptor Availability In Vivo by Regulating Receptor Affinity Induced by Facilitated Synaptic Dopamine Turnover: Positron Emission Tomography Studies with Microdialysis in the Conscious Monkey Brain

“…These observations were consistent with the previous report of inhibition of [ 11 C]raclopride binding by cholinergic blockade induced by scopolamine in anesthetized baboons (Dewey et al, 1993b). Although these authors speculated that the reduced [ 11 C]raclopride binding was attributable to the increase in synaptic dopamine level via neuronal interactions, it did not demonstrate a clear relationship between the doses administered and the reduction in magnitude of [ 11 C]raclopride binding (Dewey et al, 1993b). The lack of microdialysis data as measured in the same animals used in the PET study impaired interpretation of the previous data.…”

“…Positron emission tomography (PET) can evaluate the functional responses of neurotransmitters to pharmacological manipulation, as well as the interactions between neuronal systems. PET has been used to assess the effects of endogenous dopamine (Innis et al, 1992;Dewey et al, 1993a;Carson et al, 1997), NMDA/glutamate (Smith et al, 1997), acetylcholine (Dewey et al, 1993b), serotonin (Dewey et al, 1995), and GABA (Dewey et al, 1992) on striatal [ 11 C]raclopride binding (for review, see Laruelle, 2000). These reports suggested that the changes in striatal synaptic dopamine could be measured noninvasively by PET using [ 11 C]raclopride, which has more moderate affinity for D 2 receptors than [ 11 C]N-methyl spiperone (NMSP) (Seeman et al, 1989;Young et al, 1991).…”

Towards a muscarinic hypothesis of schizophrenia

“…[106][107][108][109][110] These effects could be secondary to an increased dopamine release associated with the application of anticholinergic agents. 111 Consistent with these findings, subjects with schizophrenia frequently report an activating effect of higher doses of anticholinergics, which occasionally results in an abuse of these medications. 112 Another important observation from the clinical use of muscarinic cholinergic receptor antagonists is that these drugs worsen cognitive impairment associated with schizophrenia.…”

Therapeutic application of transcranial magnetic stimulation in Parkinson's disease: The contribution of expectation

“…Only peaks falling within the striatum were considered. A reduction in [ 11 C]raclopride BP is indicative of an increase in extracellular dopamine concentration (Dewey et al, 1993;Laruelle et al, 1997;Endres et al, 1997;Breier et al, 1997). For the purpose of the group analysis, PET images were flipped along the horizontal axis so that the hemisphere contralateral to the more affected body side (i.e.…”