Investigating the Dopaminergic Synapse In Vivo. II. Molecular Imaging Studies in Small Laboratory Animals

Abstract

Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the postsynaptic binding sites using molecular in vivo imaging methods. Apart from the density of binding sites, parameters such as alterations in dopamine synthesis, dopamine storage or dopamine release can be quantified either by application of specific radiotracers or by assessing the competition between the exogenous radioligand and endogenous dopamine. The performance of animal studies allows the induction of specific short-term or long-term synaptic conditions via pharmacological challenges or infliction of neurotoxic lesions. Therefore, small laboratory animals such as rats and mice have become invaluable models for a variety of human disorders. This article gives an overview of those small animal studies which have been performed so far on dopaminergic neurotransmission using in vivo imaging methods, with a special focus on the relevance of findings within the functional entity of the dopaminergic synapse. Taken together, in vivo investigations on animal models of Parkinson's disease showed decreases of dopamine storage, dopamine release and dopamine transporter binding, no alterations of dopamine synthesis and DA release, and either increases or no alterations of D2 receptor binding, while in vivo investigations of animal models of Huntington's disease. showed decreases of DAT and D1 receptor binding. For D2 receptor binding, both decreases and increases have been reported, dependent on the radioligand employed. Substances of abuse, such as alcohol, amphetamine and methylphenidate, led to an increase of dopamine release in striatal regions. This held for the acute application of substances to both healthy animals and animal models of drug abuse. Findings also showed that chronic application of cocaine induced long-term reductions of both D1 and D2 receptor binding, which disappeared after several weeks of withdrawal. Finally, preliminary results yielded the first evidence that acute pplication of haloperidol might induce a reduction of dopamine transporter binding, indicating an enhancement of dopamine release into the synaptic cleft. It is remarkable to what degree the findings obtained with small animal imaging devices correspond to the results of clinical and experimental studies on humans. This agreement underlines the validity of small animal imaging methods and demonstrates the feasibility of further investigations on animal models of human diseases.

Neurochemical dysfunction in treated and nontreated schizophrenia – a retrospective analysis of in vivo imaging studies

“…During the last decades, small animal imaging has been increasingly employed to study neurochemical and physiological parameters such as perfusion, glucose utilization, or receptor and transporter binding in suitable animal models of human disorders (for review, see Nikolaus et al, 2004Nikolaus et al, , 2007b. As, for ethical reasons, numerous scientific questions cannot be assessed in humans, a complementary approach in SZ research can be the performance of investigations on certain presynaptic and/or postsynaptic constituents in suitable animal models such as neonatal ventral hippocampal lesion rat (NVHL; for review, see Lipska and Weinberger, 2000).…”

Smoking-induced change in intrasynaptic dopamine concentration: Effect of treatment for Tobacco Dependence

“…In addition, a brain imaging study of subjects with depression (Argyelan et al, 2005) demonstrated that chronic bupropion HCl treatment is associated with diminished dopamine transporter availability, which would presumably increase intrasynaptic DA since the dopamine transporter is primarily responsible for clearance of intrasynaptic DA (Hoffman et al, 1998). These studies suggest that chronic bupropion HCl treatment leads to increased intrasynaptic DA, which would be expected to result in a downregulation of D2 receptors and diminished DA release in response to pharmacological stimuli (Bilder et al, 2004; Nikolaus et al, 2007a; Nikolaus et al, 2007b; Bamford et al, 2008). As for evidence of unchanged smoking-induced DA release, a recent study of rodents demonstrated that chronic bupropion HCl treatment increases extracellular DA in the nucleus accumbens shell, but does not alter the reward-facilitating effects of experimenter-administered nicotine (Paterson et al, 2007).…”

Infantile parkinsonism-dystonia: a dopamine “transportopathy”

“…Fortunately, the tools available to link DAT biology to its function in the nervous system are quite extensive and powerful. In particular, imaging modalities for DAT using single positron emission computed tomography (SPECT) and PET with a host of available ligands will provide a crucial link among clinical characterizations, genetic investigations, and basic science studies (19,20). For DAT, effects of alterations in protein structure on the response to pharmacological agents are also providing insights.…”