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. Investigations of humans in both clinical and experimental settings have yielded evidence that disturbances of dopaminergic function may be associated with numerous neurological and psychiatric conditions, among which are movement disorders, schizophrenia, attention-deficit hyperactivity disorder, depression and drug abuse. This article gives an overview of those studies, which so far have been performed on dopaminergic neurotransmission in humans using in vivo imaging methods. We focus on disease-related deficiencies within the functional entity of the dopaminergic synapse. Taken together, in vivo findings yield evidence of presynaptic dysfunctions in Parkinson's disease with decreases in striatal dopamine synthesis, dopamine storage, dopamine release and dopamine transporter binding. In contrast, 'Parkinson plus' syndromes (multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies) are characterized by both pre- and postsynaptic deficiencies with reductions in striatal dopamine synthesis, dopamine storage, dopamine release, and dopamine transporter, as well as D, and D, receptor binding. In patients with Huntington's disease, postsynaptic dysfunctions with reductions of striatal D1 and D2 receptor binding have become apparent, whereas attention-deficit/ hyperactivity disorder is mainly characterized by presynaptic deficits with increases in dopamine transporter binding. Interestingly, findings are also consistent with respect to drug abuse: cocaine, amphetamine, methylphenidate, heroin, alcohol and nicotine invariably act via enhancement of dopamine release in dorsal and/ or ventral striatal regions. In vivo findings additionally suggest that not only D2 receptor binding but also the extent of dopamine release is lower in individuals with a history of drug abuse. Findings become inconsistent with increasing complexities of psychiatric conditions. As yet, there is no clear evidence as to the contributions of the individual presynaptic and postsynaptic constituents of the dopaminergic synapse to the pathophysiologies of schizophrenia and depression. As these diseases can be conceived as the result of a variety of dysfunctions and dysregulations within an intricate network of neurotransmitter systems, regional investigations of one single pre- or postsynaptic constituent may not reach far enough to disentagle the interrelationships between the constituents of one let alone a variety of neurotransmitter systems.

Synaptic dopamine is mainly regulated by presynaptic dopamine transporter (DAT) activity. We hypothesized that variations in synaptic dopamine are reflected by variations of DAT radioligand binding. The effect of haloperidol, which increases synaptic dopamine concentrations, was therefore assessed in the rat striatum using 123 I-N-v-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl)-nortropane ( 123 I-FP-CIT) as a DAT radioligand. Methods: Striatal 123 I-FP-CIT binding was measured in 24 rats under baseline conditions (no pretreatment) and at 1 h after injection of haloperidol or a vehicle (1 mg/kg) using a small-animal SPECT camera. Results: Baseline equilibrium ratios (V 3 $) were 1.32 6 0.24 (mean 6 SD). After the haloperidol injection, V 3 $ decreased to 0.99 6 0.38 (P 2-tailed , 0.0001), corresponding to a mean reduction of DAT binding by 25%. Conclusion: Our results are indicative of competition between the DAT ligand 123 I-FP-CIT and synaptic dopamine elevated by haloperidol, suggesting that the assessment of 123 I-FP-CIT binding may be suitable to study variations in synaptic dopamine in vivo.

Disturbances of dopaminergic neurotransmission may be caused by changes in concentrations of synaptic dopamine (DA) and/or availabilities of pre- and post-synaptic transporter and receptor binding sites. We present a series of experiments which focus on the regulatory mechanisms of the dopamin(DA)ergic synapse in the rat striatum. In these studies, DA transporter (DAT) and/or D(2) receptor binding were assessed with either small animal single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after pharmacological challenge with haloperidol, L-DOPA and methylphenidate, and after nigrostriatal 6-hydroxydopamine lesion. Investigations of DAT binding were performed with [(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([(123)I]FP-CIT). D(2) receptor bindingd was assessed with either [(123)I](S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([(123)I]IBZM) or [(18)F]1[3-(4'fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine ([(18)F]FMB). Findings demonstrate that in vivo investigations of transporter and/or receptor binding are feasible with small animal SPECT and PET. Therefore, tracers that are radiolabeled with isotopes of comparatively long half-lives such as (123)I may be employed. Our approach to quantify DAT and/or D(2) receptor binding at baseline and after pharmacological interventions inducing DAT blockade, D(2) receptor blockade, and increases or decreases of endogenous DA concentrations holds promise for the in vivo assessment of synaptic function. This pertains to animal models of diseases associated with pre- or postsynaptic DAergic deficiencies such as Parkinson's disease, Huntington's disease, attention-deficit/hyperactivity disorder, schizophrenia or drug abuse.

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.

This first in-vivo study of rat dopamine transporter binding after pre-treatment with various doses of methylphenidate showed a dose-dependent reduction of striatal dopamine transporter binding. Results indicate that in-vivo quantification of dopamine transporter binding is feasible with I-FP-CIT and the TierSPECT method. This may be of future relevance for investigating in-vivo binding properties as well as pharmacological profiles of novel agents acting at the dopamine transporter binding site. Moreover, alterations of striatal transporter densities may be investigated in animal models of neurological and psychiatric diseases such as attention-deficit/hyperactivity disorder and Parkinson's disease.