title: Pharmacological challenge and synaptic response - assessing dopaminergic function in the rat striatum with small animal single-photon emission computed tomography (SPECT) and positron emission tomography (PET).
abstract: 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.
authors: Clinic of Nuclear Medicine, University Hospital Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany.
authors: Susanne
authors: S
authors: Nikolaus
authors: Rolf
authors: R
authors: Larisch
authors: Henning
authors: H
authors: Vosberg
authors: Markus
authors: M
authors: Beu
authors: Andreas
authors: A
authors: Wirrwar
authors: Christina
authors: C
authors: Antke
authors: Konstantin
authors: K
authors: Kley
authors: Maria Angelica De Souza
authors: MA
authors: Silva
authors: Joseph P
authors: JP
authors: Huston
authors: Hans-Wilhelm
authors: HW
authors: Müller
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics; D001931:Brain Mapping; D003342:Corpus Striatum / Q000166:cytology / Q000000981:diagnostic imaging / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008698:Mesylates / Q000493:pharmacokinetics; D016627:Oxidopamine / Q000633:toxicity; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines / Q000493:pharmacokinetics; D051381:Rats; D013569:Synapses / Q000000981:diagnostic imaging* / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon; D014326:Tropanes / Q000493:pharmacokinetics
chemical_list: C110737:18F-fluoromethylbenzylsulfonate ester; D018663:Adrenergic Agents; D001549:Benzamides; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D008698:Mesylates; D011759:Pyrrolidines; D014326:Tropanes; C087552:2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide; D016627:Oxidopamine; D004298:Dopamine