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.

Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure

“…Moreover, the upregulation of ΔFosB increases the MSN D1 DA receptors density, when the D1 DA like receptors activates by chronic MPD exposure, the CN units will respond to the drug by increasing their firing rates as seen in this study. The indirect CN pathway is regulated by inhibitory DA D2 receptors, activation of this receptor results in attenuation of its neuronal activity that results in an increase in enkephalin and an increase in cAMP production in the indirect pathway (Henry & White, 1995; Nikolaus et al 2011). Nikolaus et al (2011) used in vivo experiments to measure the level of D2 DA inhibitory receptors in the striatum of both baboons and rats and reported that there was a decrease in the amount of D2 DA receptors when animals were exposed to increasing doses of MPD.…”

“…The indirect CN pathway is regulated by inhibitory DA D2 receptors, activation of this receptor results in attenuation of its neuronal activity that results in an increase in enkephalin and an increase in cAMP production in the indirect pathway (Henry & White, 1995; Nikolaus et al 2011). Nikolaus et al (2011) used in vivo experiments to measure the level of D2 DA inhibitory receptors in the striatum of both baboons and rats and reported that there was a decrease in the amount of D2 DA receptors when animals were exposed to increasing doses of MPD. It is therefore postulated that electrodes recorded from units containing DA D1 like receptors will exhibit increased neuronal activity to MPD exposure, while electrodes that are recorded from CN units containing DA D2 like receptors will express attenuation in their firing rates to MPD exposure.…”

“…Several reports state that psychostimulant exposure in some animals elicits CREB upregulation, while the same drug and dose in other animals elicits ΔFosB upregulation (Alburges et al, 2011; Brandon and Steiner, 2003; Nikolaus et al, 2011; Yano and Steiner, 2005). Direct correlations between upregulation of ΔFosB or CREB as a result of repetitive psychostimulant exposure were reported to correlate with the behavioral responses such as behavioral sensitization or tolerance, respectively (Chao and Nestler, 2004; Kim et al, 2009; Nestler, 2004; 2008).…”

How Relevant Are Imaging Findings in Animal Models of Movement Disorders to Human Disease?

“…With a focus on understanding the pharmacological consequences of dopaminergic nigral degeneration on in vivo function of presynaptic and postsynaptic dopaminergic markers, and the compensatory changes associated with PD progression and severity, a large body of imaging work with PET and SPECT has been conducted in the 6-OHDA rat and the MPTP-lesioned monkey (for reviews, see [42,58]). In general, in vivo neurochemical reports in parkinsonian animals have paralleled human idiopathic disease findings (see review of clinical imaging findings [47]).…”

The emerging discipline of behavioral neuroimaging

“…Radiotracers with longer half-lives (hours) have the advantage that they can be produced off-site, but they are limited to mainly static scans. Nikolaus et al (2011) show in their review that longer-lived PET and SPECT tracers are suitable for pharmacological challenge and lesion studies that investigate the dopamine system. Schulz and Vaska (2011) discuss the RatCAP device, a miniature, wearable PET that was developed to allow whole-brain imaging of awake, behaving rats.…”