In vivo imaging of disturbed pre- and post-synaptic dopaminergic signaling via arachidonic acid in a rat model of Parkinson's disease

Abstract

Parkinson's disease involves loss of dopamine (DA)-producing neurons in the substantia nigra, associated with fewer pre-synaptic DA transporters (DATs) but more post-synaptic dopaminergic D 2 receptors in terminal areas of these neurons.Hypothesis-Arachidonic acid (AA) signaling via post-synaptic D 2 receptors coupled to cytosolic phospholipase A 2 (cPLA 2 ) will be reduced in terminal areas ipsilateral to a chronic unilateral substantia nigra lesion in rats given D-amphetamine, which reverses the direction of the DAT, but will be increased in rats given quinpirole, a D 2 -receptor agonist.Methods-D-amphetamine (5.0 mg/kg i.p.), quinpirole (1.0 mg/kg i.v.), or saline was administered to unanesthetized rats having a chronic unilateral lesion of the substantia nigra. AA incorporation coefficients, k* (radioactivity/integrated plasma radioactivity), markers of AA signaling, were measured using quantitative autoradiography in 62 bilateral brain regions following intravenous [1-14 C]AA.Results-In rats given saline (baseline), k* was elevated in 13 regions in the lesioned compared with intact hemisphere. Quinpirole increased k* in frontal cortical and basal ganglia regions bilaterally, more so in the lesioned than intact hemisphere. D-amphetamine increased k* bilaterally but less so in the lesioned hemisphere.Conclusions-Increased baseline elevations of k* and increased responsiveness to quinpirole in the lesioned hemisphere are consistent with their higher D 2 -receptor and cPLA 2 activity levels, whereas reduced responsiveness to D-amphetamine is consistent with dropout of pre-synaptic elements containing the DAT. In vivo imaging of AA signaling using dopaminergic drugs can identify pre-and post-synaptic DA changes in animal models of Parkinson's disease.

Imaging brain signal transduction and metabolism via arachidonic and docosahexaenoic acid in animals and humans

“…In addition, large increases in k* for AA in brain regions containing appropriate receptors have been observed in rodents administered the muscarinic M 1,3,5 receptor agonist arecoline (Basselin et al, 2003; Basselin et al, 2006c; Basselin et al, 2007b; DeGeorge et al, 1991; Nariai et al, 1991), the dopaminergic D 2 -like receptor agonist quinpirole (Basselin et al, 2005a; Bhattacharjee et al, 2005; Bhattacharjee et al, 2007; Bhattacharjee et al, 2008b; Hayakawa et al, 2001), the D 1 /D 2 agonist apomorphine (Bhattacharjee et al, 2008b), the serotonergic 5-HT 2A/2C agonist (+/−)2,5-dimethoxy-4-iodophenyl-2-amino propane (DOI) (Basselin et al, 2005a; Basselin et al, 2009a; Qu et al, 2005; Qu et al, 2006) or NMDA (Basselin et al, 2006a; Basselin et al, 2007a; Basselin et al, 2008a; Ramadan et al, 2011a). On the other hand, few reductions, increases, or no changes in rCMRglc were produced by the same agonists (Basselin et al, 2006b; Browne et al, 1998; Freo et al, 1991; Soncrant et al, 1985), demonstrating independence of the two measures.…”

“…Quinpirole increased k * in frontal cortical and basal ganglia regions bilaterally, more so on the lesioned than intact hemisphere (its effects could be prevented by the dopamine receptor antagonist butaclamol). D-amphetamine increased k * bilaterally but less so on the lesioned hemisphere (Bhattacharjee et al, 2007). The increased baseline elevations of k * and increased responsiveness to quinpirole in the lesioned hemisphere are consistent with their higher D 2 -receptor (Ichise et al, 1999), COX-2 protein and cPLA 2 activity and protein levels (Lee et al, 2010), whereas the reduced responsiveness to D-amphetamine is consistent with dropout of presynaptic elements containing the DAT (Ribeiro et al, 2002).…”

“…), or saline was administered to unanesthetized rats having a chronic unilateral lesion caused by injecting the selective monoaminergic toxin, 6-hydroxydopamine (6-OHDA), into one substantia nigra. In rats given saline, baseline k * was elevated in many regions on the lesioned compared with intact hemisphere (Bhattacharjee et al, 2007; Hayakawa et al, 1998; Hayakawa et al, 2001). Quinpirole increased k * in frontal cortical and basal ganglia regions bilaterally, more so on the lesioned than intact hemisphere (its effects could be prevented by the dopamine receptor antagonist butaclamol).…”

“…The [1- 11 C]AA PET method thus may be useful for studying disturbances of dopaminergic neurotransmission in conditions such as BD, schizophrenia and Parkinson’s disease. Indeed, hyperdopaminergic signaling and an upregulated brain AA cascade are suggested to be involved in the pathophysiology of these diseases (Berk et al, 2007; Bhattacharjee et al, 2007; Cousins et al, 2009; Hayakawa et al, 2001; Kim et al, 2011b; Lee et al, 2010; Mattammal et al, 1995; Rao et al, 2012; Ross et al, 2001). …”

iPLA2β Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology

“…On the other hand, presynaptic DAT protein is reduced in Parkinson disease [46], and following ablation of the substantia nigra in rodent models of Parkinson disease [47]. Thus, at 15–20 months, the model does not have all the classical features of Parkinson disease.…”