PDE10A and PDE10A-dependent cAMP catabolism are dysregulated oppositely in striatum and nucleus accumbens after lesion of midbrain dopamine neurons in rat: A key step in parkinsonism physiopathology
Research highlights
► Dopamine loss up- or down-regulates PDE10A respectively in n. accumbens and striatum. ► cAMP is up-regulated in striatum but down-regulated in n. accumbens by dopamine loss. ► cGMP is down-regulated both in the striatum and n. accumbens by dopamine loss. ► PDE10A up- and down-regulation parallels cAMP but not cGMP altered by dopamine loss.
Introduction
The physiological actions of dopamine in nigro-striatal neurotransmission are generally well known, however, the adaptive responses of the striatal neurons secondary to a dopamine loss, such as in Parkinson's disease, are still partly understood.
According to the stimulatory interactions of dopamine with D1 receptors and the synthesis of adenosine 3′, 5′-cyclic monophosphate (cAMP) by adenylate cyclases (Garau et al., 1978, Kebabian, 1978), a deficit of dopamine in the striatum should imply a reduced stimulation of D1 receptor and hence a reduction in the synthesis of the cAMP. Unexpectedly, experimental lesions of the nigro-striatal dopaminergic projections with 6-hydroxydopamine (6-OHDA) induce an increase in cAMP levels after several weeks, as evidenced by increased basal adenylate cyclase activity in dopamine-denervated rat striata (Hossain and Weiner, 1993, Tenn and Niles, 1997). Unlike cAMP, guanosine 3′,5′-cyclic monophosphate (cGMP) levels decrease in response to dopamine loss. Such decrease in cGMP loss is associated with decreased nitric oxide synthase expression and activity, probably leading to a down-regulation of the nitric oxide–guanylate cyclase pathway (Sancesario et al., 2004).
The intracellular levels of cAMP and cGMP, are controlled by their rate of synthesis via adenylate and guanylate cyclase respectively (for a review see Cooper, 2003, Koesling et al., 1991, Wedel and Garbers, 2001), and by their rate of degradation via 3′,5′-cyclic nucleotide phosphodiesterases (PDE), a group of enzymes that hydrolyze cAMP and cGMP to their inactive 5′-derivatives (Beavo, 1995, Zhao et al., 1997). Indeed, dopamine loss has been associated with increased expression and activity of phodiesterase 1B (PDE1B) (Sancesario et al., 2004), a calcium/calmodulin dependent phodiesterase, highly localized in the caudate–putamen and nucleus accumbens, which hydrolyzes both cAMP and cGMP substrates, with higher specificity for the latter (Km value of 24 versus 2.7 μM) (Polli and Kincaid, 1994, Zhao et al., 1997). These data suggest that the down-regulation of the cGMP steady state in dopamine-denervated rat striata may be affected by long-term changes in the processes of synthesis as well as catabolism (Sancesario et al., 2004). Furthermore, the data raise the question that a differentiated process of PDE-dependent catabolism may involve an increase in cAMP levels after dopamine loss.
PDE isozymes have been classified into 11 families according to structural characteristics, substrate and inhibitor profiles (Soderling and Beavo, 2000). Aside from PDE1B, a dual-substrate phosphodiesterase gene family PDE10A has been selectively identified in the basal ganglia, which is calcium/calmodulin independent with a higher hydrolyzing activity for cAMP (Km 0.05 μM) than for cGMP (Km 3 μM) (Soderling et al., 1998, Soderling et al., 1999, Fujishige et al., 1999a, Fujishige et al., 1999b, Siuciak et al., 2006a). In addition, the PDE10A isozyme has a unique distribution in the basal ganglia, with medium spiny neurons (MSNs) in the striatum, MSN axons/terminals in the substantia nigra reticulata and external globus pallidus, and with the neuronal bodies in the nucleus accumbens (Seeger et al., 2003, Xie et al., 2006). In addition, papaverine, which aggravates all the signs and symptoms of Parkinson's disease (Duvoisin, 1975), has recently been identified as a potent, specific inhibitor of PDE10A (Siuciak et al., 2006b).
In the present study we sought to determine whether unilateral lesions of dopaminergic neurons in the rat midbrain affect PDE10A expression and related cyclic nucleotide catabolism in the basal ganglia. Moreover, we used papaverine as an inhibitor to ascertain the contribution of PDE10A to total cAMP–PDE activity in lesioned and contralateral hemisphere.
Section snippets
Materials and methods
We used young male Sprague–Dawley rats (Harlan, Milan, Italy) that weighed 175–220 g at the start of the study. The animals were housed in stainless steel cages (two per cage), and had free access to food (standardized pellet diet; Morini, Bologna, Italy) and water. The animal room was maintained at 21–23 °C under a 12-h light/dark cycle. The experimental protocols conformed to the guidelines of the European Union Council (86/609/EU) and were approved by the Institutional Animal Care and Use
Midbrain dopaminergic lesion
The effect of unilateral lesion of the dopaminergic neurons induced by 6-OHDA was assessed by immunohistochemical and biochemical techniques. In the unlesioned hemisphere TH immunohistochemistry intensely stained neuronal bodies and dendrites in substantia nigra and the ventral tegmental area, a very compact plexus of nerve fibers in the caudate–putamen and nucleus accumbens, and bundles of nerve fibers in the globus pallidus (Figs. 1A–C). After unilateral injection of 6-OHDA into the medial
Discussion
Anatomical, biochemical and pharmacological evidences demonstrate that dopamine loss causes complex changes in PDE10A and likely in other unidentified phosphodiesterase isozymes, affecting the cAMP and cGMP steady states in basal ganglia nuclei ipsilateral to 6-OHDA lesion. The possible occurrence of physiological compensatory changes of PDE10A expression in the hemisphere contralateral to dopamine loss was considered in this study and was ruled out after comparison with sham-operated animals.
Conclusion
Our study suggests for the first time that dopamine can affect PDE10A gene expression, and preferentially modulate cAMP catabolism in vivo. After dopamine loss, a down-regulation of PDE10A takes place in the caudate–putamen and in striato-nigral and striato-pallidal projections, which appears to involve: a) an up-regulation of cAMP signaling in caudate–putamen neurons and likely in their projection terminals to the globus pallidus and substantia nigra; b) a functional imbalance toward a
Conflict of interest
None declared.
Acknowledgment
This work was supported by a grant from MIUR2007/3 F M X 85.
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G.M. and M.G. contributed equally to this paper.