Dopamine D2 receptor mediated presynaptic inhibition of striatopallidal GABAA IPSCs in vitro
Introduction
Parkinson's disease results from a degeneration of dopamine neurones within the substantia nigra pars compacta. As these neurones constitute the major nigro-striatal projection it is commonly thought that alterations in the activity of neurones in other basal ganglia (BG) nuclei occur indirectly as a result of dopamine depletion in the striatum. Thus, in Parkinson's disease, the established model of BG circuitry (Alexander and Crutcher, 1990) predicts an increase in activity of the striatopallidal pathway leading to an inhibition of neuronal activity within the external segment of the globus pallidus (GP). However, in animal models of the disease, electrophysiological studies indicate that the GABA neurones of the GP shows a greater propensity to burst fire with increased synchronisation (Filion and Tremblay, 1991, Nini et al., 1995, Bergman et al., 1998), the frequency of which has been correlated with muscle tremor (Bergman et al., 1998). This re-patterning of GP activity, as a consequence of the loss of dopamine may, in part, be due to changes in GABA-mediated inhibition within the GP.
Although dopamine innervation of the GP is scarce (Lindvall and Björklund, 1979, Lavoie et al., 1989), intra-cranial injection of dopamine and dopamine agonists in the GP appear to reduce the effectiveness of applied GABA (Bergstrom and Walters, 1984). In addition, applied dopamine increases GP cell firing by the attenuation of iontophoretically applied GABA or striatal stimulation in vitro (Nakanishi et al., 1985). Systemic dopamine administration also mimicked direct dopamine GP application by increasing the activity of GP neurones (Bergstrom et al., 1982, Carlson et al., 1990), although in these studies, actions of dopamine in other nuclei cannot be discounted.
Five subtypes of dopamine receptor have been identified, which fall into distinct groups on the basis of their pharmacology and biochemical coupling mechanisms (see Missale et al., 1998 for review). ‘D1 like’ (D1 and D5) receptors are positively coupled to adenylate cyclase while ‘D2 like’ (D2, D3, D4) receptors are negatively coupled to adenylate cyclase (Stoof and Kebabian, 1981, Schwartz et al., 1992).
There is autoradiographic and immunohistochemical evidence for ‘D1 like’ receptors in the GP (Dawson et al., 1986, Savasta et al., 1986). Indeed, ‘D1 like’ receptor activation has previously been linked with increases in GABA release (Floran et al., 1990). However, there is no evidence for D1 receptor mRNA (Mengod et al., 1991, Mansour et al., 1992) indicating that D1 receptors in the GP are most likely to be located on presynaptic terminals of extrinsic origin.
In contrast, mRNA for ‘D2 like’ receptors has been found in the GP (Meador-Woodruff and Mansour, 1991) and in abundance in striatopallidal cells (Gerfen et al., 1990, Meador-Woodruff and Mansour, 1991). Thus, ‘D2 like’ receptors may well be present at the level of GP somata or on the presynaptic terminals of pallidopallidal collaterals or striatopallidal fibres. Indeed, release studies have indicated ‘D2 like’ receptor inhibition of GABA release in the GP (Floran et al., 1997). More recently, immunolocalisation of dopamine D4 receptors within the lateral GP (analogous to the rodent GP; Mrzljak et al., 1996) and rat GP (Ariano et al., 1997) has been readily detected. In contrast, evidence for dopamine D3 receptors is scant with only very low levels of receptor binding in the primate GP (Hurley et al., 1996) and a lack of extensive D3 receptor binding in the GP of rats (Landwehrmeyer et al., 1993, Kahn et al., 1998).
Therefore dopamine may alter GABA release in the GP by action at presynaptic ‘D1 like’ or pre and postsynaptic ‘D2 like’ receptors. We sort to clarify these issues using whole-cell patch clamp recordings from visually identified single GP neurones in an in vitro slice preparation.
Some of these results have been reported in abstract form (Cooper and Stanford, 2000a).
Section snippets
Slice preparation
Whole-cell patch clamp recordings were made from single GP neurones within 300 μm thick slices obtained from 80–120 g male Wistar rats. Animals were first anaesthetised with fluorothane and sacrificed by cervical dislocation in accordance with Animals (Scientific Procedures) Act, 1986, UK. The brain was quickly removed and placed in ice cold artificial cerebral spinal fluid (aCSF) containing (in mM) choline chloride 126, KCl 2.5, NaH2PO4 1.2, MgCl2 1.3, MgSO4 8, glucose 10, buffered to pH 7.4
Neuronal heterogeneity in the GP
Our previous studies have indicated that GP neurones are a heterogeneous population comprising of at least three types of neurone (Cooper and Stanford, 2000b) in agreement with previous reports (Kita and Kitai, 1991, Nambu and Llinás, 1994, Nambu and Llinas, 1997). However, there appeared to be no differences in the effects of applied dopamine, agonists or antagonists, between the various cell types. Therefore, all data from the different GP neuronal phenotypes have been pooled.
Evoked GABAA receptor IPSCs
Single shock
Presynaptic effects of dopamine
Selective stimulation of striatopallidal projections, which are well maintained in sagittal sections (Wilson and Phelan, 1982), evoked GABAA IPSCs, which were significantly reduced by applied dopamine. This action of dopamine was shown to have a presynaptic locus, as upon dopamine application there was an increase in the paired pulse ratio and a decrease in the frequency of mIPSCs, with no change in amplitude. Dopamine was without effect on postsynaptic membrane conductance, potential or
Conclusions
This study provides further evidence for the action of dopamine in BG nuclei other than the striatum and direct evidence for its action in the GP. However, the effects in GP appear confined to the modulation of striatal inputs. Thus, during dopamine depletion, one would expect the D2 receptor-mediated inhibition of striatopallidal GABA release to be relieved leading to an overall decrease in GP neuronal activity as previously observed (Filion and Tremblay, 1991, Bergman et al., 1994). This
Acknowledgments
We are grateful to Dr M.G. Lacey for valuable discussion and critical appraisal of this manuscript. I.M.S. is a Wellcome Career Development Research Fellow.
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