l-DOPA Treatment Modulates Nicotinic Receptors in Monkey Striatum

Abstract

Nicotinic acetylcholine receptor (nAChR) activation is well known to stimulate dopamine release in the striatum. This phenomenon may be physiologically significant in the control of motor function, as well as in pathological conditions such as Parkinson's disease. An understanding of the mechanisms that influence nAChR expression and function is therefore important. Because the dopamine precursor L-DOPA is the most commonly used therapeutic agent for Parkinson's disease, we investigated the effects of L-DOPA treatment on striatal nAChR expression in unlesioned and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In unlesioned animals, L-DOPA (15 mg/kg) administered twice daily for 2 weeks decreased both 125 Parkinson's disease is a movement disorder characterized by a selective loss of nigrostriatal dopaminergic neurons, with marked declines in dopamine levels in the striatum. Knowledge of these neurochemical deficits led to the therapeutic use of the dopamine precursor L-DOPA, which is currently one of the principal agents used for Parkinson's disease therapy (Bezard et al., 2001).A variety of neurotransmitter systems regulate striatal dopaminergic function, including glutamatergic inputs from the cortex (Roberts and Anderson, 1979;Desce et al., 1991) and possibly serotonergic afferents from the raphe nuclei (Barnes and Sharp, 1999). Acetylcholine released from cholinergic interneurons is also an important modulating factor through activation of nAChRs (Zhou et al., 2001). Mammalian neuronal nAChRs are heterogeneous and seem to be composed of multiple ␣ (␣2-␣7) and ␤ (␤2-␤4) subunits (Lukas et al., 1999). To date, several subtypes have been linked to striatal dopaminergic function, including nAChRs containing ␣4, ␣6, and ␤3 subunits in combination with ␤2 (Wonnacott, 1997; Quik et al., 2000;Grady et al., 2001;Champtiaux et al., 2002;Whiteaker et al., 2002;Zoli et al., 2002).Because nAChRs influence striatal dopaminergic activity, knowledge of the conditions that affect the different nAChR subtypes is critical. Studies to date have shown that nigrostriatal damage decreases striatal nAChR densities in mice, rats, monkeys, and humans, with a particular vulnerability of the 125 I-␣-CtxMII-binding population, thought to correspond to ␣6* 1 nAChRs (Schwartz et al., 1984;Clarke and Pert, 1985;Court et al., 2000;Quik et al., 2001;Zoli et al., 2002;Quik et al., 2003). Cholinergic pharmacological treat- 1 The asterisk denotes nicotinic receptors containing the indicated ␣ and/or ␤ subunit and possibly also additional undefined subunits.

Partial Recovery of Striatal Nicotinic Receptors in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Lesioned Monkeys with Chronic Oral Nicotine

“…These differential effects of nicotine treatment on ␣4␤2* and ␣3/␣6␤2* nAChR subtypes are consistent with previous results (McCallum et al, 2006). In addition, we had previously reported a differential regulation of ␣3/␣6␤2* subtypes after L-DOPA administration (Quik et al, 2003). The subunit composition of these different ␣3/␣6␤2* receptor subtypes is currently not known, although they may represent ␣3␤2* and/or ␣6␤2* nAChR subtypes also expressing ␣2, ␣4, and/or ␤3 subunits, all of which are present in monkey striatum .…”

Nicotinic receptors as CNS targets for Parkinson's disease

“…Previous rodents studies have shown that mouse striatum expresses two α6β2* nAChR subtypes, those containing the α6α4β2β3 and α6β2β3 subunits [63,79]. Similarly, our studies in monkeys suggest the presence of at least two striatal α6β2* nAChRs [87,112]. In a continued effort to more precisely determine the subunit composition of these receptors, experiments were recently performed with α-conotoxinMII analogs to determine whether these might discriminate between α6β2* subtypes.…”

Long-Term Nicotine Treatment Differentially Regulates Striatal α6α4β2*and α6(Nonα4)β2*nAChR Expression and Function

“…All ␣6␤2* nAChRs seem to be present on dopaminergic nerve terminals because they decline in parallel with dopaminergic measures after nigrostriatal damage (Quik et al, 2001;Quik et al, 2003). However, the ␣6␣4␤2* subtype is preferentially lost with moderate nigrostriatal damage, whereas the ␣6(non␣4)␤2* subtype is decreased only with more severe dopaminergic damage, suggesting that the two ␣6␤2* nAChR subtypes are present on different subsets of dopaminergic neurons .…”