Introduction

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PD is primarily a disorder of extrapyramidal motor function caused by a severe DA deficiency in the basal ganglia (Lloyd et al., 1975). Administration of L-DOPA, a precursor of DA that increases striatal DA levels, is currently the most effective treatment of PD (Coleman, 1992). However, despite the successful use of L-DOPA as a therapy for PD, there are caveats to its utilization. For instance, L-DOPA provides only symptomatic relief, failing to stop disease progression. Furthermore, prolonged L-DOPA treatment is often associated with response fluctuations ranging from ineffectiveness to hyperkinesia (the "on-off" effect), dyskinesia, and the development of psychosis. These limitations of L-DOPA have led to the search for alternative treatments to replace L-DOPA or to potentiate the therapeutic benefits of L-DOPA.

Epidemiological studies have shown that smokers have approximately half the risk of being diagnosed with PD than nonsmokers (for review see Baron, 1986; Morens et al., 1995). Nicotine may be partly responsible for this lowered occurrence of idiopathic PD (Morens et al., 1995). A similar trend is seen with respect to neuroleptic-induced Parkinsonism in smokers (Decina et al., 1990). Studies in vitro (Akaike et al., 1994; Bouchenafa et al., 1995; Hu et al., 1995; Marin et al., 1994) and in vivo (Janson et al., 1992; Janson and Moller, 1993; Prasad et al., 1994; Vaglini et al., 1994; Sershen et al., 1988) have shown that nicotine may protect cortical and nigrostriatal neurons from neurodegeneration. Moreover, nicotine induces the release of dopamine from rat striatum (Sacaan et al., 1995; Arqueros et al., 1978; Giorguieff-Chesselet et al., 1979; Blaha and Winn, 1993), suggesting that, in addition to preventing neurodegeneration, nicotine may have potential in the symptomatic treatment of PD by enhancing dopaminergic function. Indeed, nicotine administration has been reported to alleviate some symptoms of Parkinson's disease, such as tremor, bradykinesia, rigidity and lack of energy (Moll, 1926; Marshall and Schnieden, 1966; Fagerstrom et al., 1994; Ishikawa and Miyatake, 1993).

Nicotine itself, however, has limited use in treating PD because of its gastrointestinal (e.g., nausea, abdominal pain) and cardiovascular (e.g., tachychardia, peripheral vasoconstriction and hypertension) side effects (Benowitz, 1986). The undesirable widespread effects of nicotine may be due to a lack of specificity for central vs. peripheral neuronal NAChR subtypes. Therefore, NAChR subtype-selective compounds that induce the release of DA in vivo may be of greater therapeutic value in the symptomatic treatment of the motor deficits of PD.

The novel NAChR agonist [±]-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate (SIB-1765F) displaces [³H]-cytisine binding to rat cortical membranes with a high affinity and has a lower affinity than nicotine at muscarinic cholinergic and -bungarotoxin binding sites (Lloyd et al., 1995, Sacaan et al., accompanying paper). SIB-1765F has also been shown to be moderately more effective than nicotine in stimulating [³H]-DA release from rat striatal and olfactory tubercle slices (Rao et al., 1995; Sacaan et al., accompanying paper) and produces a significant release of [³H]-NE from rat thalamic and cortical slices in vitro. In contrast to nicotine, SIB-1765F only weakly stimulates [³H]-NE release from rat hippocampal slices. The NAChR subtypes responsible for modulating DA and NE release are different (Sacaan et al., 1995), suggesting that SIB-1765F may preferentially activate specific neuronal NAChR subtypes as compared to nicotine (Rao et al., 1995; Sacaan et al., accompanying paper).

A preliminary report indicated that acute s.c. administration of SIB-1765F increases ipsilateral turning in unilaterally 6-OHDA-lesioned rats, implying in vivo presynaptic activation of the intact nigrostriatal dopaminergic terminals (Lloyd et al., 1995; Cosford et al., 1996). This effect of SIB-1765F is blocked by the noncompetitive NAChR antagonist mecamylamine but not by the peripherally active NAChR antagonist hexamethonium, indicating that SIB-1765F releases striatal DA predominantly through the activation of central NAChR. SIB-1765F is more efficacious and longer acting than nicotine, and thus may have potential use in the symptomatic treatment of PD (Menzaghi et al., 1995, accompanying paper).

In this study, we show that SIB-1765F attenuates the hypolocomotion induced by reserpine in rats and potentiates the action of L-DOPA in this model. Reserpine interferes with the storage of monoamines in intracellular granules, which results in the depletion of monoamines in nerve terminals (Carlsson, 1975a) and the induction of transient hypolocomotion and muscular rigidity, thus providing a pharmacological model of Parkinsonism (Colpaert, 1987). Compounds that release dopamine from vesicular stores are less active in the reserpine model than in normal rats, reflecting the decreased availability of DA, whereas compounds that release dopamine from cytoplasmic stores maintain a strong activity in the reserpine model. In this manner, the reserpine model provides an indication of the mechanism of action of a test compound and reflects some aspects of the DA depletion that occurs in PD. To date, all clinically used anti-parkinsonian drugs such as amantadine, trihexiphenidyl, L-DOPA and DA receptor agonists have been shown to ameliorate motor deficits in this model.

In our study, SIB-1765F was administered alone or in combination with L-DOPA and its effects on reserpine-induced hypolocomotion were compared to those of nicotine, d-amphetamine (a catecholamine releasing agent) and amantadine (an antiviral agent used in the symptomatic treatment of PD). The mechanism(s) of action of SIB-1765F was evaluated by measurement of striatal and olfactory tubercle levels of DA and its metabolites and by administration of the tyrosine hydroxylase inhibitor AMPT.

	Materials and Methods

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Animals. Male Sprague-Dawley rats (200-350 g) (Harlan, San Diego, CA) were housed four per cage and maintained in a humidity- (50-55%) and temperature- (22-24°C) controlled facility on a 12 hr:12 hr light/dark cycle (lights on at 6:30 A.M.) with free access to food (Harlan-Teklad Western Res., Orange, CA, 4% rat diet 7001) and water. Rats were allowed a 1-wk period of habituation to the animal room before testing. The animals were handled once during this period.

Compounds. The following compounds were used: amantadine HCl [Research Biochemicals International (RBI), Natick, MA], d-amphetamine sulfate (RBI), benserazide HCl (Sigma Chemical Co., St. Louis, MO), L-DOPA (Sigma), AMPT (Sigma), (-)-nicotine hydrogen tartrate (Sigma), reserpine (Sigma) and SIB-1765F (SIBIA). SIB-1765F was synthesized by the Medicinal Chemistry Department of SIBIA Neurosciences Inc. (Cosford et al., 1996). Reserpine was dissolved in 50 µl of glacial acetic acid and distilled water. L-DOPA was suspended in 1% Tween 80 and 0.5% methylcellulose solution. Amantadine, d-amphetamine, benserazide and AMPT were dissolved in saline. Nicotine and SIB-1765F were dissolved in saline and the pH was adjusted to 7.0 by the addition of 10 N-NaOH solution. Nicotine and d-amphetamine doses are expressed in terms of their free base concentrations. Reserpine was administered i.v. into the lateral tail vein in a volume of 1 ml/kg. Amantadine, d-amphetamine, nicotine and SIB-1765F were administered s.c. into the dorsal neck region in a volume of 1 ml/kg. L-DOPA and benserazide were administered i.p. in the lower right quadrant of the abdomen in volumes of 4 and 1 ml/kg, respectively. Corresponding volumes of vehicle solutions served as controls.

Locomotor activity. Locomotor activity was assessed in photocell activity cages (San Diego Instruments, San Diego, CA). Each cage consisted of a standard plastic rodent cage (24 × 45.5 cm) surrounded by a stainless steel frame. Four infrared photocell beams were located across the long axis of the frame, raised 3.2 cm above the floor and spaced 9 cm apart. The numbers of photocell interruptions and crossovers (interruption of one photocell followed immediately by the interruption of an adjacent photocell) were recorded by a computer system during consecutive 5-min intervals.

Analysis of DA and its metabolites by high pressure liquid chromatography-electrochemical detection. Twenty-four hours after the administration of reserpine or vehicle, rats were treated with d-amphetamine (1 mg/kg), L-DOPA (200 mg/kg + benserazide, 50 mg/kg, 15 min before L-DOPA), amantadine (100 mg/kg), SIB-1765F (40 mg/kg) or vehicle. The animals were killed by decapitation 60 min after the administration of the compounds and the brains were rapidly removed. The striatum and olfactory tubercles were dissected and frozen at 70°C until assayed. Levels of DA and its metabolites were quantified by high pressure liquid chromatography-electrochemical detection techniques as described elsewhere (Rao et al., 1996). The acid-precipitated proteins were solubilized in sodium hydroxide (0.5 N, 5 ml) and protein levels were measured by the bicinchoninic acid (BCA, Pierce Chemicals, Rockford, IL) procedure using bovine serum albumin as a reference standard (Smith et al., 1985).

Statistics. The effects of compounds alone on the locomotor activity of reserpinized rats were analyzed by ANOVA followed by Dunnett's test for post hoc comparison with the control group (SigmaStat Software, Jandel, San Rafael, CA). The effects of test compounds in combination with L-DOPA were analyzed by two-way ANOVA followed by Newman-Keul's test for post hoc pair-wise comparison if a significant interaction existed. The statistical analyses were performed separately for the two doses of L-DOPA to prevent masking of an interaction if opposite effects occurred at the two doses used. Levels of DA and its metabolites were analyzed by one-way ANOVA followed by Dunnett's test for post hoc comparison. P < .05 was accepted as significant.

	Results

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Effects of NAChR agonists and reference compounds on reserpine-induced hypolocomotion in rats. Consistent with previous reports (Skuza et al., 1994; Klockgether and Turski, 1990), reserpine produced a significant reduction in motor activity as measured by a decrease in the number of photocell interruptions over a period of 180 min (saline: 396.8 ± 66.9, reserpine: 92.0 ± 16.3; P < .0008 Student's t test; data not shown). As shown in figure 1, L-DOPA (plus benserazide) reversed reserpine-induced hypolocomotion [F(3,25) = 20.6; P < .0001] in a dose-dependent manner, with 200 mg/kg being the most efficacious dose tested. Reserpine-induced hypolocomotion was also reversed by amantadine [F(4,34) = 67.7; P < .0001] at doses of 40 and 100 mg/kg, and by d-amphetamine [F(3,25) = 17.7; P < .0001] at doses ranging from 0.5 to 5.0 mg/kg, s.c. (fig. 1).

View larger version (22K): [in this window] [in a new window]   Fig. 1.   Effects of d-amphetamine, L-DOPA, amantadine, nicotine and SIB-1765F on locomotor activity in rats pretreated with reserpine (1 mg/kg, i.v. 24 hr before the experiment). Benserazide (50 mg/kg, i.p.) was administered 15 min before L-DOPA. Data are presented as total photocell interruptions taken over a 180-min period after the administration of compounds (mean ± S.E.M., n = 6-10/group). *P < .05 vs. respective control (0), Dunnett's test.

View larger version (19K): [in this window] [in a new window]   Fig. 2.   Effect of -methyl-p-tyrosine (AMPT) on d-amphetamine-induced locomotor activity in reserpine-treated rats. AMPT (250 mg/kg, i.p.) was administered 3 hr before the administration of d-amphetamine (1 mg/kg, s.c.). Reserpine (1 mg/kg, i.v.) was given 21 hr before AMPT injection. Data are presented as total photocell interruptions (A) and total number of crossovers (B) taken over a 180-min period after the administration of d-amphetamine (mean ± S.E.M., n = 7-8/group). *P < .05 vs. vehicle/vehicle, #P < .05 vs. vehicle/d-amphetamine, Newman-Keul's test).

View larger version (22K): [in this window] [in a new window]   Fig. 3.   Effect of AMPT on SIB-1765F-induced locomotor activity in reserpine-treated rats. AMPT (250 mg/kg, i.p.) was administered 3 hr before the administration of SIB-1765F (40 mg/kg, s.c.). Reserpine (1 mg/kg, i.v.) was given 21 hr before AMPT injection. Data are presented as total photocell interruptions (A) and total number of crossovers (B) taken over a 180-min period after the administration of SIB-1765F (mean ± S.E.M., n = 7-8/group). *P < .05 vs. vehicle/vehicle, #P < .05 vs. vehicle/SIB-1765F, Newman Keul's test.

Effects of NAChR agonists and amantadine on L-DOPA-induced locomotion in reserpine-treated rats. To determine whether SIB-1765F potentiates the stimulant locomotor effect of L-DOPA in reserpine-treated rats, an ineffective (50 mg/kg) and an effective dose (100 mg/kg) of L-DOPA were combined with two doses (20 and 40 mg/kg) of SIB-1765F. Both doses of SIB-1765F increased locomotor activity when coadministered with an ineffective dose of L-DOPA [interaction SIB-1765F × L-DOPA: F(2,47) = 3.45, P = .04] (fig. 4A). The combination of L-DOPA (50 mg/kg) and SIB-1765F (40 mg/kg) resulted in a significant greater locomotor stimulant effect than that produced by either treatment alone. Similarly, SIB-1765F potentiated an effective dose of L-DOPA [interaction SIB-1765F × L-DOPA: F(2,50) = 8.06, P = .0009] with 20 mg/kg the most effective dose tested. In contrast, neither nicotine (0.3 and 0.4 mg/kg) nor amantadine (20 and 40 mg/kg) altered the effect of L-DOPA (50 and 100 mg/kg) on overall locomotor activity in reserpinized rats (fig. 4, B and C). However, analysis of the time course of effect of amantadine in combination with a 100-mg/kg dose of L-DOPA showed that, although amantadine had no effect on the L-DOPA-induced increase in photocell interruptions, it potentiated the effect of L-DOPA on crossovers over time [amantadine × time: F(23, 483) = 1.70, P < .004] (fig. 5C). Post hoc analysis indicated that amantadine at a 40-mg/kg dose significantly increased the number of crossovers starting at 105 min after injection as compared to L-DOPA alone (fig. 5C). In contrast, potentiation of the effect of L-DOPA by SIB-1765F occurred rapidly (<5 min) and lasted for approximately 100 min. This rapid potentiation of the effect of L-DOPA by SIB-1765F was observed whether crossovers or photocell interruptions were used as the dependent measure. Nicotine did not significantly modify the effect of L-DOPA over time (fig. 5, A and B).

View larger version (19K): [in this window] [in a new window]   Fig. 4.   Dose-related effects of s.c. administration of (A) SIB-1765F, (B) nicotine and (C) amantadine in combination with L-DOPA on locomotor activity in rats pretreated with reserpine (1 mg/kg, i.v. 24 hr before the experiment). Benserazide (50 mg/kg, i.p.) was administered 15 min before L-DOPA (50 and 100 mg/kg, i.p.). The test compounds were administered 30 min after L-DOPA. Data are presented as total photocell interruptions taken over a 120-min period after the administration of the test compounds (mean ± S.E.M., n = 8/group). *P < .05 vs. respective control, Newman Keul's test.

View larger version (34K): [in this window] [in a new window]   Fig. 5.   Time course of action of (A) SIB-1765F, (B) nicotine and (C) amantadine in combination with L-DOPA (100 mg/kg, i.p.) on locomotor activity in rats pretreated with reserpine (1 mg/kg, i.v. 24 hr before the experiment). Benserazide (50 mg/kg, i.p.) was administered 15 min before L-DOPA. The test compounds were administered 30 min after L-DOPA. Data are presented as average of photocell interruptions and crossovers taken at each 5-min interval over a period of 120 min after the administration of the compounds (n = 8/group). S.E.M. were not shown for the clarity of the graphs.

Effects of NAChR agonists and reference compounds on levels of DA and its metabolites in the striatum and olfactory tubercles of reserpine-treated rats. To further characterize the mechanism(s) of action of SIB-1765F, the effects of SIB-1765F on the levels of DA and its metabolites were measured in the striatum and olfactory tubercles of reserpine-treated rats and compared to the effects of L-DOPA, amantadine, amphetamine and nicotine. In time course experiments, reserpine injection resulted in a long lasting decrease in tissue DA levels. DA levels tended to return to pretreatment levels after 72 hr. DOPAC levels markedly increased from 0.5 to 16 hr and returned to pretreatment levels by 24 hr. HVA levels also increased over the same period and remained elevated above pretreatment levels for up to 24 hr (data not shown). As DA and its metabolite levels did not significantly change between 24 to 30 hr postreserpine treatment, effects of various pharmacological treatments on DA and its metabolites were evaluated 24 hr after reserpine treatment. L-DOPA (200 mg/kg) increased the striatal levels of DA, DOPAC and HVA in reserpinized rats (post 24 hr) whereas amantadine and SIB-1765F had no effect (fig. 6A). D-amphetamine did not affect the levels of DA but decreased the levels of DOPAC and HVA in the striatum of reserpine-treated rats (fig. 6A). Similar effects of these compounds on the levels of DA, DOPAC and HVA were observed in the olfactory tubercles (fig. 6B).

View larger version (22K): [in this window] [in a new window]   Fig. 6.   Effects of L-DOPA (200 mg/kg, i.p. + benserazide 50 mg/kg, i.p.), d-amphetamine (1 mg/kg, s.c.), amantadine (100 mg/kg, s.c.) and SIB-1765F (40 mg/kg, s.c.) on the levels of dopamine (DA) and its metabolites DOPAC and HVA in the striatum (A) and olfactory tubercles (B) of reserpine-treated rats. Rats were given vehicle or reserpine (1 mg/kg, i.v.) 24 hr before the experiment. Tissue was collected 60 min after the administration of the test compounds. Values represent mean ± S.E.M. (n = 6/group). *P < .05 vs. sal/reserpine, Dunnett's test; #P < .0001 vs. sal/veh, Student's t test).

	Discussion

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Our study indicates that SIB-1765F attenuated reserpine-induced hypolocomotion in rats. This is the first demonstration of efficacy of a NAChR agonist in such an acute animal model of Parkinson's disease. SIB-1765F also potentiated the effect of L-DOPA on reserpine-induced hypolocomotion in rats with a rapid onset of action (less than 5 min after administration). The coadministration of SIB-1765F and L-DOPA produced a greater effect than an additive effect. Interestingly, nicotine did not have any effect in reserpinized rats when administered alone or in combination with L-DOPA.

The mechanism(s) of action by which SIB-1765F attenuates reserpine-induced hypolocomotion and potentiates the effect of L-DOPA is unknown, although several mechanisms can be hypothesized.

One possible mechanism of action could be an amphetamine-like inhibition of DA reuptake. However, our results showed that DOPAC levels in both striatum and olfactory tubercles were not significantly decreased by SIB-1765F, implying that inhibition of reuptake of DA does not contribute to the pharmacological effect of SIB-1765F. In vitro results also indicated that SIB-1765F did not affect DA uptake at concentrations up to 1 mM (Rao et al., 1995; Sacaan et al., accompanying paper).

A second possible mechanism of action of SIB-1765F in reserpinized rats is an antagonism of NMDA receptors, as it was proposed for amantadine (Kornhuber et al., 1994). Although amantadine has been shown to release DA in vivo (Carlsson, 1975b), several lines of evidence suggest that the antiparkinsonian activity of amantadine may not be mediated through the release of DA. Our study showed that amantadine reversed the effect of reserpine on locomotor activity in rats and produced a delayed potentiation of the locomotor stimulant effect of L-DOPA in reserpine-treated rats without significantly affecting DA, HVA or DOPAC levels in the striatum or olfactory tubercles. Moreover, Skuza et al. (1994) showed that amantadine (20 mg/kg, s.c.) potentiated the effect of L-DOPA (100 mg/kg) on locomotor activity in rats treated with reserpine and -methyl-p-tyrosine. Several reports indicated that the antiparkinsonian activity of amantadine may be mediated through an antagonism of NMDA receptors (Danysz et al., 1994; Jackisch et al., 1992; Kornhuber et al., 1994; Stoof et al., 1992), rather than through the release of DA. Therapeutic levels of amantadine found in postmortem brain are known to block NMDA receptors without affecting the dopaminergic system (Jackisch et al., 1992). However, SIB-1765F did not exhibit any appreciable affinity for excitatory amino acid receptors in vitro (Rao et al., 1995). In addition, SIB-1765F failed to attenuate NMDA-evoked striatal acetylcholine release (data not shown), a pharmacological response known to be attenuated by amantadine (Stoof et al., 1992). In addition, SIB-1765F did not show any appreciable affinity for the NMDA receptor complex (Sacaan et al., accompanying paper). These results refute a role of SIB-1765F as a NMDA receptor antagonist, and, therefore, the mechanism of action of SIB-1765F in reserpine-treated rats appears to be different from that of amantadine.

Finally, as mentioned earlier, in vitro and in vivo results indicated that SIB-1765F may act through the release of DA. SIB-1765F increased locomotor activity in rats habituated to the test environment (Menzaghi et al., 1995, accompanying paper). This effect was blocked by D1 and D2 dopamine receptor antagonists, suggesting that the effect of SIB-1765F on motor activity in rats is mediated through an activation of dopaminergic receptors subsequent to dopamine release. Indeed, microdialysis studies showed that SIB-1765F increased the release of dopamine in the striatum and the nucleus accumbens in rats (Menzaghi et al., accompanying paper; Sacaan et al., accompanying paper). Our study suggests that SIB-1765F may act, partly, by releasing DA from reserpine-insensitive and reserpine-sensitive pools of DA. As previously shown (Carlsson, 1975b), amphetamine increased locomotor activity in reserpine-treated animals despite very low catecholamine stores. To block this effect of amphetamine in reserpinized animals, it was necessary to inhibit the synthesis of catecholamines with AMPT (for review see Carlsson, 1975b; and this investigation). This suggests that amphetamine is acting on a reserpine-insensitive pool of DA (cytoplasmic pool). SIB-1765F failed to increase locomotor activity in reserpinized rats that were given AMPT, suggesting that SIB-1765F also releases DA from a reserpine-insensitive pool. However, in contrast with amphetamine, SIB-1765F appears to primarily release DA from a reserpine-sensitive pool (vesicular pool), as the locomotor stimulant effect of SIB-1765F was more robust in naive animals than in rats treated with reserpine (Menzaghi et al., 1995, accompanying paper). Furthermore, unlike amphetamine, SIB-1765F-induced release of dopamine in vitro is Ca2⁺-sensitive, confirming that SIB-1765F is acting primarily through the release of vesicular pool (Rao et al., 1995; Sacaan et al., accompanying paper). The stimulant action of SIB-1765F markedly contrasts with the lack of effect of nicotine in reserpinized rats. This difference suggests that, unlike SIB-1765F, nicotine releases DA from the vesicular pool only. In addition, the difference between SIB-1765F and nicotine may reflect activation of distinct NAChR by these two agonists.

Locomotor activity induced by nicotinic agonists is primarily mediated through the activation of the mesolimbic dopaminergic pathway (Clarke et al., 1988; Reavill and Stolerman, 1990; Balfour et al., 1991), which is rich in both pre- and postsynaptic NAChR (Clarke and Pert, 1985). The increase in mesolimbic dopamine secretion and the locomotor activation induced by systemic administration of nicotine are principally mediated by activation of NAChR at the level of the cell bodies in the ventral tegmentum area (Reavill and Stolerman, 1990; Museo and Wise, 1990; Leikola-Pelho and Jackson, 1992) and/or at the level of dopamine terminal fields in the nucleus accumbens (Damsma et al., 1990). The striatum also appears to be involved in nicotine-induced locomotor activity (Richardson and Tizabi, 1994), as nicotine has been shown to release dopamine in the striatum through the activation of presynaptic receptors. The effect of SIB-1765F on motor behavior in reserpine-treated rats may be mediated through these two dopaminergic pathways. In vivo microdialysis studies have shown that SIB-1765F induced a greater release of DA than nicotine in both the striatum and the nucleus accumbens (Menzaghi et al., 1995; Sacaan et al., accompanying paper). SIB-1765F also produced a more robust effect than nicotine on ipsilateral turning in unilaterally 6-OHDA-lesioned rats (Lloyd et al., 1995; Cosford et al., 1996). These effects of SIB-1765F on striatal dopaminergic functions are particularly relevant to the treatment of the motor symptoms of PD. Although recent reports have indicated that the densities of NAChR binding sites are decreased in the striatum of patients with PD (Aubert et al., 1992; Lange et al., 1993; Whitehouse et al., 1988; Rinne et al., 1991; Ruberg et al., 1982), approximately 50% of NAChR remain. A NAChR agonist may stimulate the remaining NAChR in the basal ganglia and consequently release DA from the remaining functional dopamine neurons. When combined with L-DOPA, a NAChR agonist may enhance the effectiveness of L-DOPA by releasing DA stored after its formation from L-DOPA. Such a combination therapy could enable the use of lower doses of L-DOPA, reducing the side effects associated with L-DOPA. Recent evidence suggests that SIB-1765F potentiates the effect of L-DOPA on motor deficits induced by MPTP in nonhuman primates (Lloyd, 1996).

In conclusion, NAChR agonists that release dopamine may provide a new therapeutic approach to the symptomatic treatment of the motor deficits in patients with PD. Furthermore, NAChR agonists have been shown to improve attentional processes in rodents (Muir et al., 1995), and in normal and cognitively impaired humans (Newhouse et al., 1988; Jones et al., 1992; Pritchard et al., 1992, Rusted and Warburton, 1992). Patients with PD exhibit cognitive deficits such as bradyphrenia and impairment in executive tasks (Cooper et al., 1994; Levin et al., 1989; Owen et al., 1992), which are poorly treated by current antiparkinsonian drugs (L-DOPA, DA agonists, anticholinergics or muscarinic antagonists) (Cooper et al., 1992). Newhouse et al. (1994) demonstrated that administration of mecamylamine to patients with PD causes deterioration in cognitive performance, suggesting an important role of NAChR in maintaining cognitive abilities of patients with PD. Other nonmotor symptoms of PD, such as depression (Fibiger, 1984; Mayberg and Solomon, 1995), do not respond to antiparkinsonian agents. These nonmotor symptoms of PD may be related to deficits in dopaminergic function and also to nondopaminergic pathology, including deficits in noradrenergic, serotoninergic and cholinergic innervation of the cerebral cortex (Agid et al., 1984; Gerlach et al., 1994). Because SIB-1765F induces the release of NE from the cortex and the thalamus (Rao et al., 1995; Sacaan et al., accompanying paper) and the release of acetylcholine from the hippocampus and the frontal cortex (Lloyd et al., 1995), it is possible that this NAChR agonist may have use in the management of motor and nonmotor dysfunctions associated with Parkinson's disease.