Locomotor activity detects subunit-selective effects of agonists and decahydroisoquinoline antagonists at AMPA/kainic acid ionotropic glutamate receptors in adult rats.

RATIONALE: In vitro studies have identified a series of decahydroisoquinoline compounds with differential selectivity for the subunits that comprise AMPA/kainic acid receptors. Compounds have been identified that have preferential activity at AMPA receptors (LY302679), whereas others (LY377770) have affinity for GluR5-kainic acid preferring subunit, which is activated by ATPA and kainic acid. OBJECTIVES: These studies set out to determine if locomotor activity could differentiate these profiles in vivo. METHODS: Locomotor activity was assessed in photocell drums in male Lister Hooded rats. RESULTS: AMPA, kainic acid and the GluR5 selective agonist ATPA, all suppressed spontaneous locomotor activity (SLA) in rats at doses of 1.0, 5.0 and 20 mg/kg resp. All three agonists achieve micromolar concentrations measured in whole brain after dosing with 10 mg/kg SC. The decahydroisoquinoline antagonist compounds, LY302679 (GluR2), LY293558 (GluR2, 5) and LY377770 (GluR5) all decreased SLA in rats (ED(min) 2.5, 5.0 and 20 mg/kg respectively). The rank order of potency at GluR2 subunits (LY302679>LY293558>LY377770) was reflected in the same rank order of activity for suppression of SLA. LY293558 reversed the suppression of SLA induced by all three agonists (0.62--2.5 mg/kg). LY377770 reversed the effects of ATPA only (ED(min) 1.0 mg/kg), LY302679 (ED(min) 2.5 mg/kg) attenuated the effect of kainic acid but was ineffective against AMPA and ATPA. CONCLUSIONS: Both agonist and antagonist suppression of SLA is associated with greater affinity for the GluR2 subunit, while compounds with affinity for the GluR5 subunit were less potent in suppressing SLA.

Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease.

Recent developments in the molecular biology and pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and evidence suggests that they play important roles in plasticity and cognitive processes. Activation of AMPA receptors also increases neuronal activation and activity-dependent signalling, which may increase brain-derived neurotrophic factor (BDNF) expression and enhance cell proliferation in the brain. We therefore hypothesised that an AMPA receptor potentiator may provide neurotrophic effects in rodent models of Parkinson's disease. In the present studies we report that the potent and selective AMPA receptor potentiator, R,S-N-2-(4-(4-Cyanophenyl)phenyl)propyl 2-propanesulfonamide (LY404187), provides both functional, neurochemical and histological protection against unilateral infusion of 6-hydroxydopamine into the substantia nigra or striatum of rats. The compound also reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice. Interestingly, we were also able to observe large functional and histological effects when we delayed treatment until after cell death had occurred (3 or 6 days after 6-hydroxydopamine infusion), supporting a neurotrophic mechanism of action. In addition, LY404187 provided a dose-dependent increase in growth-associated protein-43 expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new therapy to halt the progression and perhaps repair the degeneration in Parkinson's disease.

Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease.

The aim of the present studies was to examine the ability of a potent, systemically active, selective Group II mGlu receptor (mGluR2/3) agonist, 1R,4R,5S,6R-2-oxa-4-minobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) to provide both functional relief and neuroprotection in rodent models of Parkinson's disease (PD). In functional studies, intracerebroventricular administration of LY379268 (1, 5, 10, 20 nmol/2 microl) produced a dose-dependent increase in locomotor activity in the reserpine (5 mg/kg ip)-treated rat. In contrast, systemic administration of LY379268 (0.1, 1, 10 mg/kg ip) did not reverse reserpine-induced akinesia and failed to effect rotational behaviour 1 month after unilateral lesioning of the nigrostriatal tract by 6-hydroxydopamine (6-OHDA; 4 microg infused into the substantia nigra (SN)). In neuroprotective studies, animals were treated with LY379268 (10 mg/kg/day ip) either for 7 days following 6-OHDA injection into the SN (4 microg) or for 21 days following 6-OHDA injection into the striatum (10 microg) before measurement of tyrosine hydroxylase immunoreactivity in the striatum and/or SN as an index of neuroprotection. LY379268 provided some protection against nigral infusion of 6-OHDA and also some functional improvement and correction of dopamine turnover was observed. The compound also provided significant protection in the striatum and some protection in the SN against striatal infusion of 6-OHDA. These data suggest that activation of Group II mGlu receptors can provide some protection in models of PD, while their role in providing functional improvement is less clear.