]-5-HT over¯ow (EC 50 =64 nM; E max =31% inhibition), but its eect was partially antagonized by 10 mM naloxone. 5 It is concluded that the ORL 1 receptor is the most important presynaptic modulator of neocortical 5-HT release within the opioid receptor family. This suggests that the ORL 1 /nociceptin system may have a powerful role in the control of cerebral 5-HT-mediated biological functions.

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The effects of NMDA and a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) on endogenous acetyicholine release from rat striatal slices and synaptosomes were investigated. Both agonists (1-300 1iM) facilitated acetylcholine release from slices in a dosedependent manner. NMDA (100-300 pM) and AMPA (30-300 pM), however, subsequently inhibited acetylcholine release. NMDA (100 pM) -induced facilitation was antagonized by 3-(2-carboxypiperazin-4-yl) propyl-1phosphonic acid (CPP) and dizocilpine (both 1-10 pM), whereas the 10 pM AMPA effect was antagonized by 6cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1 -30 pM). NMDA (100 pM) -induced inhibition was counteracted by CPP, but not dizocilpine, and by the nitric oxide synthase inhibitor L-nitroarginine (1-100 pM). Tetrodotoxin (0.5 pM) prevented the facilitatory effect of 3 p.M NMDA and AMPA, but left unchanged that of 30 pM NMDA and 100 pM AM PA. Acetylcholine release from synaptosomes was stimulated by KCI (7.5-100 mM) in a dose-dependent manner. NMDA and AMPA maximally potentiated the 20 mM KCI effect at 1 pM and 0.01 pM, but were ineffective at 100 pM and 10 pM, respectively. Inhibition of acetylcholine release was never found in synaptosomes. The effects of 1 pM NMDA and 0.01 pM AMPA were antagonized by CPP (0.0001-1 pM) or dizocilpine (0.0001-10 pM) and by CNQX (0.001-1 pM), respectively. These data suggest that glutamatergic control of striatal acetylcholine release is mediated via both pre-and postsynaptic NMDA and non-NMDA ionotropic receptors.

Abstract:The NMDA-evoked acetylcholine release from striatal slices and synaptosomes was investigated in rats subjected to unilateral injection of 6-hydroxydopamine into the substantia nigra. In slices prepared from the striatum contralateral to the lesion, the NMDA-evoked endogenous acetylcholine release was not significant at 10 M NMDA and maximal at 100 M NMDA (124 Ϯ 19%). Conversely, in slices taken from the dopamine-depleted striatum, NMDA was effective even at 10 M (41 Ϯ 4%), and at 100 M (196 Ϯ 24%) efficacy was nearly doubled. In synaptosomes prepared from the contralateral striatum, NMDA maximally stimulated 20 mM KCl-induced endogenous acetylcholine release at 1 M (66 Ϯ 5.1%), with lower concentrations (0.01-0.1 M ) being ineffective. Conversely, in synaptosomes prepared from the dopamine-depleted striatum, NMDA maximally enhanced the K ϩ -evoked acetylcholine release at 0.1 M (118 Ϯ 12.4%). Concentration-response curves of NMDA-evoked acetylcholine release in sham-operated rats could be superimposed on those observed in the contralateral striatum of the 6-hydroxydopamine-lesioned animals. The present data support the view of an increased glutamatergic regulation of striatal acetylcholine release via pre-and postsynaptic NMDA receptors during Parkinson's disease.

Dual probe microdialysis was employed to characterize dialysate glutamate levels from the substantia nigra pars reticulata of awake freely moving rats, and to test its sensitivity to alterations in striatal neurotransmission including striatal N-methyl-D-aspartic acid (NMDA) receptor stimulation and blockade. Intranigral perfusion with low (0.1 mM) Ca2+ medium (60 min) did not affect nigral glutamate levels, whereas intranigral perfusion with tetrodotoxin (10 microM, 60 min) increased nigral glutamate levels. Perfusion of KCI (100 mM, 10 min) in the dorsolateral striatum transiently stimulated nigral glutamate levels (maximal increase + 60%), whereas intrastriatal perfusion (60 min) with low Ca2+ medium and tetrodotoxin gradually increased nigral glutamate levels. Intrastriatal perfusion with NMDA (0.1-100 microM, 10 min) dose-dependently stimulated glutamate levels in the substantia nigra pars reticulata. The NMDA (1 microM)-induced increase in nigral glutamate release was transient and maximal (+60% within 20 min), whereas that for NMDA (10 microM) had a slow onset but was long lasting (+35% after 60 min). Lower (0.1 microM) and higher (100 microM) NMDA concentrations were ineffective. The effect of intrastriatal NMDA (1 microM) was prevented by coperfusion with MK-801 (1 microM). Intrastriatal MK-801 (10 microM) alone gradually increased glutamate levels up to +50% after 60 min of perfusion. The present results suggest that glutamate levels in the substantia nigra pars reticulata are sensitive to changes in neuronal transmission in the dorsolateral striatum, and that striatal NMDA receptors regulate nigral glutamate release in both a tonic and phasic fashion.

Dual probe microdialysis was employed in freely moving 6-hydroxydopamine (6-OHDA) hemilesioned rats to investigate the effects of blockade of N-methyl-D-aspartate (NMDA) receptors in the dorsolateral striatum on glutamate (Glu) release from the ipsilateral substantia nigra pars reticulata (SNr). Perfusion for 60 min with the NMDA antagonist dizocilpine (0.1 and 1 microM) in the dopamine (DA)-denervated striatum stimulated nigral Glu release (peak effect of 139 +/- 7% and 138 +/- 9%, respectively). The lower (0.01 microM) and higher (10 microM) concentrations were ineffective. In sham-operated rats, dizocilpine failed to affect nigral Glu release up to 1 microM but induced a prolonged stimulation at 10 microM (153 +/- 9% at the end of perfusion). The present results show that DA-deficiency in the striatum of hemiparkinsonian rats is associated with increased responsivity of nigral Glu release to striatal NMDA receptor blockade. This suggests that changes of NMDA receptor mediated control of the striatofugal pathways occur during Parkinson's disease (PD).

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