The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor function, as well as in pathological conditions such as Parkinson's disease (PD) and related disorders. Development of a complete understanding of the roles of the STN in motor control and the pathophysiological changes in STN that underlie PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces a direct excitation of STN neurons that is characterized by depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective potentiation of NMDAevoked currents. Immunohistochemical studies at the light and electron microscopic levels indicate that both subtypes of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects is attributable to activation of mGluR5, not mGluR1, despite the presence of both subtypes in STN neurons. These results suggest that mGluR5 may play an important role in the net excitatory drive to the STN from glutamatergic afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatment of a variety of movement disorders that involve changes in STN activity. Key words: metabotropic glutamate receptor; subthalamic nucleus; basal ganglia; Parkinson's disease; burst firing; NMDA receptor; mGluR1; mGluR5The basal ganglia (BG) are a set of subcortical nuclei that play a critical role in motor control and are a primary site of pathology in a number of movement disorders, including Parkinson's disease (PD), Tourette's syndrome, and Huntington's disease. Recent studies reveal that a key nucleus in the BG motor circuit, the subthalamic nucleus (STN), plays an especially important role in BG function. The STN is an excitatory glutamatergic nucleus in the BG and provides the major excitatory input to the BG output nuclei, the substantia nigra pars reticulata (SNr) and the internal globus pallidus. Normal motor function requires an intricate balance between excitation of the output nuclei by glutamatergic neurons from the STN and inhibition of the output nuclei by GABAergic projections from the striatum (for review, see Wichmann and DeLong, 1997).Interestingly, recent studies suggest that the major pathophysiological change that occurs in response to loss of nigrostriatal dopamine neurons in PD patients is an increase in activity of STN neurons. The resultant increase in synaptic excitation of GABAergic projection neurons in the output nuclei leads to a "shutdown" of thalamocortical projections and produces the motor impairment characteristic of PD (DeLong, 199...

Over the past decade or so, CART (cocaine- and amphetamine-regulated transcript) peptides have emerged as major neurotransmitters and hormones. CART peptides are widely distributed in the CNS and are involved in regulating many processes, including food intake and the maintenance of body weight, reward and endocrine functions. Recent studies have produced a wealth of information about the location, regulation, processing and functions of CART peptides, but additional studies aimed at elucidating the physiological effects of the peptides and at characterizing the CART receptor(s) are needed to take advantage of possible therapeutic applications.

Neurons in the rat substantia nigra (SN) are enriched in group I metabotropic glutamate receptor (mGluR) subtypes and respond to group I mGluR activation. To better understand the mechanisms by which mGluR1 and mGluR5 mediate these effects, the goal of this study was to elucidate the subsynaptic localization of these two receptor subtypes in the rat and monkey substantia nigra. At the light microscope level, neurons of the SN pars reticulata (SNr) displayed moderate to strong immunoreactivity for both mGluR1a and mGluR5 in rats and monkeys. However, mGluR1a labeling was much stronger in monkey than in rat SN pars compacta (SNc) neurons, whereas a moderate level of mGluR5 immunoreactivity was found in both species. At the electron microscope level, the immunoreactivity for both group I mGluR subtypes was primarily expressed postsynaptically, although light mGluR1a labeling was occasionally seen in axon terminals in the rat SNr. Immunogold studies revealed a striking difference in the subcellular distribution of mGluR1a and mGluR5 immunoreactivity in SNr and SNc neurons. Although the bulk of mGluR1a was attached to the plasma membrane, Ͼ80% of mGluR5 immunoreactivity was intracellular. Plasma membrane-bound immunoreactivity for group I mGluRs in both SNc and SNr neurons was mostly extrasynaptic or in the main body of symmetric, putative GABAergic synapses. On the other hand, asymmetric synapses either were nonimmunoreactive or displayed perisynaptic labeling. These data raise important questions about the trafficking, internalization, and potential functions of group I mGluRs at extrasynaptic sites or symmetric synapses in the substantia nigra. Key words: metabotropic; glutamate; receptor internalization; receptor trafficking; dopamine neurons; Parkinson's disease; immunogold methodThe substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus are the main output nuclei of the basal ganglia, whereas the SN pars compacta (SNc) is a group of dopaminergic neurons that project to the striatum. Both the SNr and SNc receive glutamatergic innervation from the subthalamic nucleus), cerebral cortex, and pedunculopontine tegmental nucleus (Wichmann and DeLong, 1998).The effects of glutamate in the CNS are mediated by activation of ionotropic and metabotropic receptors. Ionotropic receptors are ligand-gated cation channels that mediate fast excitatory neurotransmission, whereas metabotropic glutamate receptors (mGluRs) belong to a family of G-protein-coupled receptors that mediate modulatory effects of synaptic transmission by activation of a number of intracellular metabolic pathways. The family of mGluRs is subdivided into three groups (Conn and Pin, 1997). The group I mGluRs consist of mGluR1, mGluR5, and all their splice variants. These receptors are coupled to phosphoinositol hydrolysis and usually induce slow depolarization. On the other hand, group II (mGluR2,3) and group III (mGluR4,6,7,8) mGluRs are negatively coupled to adenylate cyclase and often induce presynaptic inhibition of trans...

A pathological increase in excitatory glutamatergic input to substantia nigra pars reticulata (SNr) from the subthalamic nucleus (STN) is believed to play a key role in the pathophysiology of Parkinson's disease. We present an analysis of the physiological roles that group I metabotropic glutamate receptors (mGluRs) play in regulating SNr functions. Immunocytochemical analysis at the light and electron microscopic levels reveal that both mGuR1a and mGluR5 are localized postsynaptically in the SNr. Consistent with this, activation of group I mGluRs depolarizes SNr GABAergic neurons. Interestingly, although both group I mGluRs (mGluR1 and mGluR5) are expressed in these neurons, the effect is mediated solely by mGluR1. Light presynaptic staining for mGluR1a and mGluR5 was also observed in some terminals forming symmetric synapses and in small unmyelinated axons. Consistent with this, activation of presynaptic mGluR1a and mGluR5 decreases inhibitory transmission in the SNr. The combination of direct excitatory effects and disinhibition induced by activation of group I mGluRs could lead to a large excitation of SNr projection neurons. This suggests that group I mGluRs are likely to play an important role in the powerful excitatory control that the STN exerts on basal ganglia output neurons.