Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata.

Excitatory glutamatergic inputs to the subthalamic nucleus (STN), and subthalamic afferents to the substantia nigra pars reticulata (SNr) are believed to play a key role in the pathophysiology of Parkinson's disease (PD). Previously, we have shown that activation of the group I mGlus in the STN and SNr induces a direct depolarization of the neurons in these nuclei. Surprisingly, although both group I mGlus were present in the STN and SNr, mGlu5 alone mediated the DHPG-induced depolarization of the STN, and mGlu1 alone mediated the DHPG-induced depolarization of the SNr. We now report that both mGlu1 and mGlu5 are coexpressed in the same cells in both of these brain regions, and that both receptors play a role in mediating the DHPG-induced increase in intracellular calcium. Furthermore, we demonstrate that the induction of an acute PD-like state using a 16 h haloperidol treatment produces an alteration in the coupling of the group I receptors, such that post-haloperidol, DHPG-induced depolarizations are mediated by both mGlu1 and mGlu5 in the STN and SNr. Therefore, the pharmacology of the group I mGlu-mediated depolarization depends on the state of the system, and alterations in receptor coupling may be evident in pathological states such as PD.

Dopamine D2 receptor-mediated presynaptic inhibition of olfactory nerve terminals.

Olfactory receptor neurons of the nasal epithelium project via the olfactory nerve (ON) to the glomeruli of the main olfactory bulb, where they form glutamatergic synapses with the apical dendrites of mitral and tufted cells, the output cells of the olfactory bulb, and with juxtaglomerular interneurons. The glomerular layer contains one of the largest population of dopamine (DA) neurons in the brain, and DA in the olfactory bulb is found exclusively in juxtaglomerular neurons. D2 receptors, the predominant DA receptor subtype in the olfactory bulb, are found in the ON and glomerular layers, and are present on ON terminals. In the present study, field potential and single-unit recordings, as well as whole cell patch-clamp techniques, were used to investigate the role of DA and D2 receptors in glomerular synaptic processing in rat and mouse olfactory bulb slices. DA and D2 receptor agonists reduced ON-evoked synaptic responses in mitral/tufted and juxtaglomerular cells. Spontaneous and ON-evoked spiking of mitral cells was also reduced by DA and D2 agonists, and enhanced by D2 antagonists. DA did not produce measurable postsynaptic changes in juxtaglomerular cells, nor did it alter their responses to mitral/tufted cell inputs. DA also reduced 1) paired-pulse depression of ON-evoked synaptic responses in mitral/tufted and juxtaglomerular cells and 2) the amplitude and frequency of spontaneous, but not miniature, excitatory postsynaptic currents in juxtaglomerular cells. Taken together, these findings are consistent with the hypothesis that activation of D2 receptors presynaptically inhibits ON terminals. DA and D2 agonists had no effect in D2 receptor knockout mice, suggesting that D2 receptors are the only type of DA receptors that affect signal transmission from the ON to the rodent olfactory bulb.

Cyclic AMP-dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors.

Recent evidence suggests that the functions of presynaptic metabotropic glutamate receptors (mGluRs) are tightly regulated by protein kinases. We previously reported that cAMP-dependent protein kinase (PKA) directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor, and that phosphorylation of this site inhibits coupling of mGluR2 to GTP-binding proteins. This may be the mechanism by which the adenylyl cyclase activator forskolin inhibits presynaptic mGluR2 function at the medial perforant path-dentate gyrus synapse. We now report that PKA also directly phosphorylates several group III mGluRs (mGluR4a, mGluR7a, and mGluR8a), as well as mGluR3 at single conserved serine residues on their C-terminal tails. Furthermore, activation of PKA by forskolin inhibits group III mGluR-mediated responses at glutamatergic synapses in the hippocampus. Interestingly, beta-adrenergic receptor activation was found to mimic the inhibitory effect of forskolin on both group II and III mGluRs. These data suggest that a common PKA-dependent mechanism may be involved in regulating the function of multiple presynaptic group II and group III mGluRs. Such regulation is not limited to the pharmacological activation of adenylyl cyclase but can also be elicited by the stimulation of endogenous G(s)-coupled receptors, such as beta-adrenergic receptors.

Norepinephrine increases rat mitral cell excitatory responses to weak olfactory nerve input via alpha-1 receptors in vitro.

A rat olfactory bulb in vitro slice preparation was used to investigate the actions of norepinephrine on spontaneous and afferent (olfactory nerve) evoked activity of mitral cells. Single olfactory nerve shocks elicited a characteristic mitral cell response consisting of distinct, early and late spiking components separated by a brief inhibitory epoch. Bath-applied norepinephrine (1 microM) increased the early spiking component elicited by perithreshold (79% increase, P<0.02), but not by suprathreshold (3% decrease, P>0.05), intensity olfactory nerve shocks. The facilitatory effect of norepinephrine was due to a reduction in the incidence of response failures to perithreshold intensity shocks. Norepinephrine also decreased the inhibitory epoch separating the early and late spiking components by 44% (P<0.05). By contrast, norepinephrine had no consistent effect on the spontaneous discharge rate of the mitral cells. The effects of norepinephrine were mimicked by the al receptor agonist phenylephrine (1 microM, P<0.001). Both norepinephrine and phenylephrine modulation of mitral cell responses were blocked by the al adrenergic antagonist WB-4101 (1 microM). These findings are consistent with observations that the main olfactory bulb exhibits the highest density of alpha1 receptors in the brain. The alpha2 receptor agonist clonidine (100 nM) and the beta receptor agonist isoproterenol (1 microM) had inconsistent effects on mitral cell spontaneous and olfactory nerve-evoked activity. These results indicate that norepinephrine increases mitral cell excitatory responses to weak but not strong olfactory nerve inputs in vitro via activation of al receptors. This is consistent with recent findings in vivo that synaptically released norepinephrine preferentially increases mitral cell excitatory responses to weak olfactory nerve inputs. Taken together, these results suggest that the release of norepinephrine in the olfactory bulb may increase the sensitivity of mitral cells to weak odors. Olfactory cues evoke norepinephrine release in the main olfactory bulb, and norepinephrine plays important roles in early olfactory learning and reproductive/maternal behaviors. By increasing mitral cell responses to olfactory nerve input, norepinephrine may play a critical role in modulating olfactory function, including formation and/or recall of specific olfactory memories.