Activity-dependent activation of presynaptic metabotropic glutamate receptors in locus coeruleus

Synaptic activation of metabotropic glutamate receptors (mGluRs) in the loc us coeruleus (LC) was investigated in adult rat brain slice preparations. E voked excitatory postsynaptic potentials (EPSPs) resulting from stimulation of LC afferents were measured with current clamp from intracellularly reco rded LC neurons. In this preparation, mGluR agonists (+/-)-1-aminocyclopent ane-trans-1,3-dicarboxylic acid (t-ACPD) and L(+)-2-amino-4-phosphonobutyri c acid (L-AP4) activate distinct presynaptic mGluRs, resulting in an inhibi tion of EPSPs. When two stimuli were applied to afferents at intervals >200 ms, the amplitude of the second [test (T)] EPSP was identical in amplitude to the first [control(C)]. However, when a stimulation volley was delivere d before T, the amplitude of the latter EPSP was consistently smaller than C. The activity-dependent depression (ADD) was dependent on the frequency a nd duration of the train and the interval between the train and T. ADD was potentiated in the presence of an excitatory amino acid (EAA) uptake inhibi tor L-trans-pyrrolidine-2,4-dicarboxylic acid (t-PDC, 100 mu M), changing t he T/C ratio from 0.84 +/- 0.05 (mean +/- SE) in control to 0.69 +/- 0.04 i n t-PDC (n = 9). In the presence of t-PDC, the depolarizing response of LC neurons to focally applied glutamate was also increased. Together, these re sults suggest that accumulation of EAA after synaptic stimulation may be re sponsible for ADD. To test if ADD is a result of the activation of presynap tic mGluRs, the effect of selective mGluR antagonists on ADD was assessed. In the presence of t-PDC, bath applied (S)-amino-2-methyl-4-phosphonobutano ic acid (MAP4, 500 mu M), a mGluR group In antagonist, significantly revers ed the decrease in T/C ratio after a train stimulation [from 0.66 +/- 0.04 to 0.81 +/- 0.02 (mean +/- SE), n = 5]. The T/C ratio in the presence of MA P4 was not different from that measured in the absence of a stimulation vol ley. Conversely, ethyl glutamic acid (EGLU, 500 mu M), a mGluR group II ant agonist, failed to alter the TIC ratio. Together, these results suggest tha t, in LC, group III presynaptic mGluR activation provides a feedback mechan ism by which excitatory synaptic transmission can be negatively modulated d uring high-frequency synaptic activity. Furthermore, this study provides fu nctional differentiation between presynaptic groups II and III mGluR in LC and suggests that the group II mGluR may be involved in functions distinct from those of group III mGluRs.