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We have shown earlier that activation of metabotropic glutamate (mGlu) receptors using a group I-specific mGlu receptor agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG), can induce long-term depression (LTD) in the CA1 region of the hippocampus. In an attempt to determine the signal transduction mechanisms involved in this form of synaptic plasticity, we have tested the effects of a range of inhibitors on DHPG-induced LTD. In vitro grease-gap electrophysiological recordings were performed in the rat hippocampal CA1 region. We have found that DHPG-induced LTD is resistant to the two potent protein kinase C (PKC) inhibitors, Gö 6976 (10 microM) and Gö 6983 (10 microM), the potent and selective protein kinase A (PKA) inhibitor, KT 5720 (10 microM), and the potent broad spectrum kinase inhibitor, staurosporine (10 microM). In contrast, non-selective inhibitors of protein phosphatases (PP1 and PP2A), okadaic acid (1 microM) or calyculin A (1 microM), facilitated DHPG-induced LTD. However, an inhibitor of protein phosphatase 2B, FK 506 (1 microM), did not influence this process. The PP1/PP2A protein phosphatase inhibitors, but none of the other agents tested, also inhibited (S)-alpha-methyl-4-carboxyphenylglycine (MCPG)-induced reversal of DHPG-induced LTD. These data suggest that activation of neither PKC nor PKA is involved in DHPG-induced LTD. They do, however, suggest that the process is under regulation by protein phosphorylation and dephosphorylation.

1. The influence of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on haloperidol-induced increases in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), was measured in three microdissected brain regions of the rat following a quantitative assessment of catalepsy. 2. Haloperidol alone (2.66 mumol kg-1, i.p.) caused a robust cataleptic response. Given 30 min after haloperidol, 8-OH-DPAT (76 or 760 nmol kg-1, s.c.) prevented catalepsy in 30% and 100% of rats, respectively. 3. Haloperidol significantly increased the DOPAC (by 2 to 4 fold) and HVA (by 3 to 7 fold) contents of the caudate-putamen, nucleus accumbens and medial prefrontal cortex. Given alone, only the lower dose of 8-OH-DPAT caused a significant biochemical change, a doubling of cortical DOPAC. 4. In the cases where catalepsy was prevented by either dose of 8-OH-DPAT, the haloperidol-induced increases in DOPAC and HVA were consistently lower in the caudate-putamen. This pattern was true for the rise in cortical HVA but only in response to the lower dose of 8-OH-DPAT. In contrast, neither dose of 8-OH-DPAT was able to influence the haloperidol-induced rises in cortical DOPAC. In the nucleus accumbens, 8-OH-DPAT did not affect the haloperidol-induced increases in the dopamine metabolites, irrespective of the dose employed or the resulting behaviour. When catalepsy was not prevented, 8-OH-DPAT did not alter the neurochemical responses to haloperidol in any region. 5. These results suggest that part of the mechanism by which 8-OH-DPAT prevents haloperidol-induced catalepsy is reflected by a reversal of the compensatory increase in meso-striatal and/or meso-cortical dopamine neuronal activity that normally accompanies postsynaptic dopamine receptor blockade with haloperidol.