D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus.

Abstract

Agonists of the dopamine D1/D5 receptors that are positively coupled to adenylyl cyclase specifically induce a slowly developing long-lasting potentiation of the field excitatory postsynaptic potential in the CAl region ofthe hippocampus that lasts for >6 hr. This potentiation is blocked by the specific D1/D5 receptor antagonist SCH 23390 and is occluded by the potentiation induced by cAMP agonists. An agonist of the D2 receptor, which is negatively coupled to adenylyl cyclase through Gai, did not induce potentiation. Although this slow D1/D5 agonist-induced potentiation is partially independent of N-methyl-D-aspartate receptors, it seems to share some steps with and is occluded by the late phase of long-term potentiation (LTP) produced by three repeated trains of nerve stimuli applied to the Schaffer One modulatory system known to innervate the CAl region of the hippocampus is the mesolimbic dopaminergic pathway that ends on both the Dl and D5 dopaminergic receptors coupled to adenylyl cyclase (10, 11). Immunohistochemical localization of Dl and D5 receptors reveals a heavy staining along pyramidal cells and the stratum radiatum (12). Retrograde fluorescent tracers show that dopaminergic fibers that project from the ventral tegmental area innervate the CAl MATERIALS AND METHODSTransversely cut hippocampal slices (400 jim) were prepared from 5-to 6-week-old Sprague-Dawley rats and maintained in an interface chamber with continuous superfusion at 1.5-2 ml/min. The solution composition was 124 mM NaCl, 1.3 mM MgCl2, 4 mM KCl, 1.2 mM KH2PO4, 2.0-2.5 mM CaCl2, 25.6 mM NaHCO3, and 10 mM D-glucose, bubbled with 95% 02/5% CO2. The temperature of the bath was maintained at 28-29°C. After equilibration of the slices in the chamber for 2 hr, extracellular recordings were performed as described in a previous paper (7). Baseline responses were recorded for 30-60 min before drug application or LTP-inducing tetanization. Four biphasic constant current pulses (0.2 Hz; duration, 0.1-ms pulse) were used to generate test excitatory postsynaptic potentials (EPSPs) at 10-min intervals during the first hour after drug application or LTP induction and at 30-min intervals during the following hours. In LTP experiments an additional test was performed 1 min after tetanization to induce LTP. Three stimulus trains at 100 Hz, 1 s of 0.2-ms pulse duration were used, a tetanization protocol that produces long-lasting potentiation for up to 8 hr (6). The average waveform from four successive responses was saved and the EPSP slope (mV/ms) was measured.The following drugs were made and stored as concentrated stock solutions and dissolved in the superfusing medium to achieve the final concentrations used: D1/D5 agonist, SKF Abbreviations: LTP, long-term potentiation; E-LTP and L-LTP, early and late components of LTP; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; EPSP, excitatory postsynaptic potential; APV, (±)-2-amino-5-phosphonopentanoic acid; PPHT, (±)-2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin hydrochloride; Sp-cAMPS, ad...

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