Forskolin Enhances Synaptic Transmission in Rat Dorsal Striatum through NMDA Receptors and PKA in Different Phases

The effect of forskolin on corticostriatal synaptic transmission was examined by recording excitatory postsynaptic currents (EPSCs) in rat brain slices using the whole-cell voltage-clamp technique. Forskolin produced a dose-dependent increase of corticostriatal EPSCs (1, 3, 10, and 30micrometer) immediately after its treatment, and the increase at 10 and 30micrometer was maintained even after its washout. When the brain slices were pre-treated with (DL)-2-amino-5-phosphonovaleric acid (AP-V, 100micrometer), an NMDA receptor antagonist, the acute effect of forskolin (10micrometer) was blocked. However, after washout of forskolin, an increase of corticostriatal EPSCs was still observed even in the presence of AP-V. When KT 5720 (5micrometer), a protein kinase A (PKA) inhibitor, was applied through the patch pipette, forskolin (10micrometer) increased corticostriatal EPSCs, but this increase was not maintained. When forskolin was applied together with AP-V and KT 5720, both the increase and maintenance of the corticostriatal EPSCs were blocked. These results suggest that forskolin activates both NMDA receptors and PKA, however, in a different manner.

Fluoxetine Modulates Corticostriatal Synaptic Transmission through Postsynaptic Mechanism

Fluoxetine, widely used for the treatment of depression, is known to be a selective serotonin reuptake inhibitor (SSRI), however, there are also reports that fluoxetine has direct effects on several receptors. Employing whole-cell patch clamp techniques in rat brain slice, we studied the effects of fluoxetine on corticostriatal synaptic transmission by measuring the change in spontaneous excitatory postsynaptic currents (sEPSC). Acute treatment of rat brain slice with fluoxetine (10microM) significantly decreased the amplitude of sEPSC (84.1+/-3.3%, n=7), but did not alter its frequency (99.1+/-4.7%, n=7). Serotonin (10microM) also significantly decreased the amplitude (81.2+/-3.9%, n=4) of sEPSC, but did not affect its frequency (105.8+/-8.0, n=4). The effect of fluoxetine was found to have the same trend as that of serotonin. We also found that the inhibitory effect of fluoxetine on sEPSC amplitude (93.0+/-1.9%, n=8) was significantly blocked, but not serotonin (84.3+/-1.6%, n=4), when the brain slice was incubated with p-chloroamphetamine (10microM), which depletes serotonin from the axon terminals and blocks its reuptake. These results suggest that fluoxetine inhibits corticostriatal synaptic transmission through postsynaptic, and that these effects are exerted through both serotonin dependent and independent mechanism.

NMDA Receptor-dependent Inhibition of Synaptic Transmission by Acute Ethanol Treatment in Rat Corticostriatal Slices

The effects of ethanol on corticostriatal synaptic transmission were examined, using extracellular recording and analysis of population spike amplitudes in rat brain slices, to study how acute ethanol intoxication impairs striatal function. Ethanol caused a decrease in population spike amplitudes in a dose dependent manner (50~200 mM). Pretreatment with picrotoxin, a gamma-amino butyric acid (GABA)A receptor antagonist, increased the population spikes but ethanol (100 mM) was still effective in decreasing the population spikes under this condition. In the presence of (DL)-2-amino-5-phosphonovaleric acid (APV), N-methyl-D-aspartate (NMDA) receptor antagonist, the inhibitory action of ethanol on population spikes was not shown. These results suggest that ethanol inhibits the glutamatergic corticostriatal synaptic transmission through blockade of NMDA receptors.

5-Hydroxytryptamine Inhibits Glutamatergic Synaptic Transmission in Rat Corticostriatal Brain Slice

Striatum is involved in the control of movement and habitual memory. It receives glutamatergic input from wide area of the cerebral cortex as well as an extensive serotonergic (5-hydroxytryptamine, 5-HT) input from the raphe nuclei. In our study, the effects of 5-HT on synaptic transmission were studied in the rat corticostriatal brain slice using in vitro whole-cell recording technique. 5-HT inhibited the amplitude as well as frequency of spontaneous excitatory postsynaptic currents (sEPSC) significantly, and neither gamma-aminobutyric acid (GABA) A receptor antagonist bicuculline (BIC), nor N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonovaleric acid (AP-V) could block the effect of 5-HT. In the presence non-NMDA receptor antagonist, 2, 3-dioxo-6-nitro-1, 2, 3, 4-tetrahydrobenxo[f] quinoxaline-7-sulfonamide (NBQX), the inhibitory effect of 5-HT was blocked. We also figured out that 5-HT change the channel kinetics of the sEPSC. There was a significant increase in the rise time during the 5-HT application. Our results suggest that 5-HT has an effect on both pre- and postsynaptic site with decreasing neurotransmitter release probability of glutamate and decreasing the sensitivity to glutamate by increasing the rise time of non-NMDA receptor mediated synaptic transmission in the corticostriatal synapses.

Dopamine Modulates Corticostriatal Synaptic Transmission through Both D1 and D2 Receptor Subtypes in Rat Brain

Striatum has important roles in motor control, habitual learning and memory. It receives glutamatergic inputs from neocortex and thalamus, and dopaminergic inputs from substantia nigra. We examined effects of dopamine (DA) on the corticostriatal synaptic transmission using in vitro extracellular recording technique in rat brain corticostriatal slices. Synaptic responses were elicited by stimulation of cortical glutamatergic inputs on the corpus callosum and recorded in the dorsal striatum. Corticostriatal population spike (PS) amplitudes were decreased (39.4+/-7.9%) by the application of 100microM DA. We applied receptor subtype specific agonists and antagonists and characterized the modulation of corticostriatal synaptic transmission by different DA receptor subtypes. D2 receptor agonist (quinpirole), antagonist (sulpiride), and D1 receptor antagonist (SKF 83566), but not D1 receptor agonist (SKF 38393), induced significantly the reduction of striatal PS. Pretreatment neither with SKF 83566 nor sulpiride significantly affected corticostriatal synaptic inhibition by DA. However, the inhibition of DA was completely blocked by pretreatment with mixed solution of both SKF 83566 and sulpiride. These results suggest that DA inhibits corticostriatal synaptic transmission through both D1 and D2 receptors in concert with each other.

Inhibitory Modulation of 5-Hydroxytryptamine on Corticostriatal Synaptic Transmission in Rat Brain Slice

Striatum plays a crucial role in the movement control and habitual learning. It receives an information from wide area of cerebral cortex as well as an extensive serotonergic (5-hydroxytryptamine, 5-HT) input from raphe nuclei. In the present study, the effects of 5-HT to modulate synaptic transmission were studied in the rat corticostriatal brain slice using in vitro extracellular recording technique. Synaptic responses were evoked by stimulation of cortical glutamatergic inputs on the corpus callosum and recorded in the dorsal striatum. 5-HT reversibly inhibited coticostriatal glutamatergic synaptic transmission in a dose-dependent fashion (5, 10, 50, and 100 microM), maximally reducing in the corticostriatal population spike (PS) amplitude to 40.1+/-5.0% at a concentration of 50 microM 5-HT. PSs mediated by non-NMDA glutamate receptors, which were isolated by bath application of the NMDA receptor antagonist, d, l-2-amino-5-phospohonovaleric acid (AP-V), were decreased by application of 50 microM 5-HT. However, PSs mediated by NMDA receptors, that were activated by application of zero Mg2+ aCSF, were not significantly affected by 50 microM 5-HT. To test whether the corticostriatal synaptic inhibitions by 5-HT might involve a change in the probability of neurotransmitter release from presynaptic nerve terminals, we measured the paired-pulse ratio (PPR) evoked by 2 identical pulses (50 ms interpulse interval), and found that PPR was increased (33.4+/-5.2%) by 5-HT, reflecting decreased neurotransmitter releasing probability. These results suggest that 5-HT may decrease neurotransmitter release probability of glutamatergic corticostriatal synapse and may be able to selectively decrease non-NMDA glutamate receptor-mediated synaptic transmission.