Chronic fluoxetine treatment suppresses plasticity (long-term potentiation) in the mature rodent primary auditory cortex in vivo

Abstract

Several recent studies have provided evidence that chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine can facilitate synaptic plasticity (e.g., ocular dominance shifts) in the adult central nervous system. Here, we assessed whether fluoxetine enhances long-term potentiation (LTP) in the thalamocortical auditory system of mature rats, a developmentally regulated form of plasticity that shows a characteristic decline during postnatal life. Adult rats were chronically treated with fluoxetine (administered in the drinking water, 0.2 mg/mL, four weeks of treatment). Electrophysiological assessments were conducted using an anesthetized (urethane) in vivo preparation, with LTP of field potentials in the primary auditory cortex (A1) induced by theta-burst stimulation of the medial geniculate nucleus. We find that, compared to water-treated control animals, fluoxetine-treated rats did not express higher levels of LTP and, in fact, exhibited reduced levels of potentiation at presumed intracortical A1 synapses. Bioactivity of fluoxetine was confirmed by a reduction of weight gain and fluid intake during the four-week treatment period. We conclude that chronic fluoxetine treatment fails to enhance LTP in the mature rodent thalamocortical auditory system, results that bring into question the notion that SSRIs act as general facilitators of synaptic plasticity in the mammalian forebrain.

Figure 1

Body weight and water intake of rats given access to drinking water (n = 18) or drinking water containing fluoxetine (0.2 mg/mL; n = 20) during a 4-week treatment period. (a) Fluoxetine treatment significantly reduced body weight gain during the treatment period. ANOVA results: effect of time, F(4,144) = 370.8, P < 0.0001; effect of group, F(1,36) = 5.8, P = 0.02; interaction, F(4,144) = 13.8, P < 0.0001; * indicates significant (P < 0.05) simple effects tests. (b) Fluoxetine also reduced fluid intake relative to the control (water) condition during the entire treatment period. ANOVA results: effect of time, F(13,286) = 2.3, P = 0.006; effect of group, F(1,22) = 43.9, P < 0.0001; interaction, F(13,286) = 0.9, P = 0.6. Note that statistics for fluid intake are limited to n = 12 for both groups since some of the water bottles used did not permit accurate measurement of fluid consumption.

Figure 2

(a) Schematic diagram of electrode placements in the medial geniculate nucleus (MGN) and primary auditory cortex (A1); numbers indicate distance (in mm) from bregma. Diagrams adapted from Paxinos and Watson [40]. (b) Field postsynaptic potentials (fPSPs) recorded in A1 in response to single pulse MGN stimulation consisted of two successive, negative-going peaks. (the initial, sharp, negative spike is the stimulation artifact.) Red and blue traces are taken before and after theta-burst stimulation of the MGN, respectively. Note the absence of clear potentiation of the second fPSP peak in the fluoxetine-treated rat. (c) Final urethane dose required for anesthesia induction in the two treatment groups. (d) Stimulation intensities used for the electrophysiological experiments. (e) Baseline (pre-LTP induction) amplitude of the first fPSP peak. (f) The second fPSP peak recorded in A1 of rats given access to drinking water (n = 11) or water containing fluoxetine (0.2 mg/mL; n = 14) during a 4-week treatment period. Statistical analyses for all comparisons did not reveal any significant group differences. (P's >0.05; note that the 23% amplitude increase for the second fPSP peak in fluoxetine animals also failed to approach statistical significance, P = 0.3.)

Figure 3

Amplitude of the first (a) and second (b) peak of field postsynaptic potentials (fPSPs) in the auditory cortex of rats treated with water (n = 11) or fluoxetine (n = 14), and the effect of theta-burst stimulation (TBS, at arrow) of the medial geniculate nucleus. Two episodes of TBS resulted in significant increases of amplitude of both the first (a) and second (b) fPSP peak in both groups of rats. However, for the second fPSP peak, fluoxetine-treated rats showed significantly less LTP than that seen in water animals. ANOVA results for (a) effect of time, F(14,322) = 10.4, P < 0.0001; effect of group, F(1,23) = 0.8, P = 0.4; interaction, F(14,322) = 0.5, P = 0.9. ANOVA results for (b) effect of time, F(14,252) = 10.0, P < 0.0001; effect of group, F(1,18) = 3.6, P = 0.08; interaction, F(14,252) = 2.2, P = 0.007; * indicates significant (P < 0.05) simple effects tests comparing the two treatment groups. (Note that group sizes for the analysis of the second peak were n = 9 and n = 11 for water and fluoxetine rats, resp., since this peak could not be consistently resolved in all animals.)

Figure 4

Baseline (pre-theta-burst stimulation) amplitude of the second field postsynaptic potentials (fPSPs) peak and levels of long-term potentiation (LTP) in rats treated with fluoxetine (n = 11). Data are expressed as rank, with Rank 1 indicating the highest fPSP amplitude and greatest level of LTP. Note the absence of a significant correlation (P > 0.05) between the two variables.