Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: role of 5-HT1A receptors

Abstract

1 Microdialysis was used to study the acute and chronic effects of escitalopram (S-citalopram; ESCIT) and chronic citalopram (CIT), together with the 5-HT1A receptor antagonist WAY100,635 (N-[2-[methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride) and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on extracellular 5-hydroxytryptamine (5-HT) levels in the rat prefrontal cortex. 2 Extracellular 5-HT rose to 234 and 298% of basal values after subcutaneous (s.c.) acute doses of 0.15 and 0.63 mg kg(-1) ESCIT. No further increase was observed at 2.5 mg kg(-1) ESCIT (290%). 3 The effect of 13-day s.c. infusion of 10 mg kg(-1) day(-1) ESCIT on extracellular 5-HT (422% of baseline) was greater than after 2 days (257% of baseline), whereas exposure to ESCIT was similar. In contrast, the increase in extracellular 5-HT induced by the infusion of CIT for 2 (306%) and 13 days (302%) was similar. However, brain and plasma levels of S-citalopram in rats infused with CIT for 13 days were lower than after 2 days. 4 Acute treatment with 2.5 mg kg(-1) ESCIT or 5 mg kg(-1) CIT raised extracellular 5-HT by 243 and 276%, respectively, in rats given chronic vehicle but had no effect in rats given ESCIT (10 mg kg(-1) day(-1)) or CIT (20 mg kg(-1) day(-1)) for 2 or 13 days, suggesting that the infused doses had maximally increased extracellular 5-HT. WAY100,635 (0.1 mg kg(-1) s.c.) increased extracellular 5-HT levels by 168, 174 and 169% of prechallenge values in rats infused with vehicle or ESCIT for 2 or 13 days, respectively. WAY100,635 enhanced extracellular 5-HT levels to 226, 153 and 164% of prechallenge values in rats infused with vehicle or CIT for 2 and 13 days, respectively. 5 8-OH-DPAT (0.025 mg kg(-1)) reduced extracellular 5-HT by 54% in control rats, but had no effect in those given ESCIT and CIT for 13 days. 6 This series of experiments led to the conclusion that chronic treatment with ESCIT desensitizes the 5-HT1A receptors, regulating the release of 5-HT in the prefrontal cortex and enhances the effect of the drug on extracellular 5-HT. They also indicate that chronic treatment with ESCIT and CIT did not prevent WAY100,635 from raising extracellular 5-HT.

Figure 1

Extracellular 5-HT levels in the prefrontal cortex of rats injected subcutaneously with PBS, 0.02, 0.04, 0.15, 0.63 and 2.5 mg kg⁻¹ ESCIT. Once the extracellular concentration of 5-HT was stable, rats were injected s.c. with ESCIT or vehicle (arrow). Data are means±s.e.m. and are percentages of preinjection values. Basal levels of 5-HT in fmol 20 μl⁻¹ (mean±s.e.m.) were: PBS, 4.5±0.4 (n=4); 0.02 mg kg⁻¹, 4.1±0.4 (n=3); 0.04 mg kg⁻¹, 4.6±0.6 (n=5); 0.15 mg kg⁻¹, 3.7±0.5 (n=4); 0.63 mg kg⁻¹, 6.3±1.1 (n=4); 2.5 mg kg⁻¹, 4.7±0.6 (n=8). Solid symbols indicate P<0.05 vs PBS (Tukey–Kramer's test).

Figure 2

Effect of a challenge dose of ESCIT and the selective 5-HT_1A receptor antagonist WAY100,635 (WAY) on extracellular 5-HT levels in the prefrontal cortex in rats given chronic ESCIT. Rats were infused with PBS or 10 mg kg⁻¹ day⁻¹ ESCIT for 2 and 13 days. On the last day, with the osmotic pump in place, rats were injected s.c. with two consecutive drug challenges: 2.5 mg kg⁻¹ ESCIT (first arrow), followed by 0.1 mg kg⁻¹ WAY100,635 or saline (SAL) 60 min apart (second arrow). Data are means±s.e.m. Basal levels of 5-HT in fmol 20 μl⁻¹ (mean±s.e.m.) were: PBS+PBS+SAL, 4.8±0.3 (n=5); PBS+ESCIT+ SAL, 4.6±0.6 (n=4); PBS+ ESCIT+WAY, 4.6±0.4 (n=10); ESCIT × 2+ESCIT+WAY, 11.8±1.6 (n=6); ESCIT × 13+ESCIT+WAY, 19.4±2.9 (n=6). Solid symbols indicate P<0.05 vs PBS+PBS+SAL (Tukey–Kramer's test). Asterisks indicate a significant increase of extracellular 5-HT in rats given WAY100,635 compared to those receiving ESCIT alone (P<0.05; Tukey–Kramer's test).

Figure 3

Effect of a challenge dose of CIT and the selective 5-HT_1A receptor antagonist WAY100,635 (WAY) on extracellular 5-HT levels in the prefrontal cortex in rats given chronic CIT. Rats were infused with PBS or 20 mg kg⁻¹ day⁻¹ CIT for 2 and 13 days. On the last day, with the osmotic pump in place, rats were injected s.c. with two consecutive drug challenges: 5 mg kg⁻¹ CIT (first arrow), followed by 0.1 mg kg⁻¹ WAY100,635 or saline (SAL) 60 min apart (second arrow). Data are means±s.e.m. Basal levels of 5-HT in fmol 20 μl⁻¹ (mean±s.e.m.) were: PBS+PBS+SAL, 4.8±0.3 (n=5); PBS+CIT+SAL, 5.5±1.1 (n=5); PBS+CIT+WAY, 5.2±0.8 (n=10); CIT × 2+CIT+WAY, 15.9±1.6 (n=9); CIT × 13+CIT+WAY, 15.7±1.6 (n=10). Solid symbols indicate P<0.05 vs PBS+PBS+SAL (Tukey–Kramer's test). Asterisks indicate a significant increase of extracellular 5-HT in rats given WAY100,635 compared to those receiving CIT alone (P<0.05; Tukey–Kramer's test).

Figure 4

Effect of chronic ESCIT and CIT on 8-OH-DPAT-induced decrease of extracellular 5-HT in the prefrontal cortex. Rats were infused with PBS, 10 mg kg⁻¹ day⁻¹ ESCIT or 20 mg/kg CIT for 13 days. On day 14, about 24 h after removal of the osmotic pump, rats were injected with a challenge dose of the selective 5-HT_1A receptor agonist 8-OH-DPAT (DPAT; 0.025 mg kg⁻¹ s.c.) or saline (SAL) (arrow). Data are means±s.e.m. Basal levels of 5-HT in fmol 20 μl⁻¹ were: PBS+SAL, 6.2±0.5 (n=5); PBS+DPAT, 5.4±0.5 (n=6); ESCIT+DPAT, 6.9±0.9 (n=7); CIT+DPAT, 6.2±0.8 (n=8). Solid symbol indicates P<0.05 vs PBS+SAL (Tukey–Kramer's test). The asterisk indicates a significant difference between extracellular 5-HT levels in rats given chronic ESCIT or CIT and those infused with PBS (P<0.05 for both comparisons; Tukey–Kramer's test).