SEARCH

SEARCH BY CITATION

Keywords:

  • atypical antipsychotic drugs;
  • D2 receptor;
  • dopamine release;
  • 5-HT2A receptor;
  • 5-HT1A receptor;
  • rat medial prefrontal cortex

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)2A than dopamine D2 antagonists, may improve negative symptoms and cognitive dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT1A agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT1A receptor activation, as a result of the blockade of 5-HT2A and D2 receptors. M100907 (0.1 mg/kg), a 5-HT2A antagonist, significantly increased the ability of both S(–)-sulpiride (10 mg/kg), a D2 antagonist devoid of 5-HT1A affinity, and R(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT1A agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT1A antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT1A partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT2A and D2 receptor blockade, regardless of intrinsic 5-HT1A affinity, may promote the ability of 5-HT1A receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT2A antagonists and typical APDs, which are D2 antagonists, may facilitate 5-HT1A agonist activity.

Abbreviations used
APDs

antipsychotic drugs

AUC

area under the curve

DA

dopamine

5,7-DHT

5,7-di-hydroxytryptamine

DRN

dorsal raphe nucleus

5-HT

serotonin

mPFC

medial prefrontal cortex

NAC

nucleus accumbens

STR

striatum

VTA

ventral tegmental area

The atypical antipsychotic drugs (APDs) clozapine, and olanzapine at high doses, but not the typical APDs haloperidol or S(–)-sulpiride, produce greater increases in dopamine (DA) release in rat medial prefrontal cortex (mPFC) compared with the nucleus accumbens (NAC) or striatum (STR) (Moghaddam and Bunney 1990; Volontéet al. 1997; Li et al. 1998; Kuroki et al. 1999). However, low dose olanzapine and another atypical APD, risperidone, increase DA release, to a similar extent, in the mPFC and NAC (Kuroki et al. 1999). The increased DA release in the mPFC has been hypothesized to contribute to the ability to improve negative symptoms and some domains of cognition in schizophrenia (Moghaddam and Bunney 1990; Kuroki et al. 1999; Meltzer and McGurk 1999). The ability to increase DA release in the mPFC has been shown to inversely correlate with the ratio of the affinity of atypical APDs for serotonin (5-HT)2A and D2 receptors (Kuroki et al. 1999). Atypical APDs have been shown to have higher affinity for 5-HT2A than D2 receptors in vitro (Meltzer et al. 1989) and in vivo (Stockmeier et al. 1993; Zhang and Bymaster 1999). Therefore, it was of interest to study the mechanism by which 5-HT2A and D2 receptor blockade facilitate DA release in the mPFC. However, atypical APDs have variable and often potent affinity for other monoamine receptors (Schotte et al. 1996). Thus, direct and/or indirect effects of these agents on receptors other than 5-HT2A and D2 receptors could modulate DA release in the mPFC. In particular, opposite effects of 5-HT2A and 5-HT1A receptor stimulation are well-known (Millan et al. 1992).

Selective 5-HT1A receptor agonists, e.g. R(+)-8-OH-DPAT, increase DA release in the mPFC (Tanda et al. 1994; Kuroki et al. 1996; Gobert et al. 1998; Rollema et al. 2000; Sakaue et al. 2000), suggesting this is a potential basis for the action of at least some of the atypical APDs. 5-HT1A receptor activation may be one of the mechanisms which influence clozapine-induced DA release in the mPFC. Clozapine has been reported to be a 5-HT1A receptor partial agonist (Newman-Tancredi et al. 1998) and its ability to increase DA release in the mPFC is inhibited by WAY100635, a 5-HT1A receptor antagonist (Rollema et al. 1997). Ziprasidone and quetiapine are also 5-HT1A receptor partial agonists, while olanzapine, risperidone, sertindole and haloperidol have low affinity for 5-HT1A receptors (Newman-Tancredi et al. 1998). 5-HT2A receptor antagonists, e.g. M100907, do not increase DA release in the mPFC (Gobert and Millan 1999; Rollema et al. 2000).

As examples of 5-HT1A/5–HT2A interactions, ritanserin, a 5-HT2A/2C, or ketanserin, a 5-HT2A receptor antagonist, increases the 5–HT1A behavioral syndrome (Backus et al. 1990), whereas 8-OH-DPAT, a 5-HT1A receptor agonist, attenuated, and WAY100635 potentiated, the head twitch response in rats given DOI, a 5-HT2A/2C receptor agonist, directly into the mPFC (Willins and Meltzer 1997). Electrophysiological studies have demonstrated that both 5-HT1A receptor activation and 5-HT2A receptor blockade produce membrane hyperpolarization in the mPFC that inhibits neuronal activity (Araneda and Andrade 1991). There is also evidence that 8-OH-DPAT, ritanserin, and M100907, a selective 5-HT2A receptor antagonist, potentiate the effect of raclopride, a D2/3 receptor antagonist, to suppress conditioned avoidance response (Wadenberg et al. 1996, 1998), a model for antipsychotic activity. Furthermore, ritanserin potentiated raclopride-induced DA release in the mPFC (Andersson et al. 1995), while R(+)-8-OH-DPAT potentiated the ability of S(–)-sulpiride, another D2/3 receptor antagonist, to increase DA release in the mPFC, an effect reversed by WAY100635 (Ichikawa and Meltzer 1999a). These results indicate that either 5-HT1A receptor activation or 5-HT2A receptor blockade can interact with D2 receptor antagonism to increase DA release in the mPFC. However, it should be noted that ritanserin has appreciable affinity (Ki values, nM) for D2 (36), α1-adrenergic (35), and α2-adrenergic (54) receptors (Leysen et al. 1993), and could potentiate raclopride-induced DA release in the mPFC via α2-adrenoceptor blockade, as has been shown by idazoxan, an α2-adrenoceptor antagonist (Hertel et al. 1999). Thus, selective 5-HT2A receptor antagonists, e.g. M100907, are needed to determine the effect of 5-HT2A and D2 receptor blockade on DA release.

The present study was designed to test the hypothesis, by using selective agonists and antagonists, that: (1) 5-HT1A receptor activation, but not 5-HT2A receptor blockade, increases DA release; (2) 5-HT2A receptor blockade and 5-HT1A receptor activation have synergistic effects on DA release; (3) 5-HT1A receptor activation, 5-HT2A receptor blockade, or the combination, potentiate the ability of D2 receptor blockade to increase DA release; and that (4) 5-HT1A receptor blockade attenuates the ability of the atypical APDs clozapine, olanzapine and risperidone, to increase DA release in the mPFC.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Animals

Male Sprague-Dawley albino rats (Zivic-Miller Laboratories, Porterville, PA, USA) weighing 250–350 g were housed two to three per cage and maintained in a controlled 12 : 12-h light–dark cycle and under constant temperature at 22°C, with free access to food and water.

Surgery and microdialysis

Rats were anesthetized with a combination (i.p.) of xylazine (13 mg/kg, Rompun; Shawnee Mission, KS, USA) and ketamine hydrochloride (87 mg/kg, Ketaset; Fort Dodge Laboratories, Fort Dodge, IA, USA) and mounted in a stereotaxic frame (Stoetling, Wood Dale, IL, USA). Two stainless 21 G guide cannula with a dummy probe were placed and fixed by cranioplastic cement (Plastic One, Roanoke, VA, USA) onto the cortex dorsal to the mPFC. Stereotaxic coordinate of probe, when implanted, is A + 3.2, L-0.8, V-5.5 mm, relative to bregma; incision bar level: − 3.0 mm, according to the atlas of Paxinos and Watson (1986).

Concentric-shaped dialysis probes were constructed as follows. A silica-glass capillary tube (150 µm o.d., 75 µm i.d., Polymicro Technologies, Phoenix, AZ, USA) was inserted through the inner bore of a 25 G stainless tube. The stainless tube was inserted into a 28 G Teflon tubing and then the Teflon tubing was inserted into the inner bore of a 18 G stainless-tube. The hollow fiber dialysis membrane (polyacrylonitrile/sodium methalylsulfonate polymer, 310 µm o.d., 220 µm i.d., molecular weight cut-off 40 000, AN69 HF, Hospal) was fitted over the glass capillary and into the end of the 25 G stainless tube. This junction (0.5 mm) was glued with epoxy (5-Minute Epoxy; Devkon, Danverse, MA, USA) after the length of the hollow dialysis fiber was cut to 3.0 mm and the tip of the membrane (0.5 mm) plugged with epoxy. Thus, the length of exposed non-glued surface for dialyzing was 2 mm.

Three to five days following cannulation, a dialysis probe was implanted into the mPFC under slight anesthesia with methoxyflurane (Metofane; Pitman-Moore, Mundelein, IL, USA). For systemic administration of drugs or vehicle, a catheter constructed from microbore Tygon tubing (TGY-010, 0.03' o.d., 0.01' i.d.; Small Parts Inc., Miami Lakes, FL, USA) was implanted subcutaneously in the intrascapular space of the rats. Rats were then housed individually overnight in a dialysis cage. After the overnight perfusion (0.4 µL/min) of the probe (approximately 15 h), dialysate samples (12 µL) were collected every 30 min. The perfusion medium was Dulbecco's phosphate-buffered saline solution (Sigma, St Louis, MO, USA) including Ca2+ (138 mm NaCl, 8.1 mm Na2HPO4, 2.7 mm KCl, 1.5 mm KH2PO4, 0.5 mm MgCl, 1.2 mm CaCl2, pH = 7.4). After stable baseline values in the dialysates were obtained, each drug or vehicle was administered to the rats. The location of the dialysis probes were verified at the end of each experiment by manual brain dissection and with 100-µm brain slices (OTS-4000; FHC, Bowdoinham, ME, USA). The procedures applied in these experiments were approved by the Institutional Animal Care and Use Committee of Vanderbilt University in Nashville, TN, USA.

Biochemical assay

Dialysate samples (12 µL/30 min) were directly applied onto a HPLC with electrochemical detection with a 10-µL sample loop and analyzed for DA with a Millennium chromatogram manager (Waters, Milford, MA, USA). DA was separated on a stainless steel, reversed phase column (BDS Hypersil 3 µm C18, 1.0 × 100 mm; Keystone Scientific, Bellefonte, PA, USA) at 35°C maintained by column oven (831 Temperature Controller; Gilson, Middleton, WI, USA) or by column heater (LC-22C Temperature Controller; BAS, West Lafayette, PA, USA). The mobile phase consisted of 48 mm anhydrous citric acid and 24 mm sodium acetate trihydrate containing 0.5 mm EDTA-Na2, 10 mm NaCl, 2 mm dodecyl sulfate sodium salt (Acros, Pittsburgh, PA, USA) and 17% (v/v) acetonitrile, adjusted to pH 4.8 with concentrated NaOH, and was pumped at the flow rate of 0.05 mL/min by LC-10AD (Shimadzu, Kyoto, Japan). DA was detected by a 3-mm glassy carbon unijet working electrode (MF-1003, BAS) set at + 0.58 V (LC-4C, BAS) vs. an Ag/AgCl reference electrode. Reagents used were analytical or HPLC grade.

Drugs

R(+)-8-OH-DPAT (RBI, Natick, MA, USA), WAY100635 (Sandoz, Basel, Switzerland) and (+/–)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) (RBI, Natick, MA, USA) were dissolved in deionized water. Clozapine hydrochloride (Sandoz, Basel, Switzerland), risperidone (RBI, Natick, MA, USA), S(–)-sulpiride (RBI, Natick, MA, USA) and M100907 (Marion Merrell Dow, OH, USA) were dissolved in 0.1 m tartaric acid solution and was adjusted to pH 6–7 with NaOH. Vehicle or drugs were administered through the indwelling subcutaneous catheter.

Data analysis

Only results derived from healthy rats with correctly positioned dialysis probes were included in the data analysis. Mean predrug baseline levels (time − 60, time − 30 and time 0) were designated as 100%. Repeated measure anova followed by Fisher's protected least significant difference posthoc pairwise comparison procedure and one-way anova were used to determine group differences (StatView 4.5 for the Macintosh). A p < 0.05 was considered significant in this study. All results are given as means ± SE.

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Basal DA levels in the dialysates from the mPFC were 1.91 ± 0.09 (fmol/10 µL/30 min, not corrected by percentage recovery of a dialysis probe) (n = 104). There were no significant differences in basal extracellular DA levels in the mPFC between treatment groups. The injection of either 0.1 m tartaric acid neutralized with NaOH or deionized water through an indwelling subcutaneous catheter had no significant effect on extracellular levels of DA in the mPFC. Therefore, the data for the effects of either 0.1 m tartaric acid neutralized with NaOH or deionized water on extracellular DA levels were combined and used as the vehicle controls for statistical analysis and graphical presentation.

R(+)-8-OH-DPAT (0.1, 0.2 and 0.5, but not 0.05, mg/kg) produced an inverted U-shape increase in DA release in the mPFC with the maximum increase at 0.2 mg/kg (Fig. 1a); this increase was completely reversed by WAY100635 (0.2 mg/kg) (Fig. 1c). R(+)-8-OH-DPAT (0.05 mg/kg) produced a significant increase in DA release only at 30 min following injection. WAY100635 (0.05, 0.1, 0.2 or 0.5 mg/kg) by itself had no significant effect on DA release in the mPFC (Fig. 1b).

image

Figure 1. The effect of R(+)-8-OH-DPAT, a selective 5-HT1A receptor agonist, and WAY100635, a selective 5-HT1A receptor antagonist, on DA release in the mPFC. (a) R(+)-8-OH-DPAT (II) significantly increased DA release at 0.1 mg/kg (●; F1,9 = 40.38, p < 0.001), 0.2 mg/kg (▿F1,9 = 176.70, p < 0.001) and 0.5 mg/kg (▾; F1,9 = 39.07, p < 0.001), but not 0.05 mg/kg (○; F1,9 = 3.61, p = 0.09), compared with vehicle controls (□). One-way anova showed that the effect of R(+)-8-OH-DPAT (0.05 mg/kg) on DA release at 30 min following injection, was significantly different from that of vehicle controls at the corresponding time (F1,9 = 24.93, p < 0.001). (b) WAY100635 (I) had no effect on DA release at 0.05 (○), 0.1 (●), 0.2 (▿) or 0.5 mg/kg (▾), compared with vehicle controls (□). (c) The ability of R(+)-8-OH-DPAT (0.2 mg/kg) (II) to increase DA release was abolished by WAY100635 (0.2 mg/kg) (I), given 30 min prior to R(+)-8-OH-DPAT (●; F1,9 = 43.40, p = 0.001), compared with the effect of R(+)-8 OH-DPAT alone (○). R(+)-8-OH-DPAT-induced DA release abolished by WAY100635 (●; F1,10 = 4.27, p = 0.07) was not significantly different from vehicle controls (□). n = 4–6.

Download figure to PowerPoint

M100907 (0.03, 0.1 and 1 mg/kg) significantly potentiated R(+)-8-OH-DPAT (0.05 and 0.1 mg/kg)-induced DA release in the mPFC (Fig. 2a). M100907 (0.1 mg/kg) also significantly potentiated R(+)-8-OH-DPAT (0.1, but not 0.2, mg/kg)-induced DA release in the mPFC (Fig. 2b). The potentiation by M100907 (0.1 mg/kg) of R(+)-8-OH-DPAT (0.0.5 mg/kg) was completely reversed by WAY100635 (0.05 mg/kg) (Fig. 2c). M100907 (0.03, 0.1 and 1 mg/kg) by itself had no significant effect on DA release in the mPFC.

image

Figure 2. The effect of M100907, a selective 5-HT2A receptor antagonist, on the ability of R(+)-8-OH DPAT, a selective 5-HT1A receptor agonist, to increase DA release in the mPFC. (a) The ability of R(+)-8-OH-DPAT (0.05 mg/kg) (II) to increase DA release was significantly increased by M100907 (I), given 30 min prior to R(+)-8-OH-DPAT, at 0.03 mg/kg (●; F1,9 = 23.60, p < 0.001), 0.1 mg/kg (▿F1,9 = 13.14, p = 0.006) and 1 mg/kg (▾; F1,9 = 21.42, p = 0.001), respectively, compared with the effect of R(+)-8-OH-DPAT alone which had no significant effect on DA release (○). (b) M100907 (0.1 mg/kg) (I), given 30 min prior to R(+)-8-OH-DPAT (II), significantly increased the ability of R(+)-8-OH-DPAT at 0.1 (●; F1,9 = 7.77, p = 0.021), but not 0.2 mg/kg (▾; F1,9 = 0.02, p = 0.89), to increase DA release, compared with the effect of R(+)-8-OH-DPAT alone at 0.1 (○) or 0.2 mg/kg (▿), respectively. (c) WAY100635 (0.05 mg/kg) (WAY), given 5 min prior to M100907 (I), abolished R(+)-8-OH-DPAT (0.05 mg/kg) (II)-induced DA release enhanced by M100907 (0.1 mg/kg) (▿F1,10 = 13.42, p = 0.004), compared with the effect of a combination of M100907 and R(+)-8-OH-DPAT (●). (d) M100907 alone (I) had no significant effect on DA release at 0.03 (○), 0.1 (●) or 1.0 mg/kg (▿), compared with vehicle controls (□).

Download figure to PowerPoint

S(–)-sulpiride (10 mg/kg) alone slightly but significantly increased DA release in the mPFC (Fig. 3a). This effect was further increased by R(+)-8-OH-DPAT (0.05 mg/kg) as well as M100907 (0.1 mg/kg) (Figs 3a and b, respectively). The combination of R(+)-8-OH-DPAT (0.05 mg/kg), M100907 (0.1 mg/kg), and S(–)-sulpiride (10 mg/kg) also significantly increased DA release in the mPFC (Fig. 3c). However, this increase was comparable to that produced by the combination of R(+)-8-OH-DPAT (0.05 mg/kg) and M100907 (0.1 mg/kg) without S(–)-sulpiride (Fig. 3c), and was not significantly different from the increase produced by the combination of R(+)-8 OH-DPAT (0.05 mg/kg) and S(–)-sulpiride (10 mg/kg) (Fig. 3a), or the combination of M100907 (0.1 mg/kg) and S(–)-sulpiride (10 mg/kg) (Fig. 3b), respectively. Most importantly, WAY100635 (0.05 mg/kg) completely abolished the effect of the combination of M100907 (0.1 mg/kg) and S(–)-sulpiride (10 mg/kg) on DA release in the mPFC (Fig. 3d).

image

Figure 3. The effect of R(+)-8-OH-DPAT, a selective 5-HT1A receptor agonist, and M100907, a selective 5 HT2A receptor antagonist, on the ability of S(–)-sulpiride, a selective D2/3 receptor antagonist, to increase DA release in the mPFC. (a) S(–)-sulpiride (10 mg/kg) (II) significantly increased DA release (▿F1,10 = 17.21, p = 0.002), compared with vehicle controls (□). R(+)-8-OH-DPAT (0.05 mg/kg) (I),given 30 min prior to S(–)-sulpiride (II), significantly increased the ability of S(–)-sulpiride (10 mg/kg) to increase DA release (○; F1,10 = 8.98, p = 0.013), compared with the effect of S(–)-sulpiride alone. (b) M100907 (0.1 mg/kg) (I), given 30 min prior to S(–)-sulpiride (II), significantly increased the ability of S(–)-sulpiride (10 mg/kg) to increase DA release (○; F1,10 = 18.27, p = 0.0021), compared with the effect of S(–)-sulpiride alone (▿). (c) The combination (I) of M100907 (0.1 mg/kg), given 5 min prior to R(+)-8-OH-DPAT, and R(+)-8-OH-DPAT (0.05 mg/kg), given 30 min prior to S(–)-sulpiride (II), significantly increased the ability of S(–)-sulpiride (10 mg/kg) to increase DA release (●; F1,10 = 8.96, p = 0.0112), compared with the effect of S(–)-sulpiride alone (○), but not significantly different (F1,12 = 0.02, p = 0.89) from the effect of combination alone (▿). (d) WAY100635 (WAY, 0.05 mg/kg), a selective 5-HT1A receptor antagonist, given 5 min prior to M100907 (I), abolished S(–)-sulpiride (10 mg/kg) (II)-induced DA release enhanced by M100907 (0.1 mg/kg) (●; F1,10 = 39.95, p < 0.0001), compared with the effect of a combination of M100907 and S(–)-sulpiride (○). n = 6–8.

Download figure to PowerPoint

Clozapine (20 mg/kg), risperidone (1 mg/kg) and olanzapine (1 mg/kg) markedly increased DA release in the mPFC; these increases were significantly attenuated by WAY100635 (0.2 mg/kg) (Figs 4a–c), respectively. Interestingly, however, the ability of high dose olanzapine (10 mg/kg) to increase DA release in the mPFC was not significantly affected by WAY100635 (0.2 mg/kg) (Fig. 4d).

image

Figure 4. The effect of WAY100635, a selective 5-HT1A receptor antagonist on the ability of clozapine, risperidone and olanzapine, atypical antipsychotic drugs which are 5 HT2A/D2 antagonist and 5-HT1A receptor partial agonist (clozapine), to increase DA release in the mPFC. WAY100635 (0.2 mg/kg) (I), given 30 min prior to clozapine (20 mg/kg, a), risperidone (1 mg/kg, b) and olanzapine (1 mg/kg, c) (II), significantly attenuated their ability to increase DA release (clozapine: ●; F1,10 = 11.58, p = 0.007) (risperidone: ●; F1,11 = 11.16, p = 0.007), and (olanzapine: ●; F1,10 = 13.92, p = 0.004), respectively, compared with each effect of themselves (○). The DA release (●) attenuated by WAY100635 (clozapine 20 mg/kg: F1,10 = 13.26, p = 0.005; risperidone 1 mg/kg: F1,10 = 20.11, p = 0.001; olanzapine 1 mg/kg: F1,10 = 83.86, p < 0.001) was significantly different from vehicle controls (□). (d) WAY100635 (0.2 mg/kg) (I), given 30 min prior to high dose olanzapine (10 mg/kg) (II), had no significant effect on the ability to increase DA release (●; F1,10 = 1.80, p = 0.21), compared with olanzapine alone (○). WAY100653 (▿; 0.2 mg/kg) alone had no effect on DA release. n = 5–8.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The present results demonstrate that in the mPFC: (1) activation of 5-HT1A receptors by R(+)-8 OH-DPAT increases DA release; (2) 5-HT2A receptor blockade by M100907 potentiates the effect of 5-HT1A receptor activation by R(+)-8-OH-DPAT on DA release; (3) D2 receptor blockade by S(–)-sulpiride potentiates the effect of 5-HT1A receptor activation by R(+)-8-OH-DPAT on DA release; (4) combined blockade of 5-HT2A and D2 receptors by M100907 and S(–)-sulpiride, respectively, produces a greater increase in DA release than that by each alone; (5) 5-HT1A receptor blockade by WAY100635 abolishes the effect of the combination of M100907 and S(–)-sulpiride on DA release; and (6) WAY100635 attenuated the ability of clozapine, risperidone and olanzapine to increase DA release.

Role of 5-HT1A receptors

Stimulation of 5-HT1A receptors by R(+)-8-OH-DPAT increased DA release in the mPFC, consistent with previous reports (Tanda et al. 1994; Kuroki et al. 1996; Gobert et al. 1998; Rollema et al. 2000). These increases were abolished by WAY100635 (Fig. 1). Sakaue et al. (2000) have recently reported that: (1) local application of 8-OH-DPAT in the perfusion medium significantly increased DA release in the mPFC; (2) systemic administration and local application of MKC-242, a selective 5-HT1A receptor agonist (Matsuda et al. 1995), increased DA release in the mPFC, and that this increase was antagonized by coperfusion of WAY100635; and (3) pretreatment of rats with 5,7-DHT (di-hydroxytryptamine), which has toxic effects on 5-HT neurons and destroys 5-HT neuron terminals, had no significant effect on the ability of MKC-242 to increase DA release in the mPFC. The results of Sakaue et al. (2000) suggest that activation of postsynaptic 5-HT1A receptors in the mPFC may increase DA release in that region. Electrophysiological studies demonstrated that systemic administration of R(+)-8-OH-DPAT (Arborelius et al. 1993) and 8-OH-DPAT (Prisco et al. 1994) increases the burst firing rate of DA neurons in the ventral tegmental area (VTA), possibly via stimulation of 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN). This increase in the firing rate could result in an increase in DA release in the mPFC. However, this seems to be unlikely, since R(+)-8-OH-DPAT has been reported to increase the DA neuron firing in the VTA, only at a much higher dose range (0.01–0.1 mg/kg, i.v.), compared with the dose (< 0.001 mg/kg, i.v.) which completely shut down the firing of 5-HT neurons in the DRN (Lejeune et al. 1997). The results of Lejeune et al. (1997) suggested that reduction of 5-HT activity in the DRN via stimulation of 5-HT1A autoreceptors is not related to increased DA neuron firing in the VTA. There is also a dissociation between the VTA DA neuron activity and the release of DA from the VTA DA terminals, since ritanserin, a 5-HT2A/2C receptor antagonist, which increases DA neuron firing in the VTA (Ugedo et al. 1989), did not increase DA release in the mPFC (Andersson et al. 1995; Hertel et al. 1996). Therefore, it is more likely that stimulation of 5-HT1A receptors located in the mPFC (Pompeiano et al. 1992; Khawaja et al. 1995) increases DA release in that region. The present finding that R(+)-8-OH-DPAT produced an inverted U-shape increase in DA release in the mPFC is of interest in this regard. This effect may be due to increased stimulation of postsynaptic 5-HT1A receptors or nonselective effects in the mPFC at higher dose of R(+)-8-OH-DPAT, although the precise mechanism remains unknown.

Interaction of 5-HT1A and 5-HT2A receptors

WAY100635 completely abolished the effect of M100907 to potentiate R(+)-8-OH-DPAT-induced DA release in the mPFC (Fig. 2). This indicates that 5-HT2A receptor blockade increases the effect of 5-HT1A receptor activation on DA release in the mPFC. This hypothesis is consistent with electrophysiological studies which demonstrated that systemic M100907 potentiates the ability of 8-OH-DPAT to suppress the basal firing rate of spontaneously active cells in the mPFC whereas 8-OH-DPAT attenuates the ability of DOI, a 5-HT2A/2C receptor agonist, to potentiate the l-glutamate-induced excitation of quiescent cells in the mPFC (Ashby et al. 1994). 5-HT1A and 5-HT2A receptors in the mPFC (Pazos et al. 1985; Pompeiano et al. 1992) are co-localized on the same cell and may mediate hyperpolarization and depolarization, respectively (Araneda and Andrade 1991). M100907 (0.1 mg/kg) had no effect on the ability of R(+)-8-OH-DPAT (0.2 mg/kg) to produce maximal increase in DA release, possibly because the effect of 5-HT1A receptor stimulation on DA release was already maximal. M100907, 0.03 mg/kg, may also provide maximal blockade of 5-HT2A receptors with regard to potentiating the effect of 5-HT1A receptor activation, because the effects of M100907 (0.03, 0.1 and 1 mg/kg) on R(+)-8-OH-DPAT (0.05 mg/kg)-induced DA release in the mPFC were virtually identical. These results suggest that 5-HT2A receptor blockade does not lead to excessive 5-HT1A receptor activation, which might be expected to diminish the effect of 5-HT1A receptor activation on DA release in the mPFC. M100907 by itself had no significant effect on DA release in the mPFC (Fig. 2d); these results are consistent with the report of Gobert and Millan (1999) and Rollema et al. (2000).

5-HT1A receptor activation by simultaneous blockade of 5-HT2A and D2 receptors

S(–)-sulpiride has not been reported to have appreciable affinity for 5-HT1A, 5-HT2A, α1-adrenergic, and α2-adrenergic receptors, and appears to be selective for D2 and D3 receptors. The effect of S(–)-sulpiride on DA release is most likely due to blockade of D2 autoreceptors (Santiago and Westerink 1991a, 1991b). R(+)-8-OH-DPAT and M100907, respectively, potentiated S(–)-sulpiride (10 mg/kg)-induced DA release in the mPFC (Figs 3a–b), an effect reversed by WAY100635 (Ichikawa and Meltzer 1999a; Fig. 3d, respectively). We have extended these findings to the combination of M100907 and haloperidol, a D2 receptor antagonist, and found that M100907 also potentiates haloperidol-induced DA release in the mPFC (Liégeois et al. 2000). R(+)-8-OH-DPAT had no additional effect on the ability of the combination of M100907 and S(–)-sulpiride to increase DA release in the mPFC (Fig. 3c), indicating that this combination may not produce excessive 5-HT1A receptor activation with respect to the effect on DA release in the mPFC. Thus, it is hypothesized that simultaneous blockade of 5-HT2A and D2 receptors increases DA release in the mPFC by enhancing the effect of 5-HT1A receptor stimulation by endogenous 5-HT.

5-HT1A receptor activation by atypical APDs

We reported that the ability of clozapine, olanzapine, risperidone, amperozide, haloperidol and S(–)-sulpiride to preferentially increase DA release in the mPFC compared with the NAC was inversely correlated with the difference in affinity for 5-HT2A and D2 receptors (Kuroki et al. 1999), i.e. potent blockade of 5-HT2A receptors relative to weak D2 receptor blockade (Ichikawa and Meltzer 1999b; Meltzer et al. 1989). Ziprasidone, a 5-HT2A/D2 antagonist and 5-HT1A receptor partial agonist (Seeger et al. 1997), also has greater effects on DA release in the mPFC, compared with the NAC (Ichikawa and Meltzer 1997) or the STR (Rollema et al. 2000). Attenuation by WAY100635 of the ability of clozapine, risperidone and low dose olanzapine (1 mg/kg) to increase DA release in the mPFC (Figs 4a–c) suggests that clozapine, risperidone and low dose olanzapine increase DA release in the mPFC, in part, via 5-HT1A receptor activation. The lack of an effect of WAY100635 on the ability of high dose olanzapine (10 mg/kg) to increase DA release in the mPFC (Fig. 4d) suggests that factors other than 5-HT1A receptor activation may contribute to the DA release induced by 10 mg/kg olanzapine. Similar results have also been reported by Rollema et al. (2000) that WAY100635 (0.1 mg/kg, s.c.) attenuated the ability of clozapine (3.2 mg/kg, p.o.) and ziprasidone (10 mg/kg, p.o.) to increase DA release in the mPFC, whereas WAY100635 had no significant effect on olanzapine (10 mg/kg, p.o.)-induced DA release in that region. These authors (Rollema et al. 2000) suggested that clozapine and ziprasidone, but not olanzapine (see Table 1), increase DA release in the mPFC via direct activation of 5-HT1A receptors. However, the present data demonstrate that the ability of olanzapine, at a low dose (1 mg/kg), but not at 10 mg/kg, to increase DA release in the mPFC, may result from 5-HT1A receptor activation. The dose-dependent and preferential increase in DA release in the mPFC produced by high dose olanzapine compared with the NAC (Kuroki et al. 1999) may be related to other mechanisms, e.g. noradrenergic system (Hertel et al. 1999). We have recently reported that M100907 potentiated the ability of haloperidol at a low to moderate dose (0.01–0.1 mg/kg), but not higher dose (0.3–1 mg/kg), to increase DA release in the mPFC (Liégeois et al. 2000). This potentiation by M100907 was also reversed by WAY100635 (Ichikawa et al. unpublished data). These results suggest that functional 5-HT1A receptor activation, leading to an increase in cortical DA release, may be resulted from an appropriate combination of potent 5-HT2A and relatively weak D2 receptor blockade.

Table 1.  Receptor binding affinity (Ki, nM) of antipsychotic drugs
 5-HT1A5-HT2AD2α1α2
  1. The Ki values in rats are from Schotte et al. (1996). aCloned human receptors; bfrom Bymaster et al. (1996); cfrom Arnt and Skarsfeldt (1998).

Clozapine1803.31507b8b
Risperidone2500.163.32a,b3b
Olanzapine2720a1.91719b230b
Ziprasidone37c0.25c2.8c12c> 1000c
Haloperidol3080251.446b360b

The mechanism by which atypical APDs increase DA release in the mPFC may be due to: (1) direct 5-HT1A receptor activation (e.g. clozapine and ziprasidone); (2) 5-HT1A receptor activation secondary to combined blockade of 5-HT2A and D2 receptors (e.g. olanzapine and risperidone); or (3) both of the above (e.g. clozapine and ziprasidone). Risperidone, 1 mg/kg, is unlikely to directly activate 5-HT1A receptors, because of its modest affinity for 5-HT1A receptors (Ki = 250 nm), relative to that for D2 and 5-HT2A receptors (Ki = 3.3 and 0.16 nm, respectively, Table 1). It may do so indirectly since risperidone (1 mg/kg) increased 5-HT release in the mPFC (Hertel et al. 1996; Ichikawa et al. 1998), and has been reported to inhibit 5-HT neuronal activity in the dorsal raphe nucleus by increased 5-HT release in that region (Hertel et al. 1997). It should be noted that WAY100635 partially attenuated the ability of clozapine, olanzapine and risperidone to increase DA release at a dose which completely abolished the maximum effect of R(+)-8-OH-DPAT on DA release in the mPFC. The partial attenuation indicates that some other mechanisms, e.g. α2-adrenoceptor blockade, may also contribute to the ability of clozapine (Ki = 8 nm; see the Table 1) and risperidone (3 nm) to increase DA release in the mPFC since idazoxan, an α2-adrenoceptor antagonist, potentiated the ability of raclopride, a D2 receptor antagonist, to increase DA release in the mPFC (Hertel et al. 1999). It is also possible that the clozapine-induced increase in extracellular glutamate in the mPFC (Daly and Moghaddam 1993; Cartmell et al. 2000) contributes to the ability of clozapine to increase DA release in the mPFC, since the clozapine-induced DA release was blocked by LY341495, a selective metabolic glutamate mGlu2/3 receptor antagonist (Cartmell et al. 2000). However, it is unlikely that this explains the inhibitory effect of WAY100635 since 5-HT1A receptor blockade by NAN-190 has been reported to increase extracellular glutamate, an effect antagonized by 8-OH-DPAT (Matsuyama et al. 1996).

Clinical significance

Many, but not all, of the current generation of atypical APDs have been developed on the basis of the model of weak D2 and potent 5-HT2A receptor blockade (Meltzer et al. 1989). It was subsequently noted that some of these APDs were also 5-HT1A receptor partial agonists:, e.g. clozapine, quetiapine and ziprasidone (Seeger et al. 1997; Newman-Tancredi et al. 1998). The results reported here suggest that atypical APDs, which are all 5-HT2A/D2 receptor antagonist, have the ability to act via 5-HT1A receptor stimulation, at least with respect to the ability to preferentially increase cortical DA release, regardless of whether they are direct acting 5-HT1A receptor agonists or partial agonists. 5-HT1A receptor activation by atypical APDs may also contribute to their effects as antipsychotics by diminishing APD-induced DA release in the NAC since R(+)-8-OH-DPAT inhibits the ability of clozapine and risperidone to increase DA release in the NAC (Ichikawa and Meltzer 2000). We have also reported that R(+)-8-OH-DPAT potentiated high dose S(–)-sulpiride (25 mg/kg)-induced DA release in the mPFC, but not NAC (Ichikawa and Meltzer 1999a). Based on these consideration, 5-HT1A partial agonists/D2 receptor antagonists, which lack 5-HT2A receptor antagonist efficacy, e.g. buspirone (pKi = 7.8 for 5-HT1A and 7.8 for D2 receptors; Glennon et al. 1992), NAN-190 (8.9 and 8.0, respectively; Glennon et al. 1992), and LY165163 (8.7 and 7.0, respectively; Millan et al. 1995) may be of some use as adjunctive treatments for schizophrenia. However, clinical effects of buspirone in schizophrenia are controversial. A pilot study of buspirone added to typical APDs demonstrated no improvement in positive and negative symptoms in patients with schizophrenia (Brody et al. 1990), whereas an open trial of buspirone added to haloperidol in schizophrenic patients showed significant decrease in positive symptoms with no change in negative symptoms (Goff et al. 1991). Concomitant use of tandospirone, a 5 HT1A receptor agonist and weak D2 receptor antagonist (Shimizu et al. 1988), with haloperidol has been reported to improve some elements of memory functions in schizophrenic patients, and did not reduce psychotic symptoms (Sumiyoshi et al. 2000). Doses and treatment period may be critical factors (e.g. buspirone, 10–60 mg/kg/day for up to 4 weeks; Brody et al. 1990). Additional controlled studies are needed to determine the therapeutic effects of buspirone and tandospirone.

In conclusion, the combination of 5-HT2A and D2 receptor blockade increases DA release in the mPFC, via activation of 5-HT1A receptors. Clozapine, olanzapine, and risperidone may increase DA release in the mPFC, in part, via 5-HT1A receptor activation, which is produced by simultaneous blockade of 5-HT2A/D2 receptors and the 5-HT1A receptor agonist property of clozapine itself, but not olanzapine or risperidone.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The present study was supported, in part, by Warren Medical Institute foundation. We are grateful to Ms Anna R. Alboszta for an excellent technical assistance.

References

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  • Andersson J. L., Nomikos G. G., Marcus M., Hertel P., Mathé J. M. & Svensson T. H. (1995) Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectively in the mesolimbic dopaminergic system. Naunyn-Schmiedeberg's Arch. Pharmacol. 352, 374385.
  • Araneda R. & Andrade R. (1991) 5-Hydroxytryptamine2 and 5-hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience 40, 399412.
  • Arborelius L., Chergui K., Murase S., Nomikos G. G., Hook B. B., Chouvert G., Hacksell U. & Svensson T. H. (1993) The 5-HT1A receptor selective ligands, R (+)-8-OH-DPAT and (S)-UH 301, differentially affect the activity of midbrain dopamine neurons. Naunyn-Schmiedeberg's Arch. Pharmacol. 347, 353362.
  • Arnt J. & Skarsfeldt T. (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18, 63101.DOI: 10.1016/s0893-133x(97)00112-7
  • Ashby C. R., Edwards E. & Wang R. Y. (1994) Electrophysiological evidence for a functional interaction between 5-HT1a and 5-HT2a receptors in the rat medial prefrontal cortex: an iontophoretic study. Synapse 17, 173181.
  • Backus L. I., Sharp T. & Grahame-Smith D. G. (1990) Behavioural evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors. Br. J. Pharmacol. 100, 793799.
  • Brody D., Adler L. A., Kim T., Angrist B. & Rotrosen J. (1990) Effects of buspirone in seven schizophrenic subjects. J. Clin. Psychopharmacol. 10, 6869.
  • Bymaster F. P., Calligaro D. O., Falcone J. F., Marsh R. D., Moore N. A., Tye N. C., Seeman P. & Wong D. T. (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14, 8796.DOI: 10.1016/0893-133x(94)00129-n
  • Cartmell J., Perry K. W., Salhoff C. R., Monn J. A. & Schoepp D. D. (2000) The potent, selective mGlu2/3 receptor agonist LY379268 increases extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole-3-acetic acid in the medial prefrontal cortex of the freely moving rat. J. Neurochem. 75, 11471154.
  • Daly D. A. & Moghaddam B. (1993) Actions of clozapine and haloperidol on the extracellular levels of excitatory amino acids in the prefrontal cortex and striatum of conscious rats. Neurosci. Lett. 152, 6164.
  • Glennon R. A., Raghupathi R., Bartyzel P., Teitler M. & Leonhardt S. (1992) Binding of phebylalkylamine derivatives at 5-HT1C and 5-HT2 serotonin receptors: evidence for a lack of selectivity. J. Med. Chem. 35, 734740.
  • Gobert A. & Millan M. J. (1999) Serotonin (5-HT) 2A receptor activation enhances dialysis levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats. Neuropharmacology 38, 315317.DOI: 10.1016/s0028-3908(98)00188-9
  • Gobert A., Rivet J. M., Audinot C., Newman-Tancredi A. N., Cistarelli L. & Millan M. J. (1998) Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release. Neuroscience 84, 413429.DOI: 10.1016/s0306-4522(97)00565-4
  • Goff D. C., Midha K. K., Brotman A. W., McCormick S., Waites M. & Amico E. T. (1991) An open trial of buspirone added to neuroleptics in schizophrenic patients. J. Clin. Psychopharmacol. 11, 193197.
  • Hertel P., Nomikos G. G., Iurlo M. & Svensson T. H. (1996) Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain. Psychopharmacology 124, 7486.
  • Hertel P., Nomikos G. G. & Svensson T. H. (1997) risperidone inhibits 5-hydroxytryptaminergic neuronal activity in the dorsal raphe nucleus by local release of 5-hydroxytryptamine. Br. J. Pharmacol. 122, 16391646.
  • Hertel P., Fagerquist M. V. & Svensson T. H. (1999) Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by α2 adrenoceptor blockade. Science 286, 105107.DOI: 10.1126/science.286.5437.105
  • Ichikawa J. & Meltzer H. Y. (1997) Ziprasidone, a new antipsychotic, produces a preferential increase in extracellular dopamine (DA) utilization in the medial prefrontal cortex (mPFC). Soc. Neurosci. Abstract. 23, 161.7.
  • Ichikawa J. & Meltzer H. Y. (1999a) R (+)-8-OH-DPAT, a serotonin1A receptor agonist, potentiated S (-)-sulpiride-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens but not striatum. J. Pharmacol. Exp. Ther. 291, 12271232.
  • Ichikawa J. & Meltzer H. Y. (1999b) Relationship between dopaminergic and serotonergic neuronal activity in the frontal cortex and the action of typical and atypical antipsychotic drugs. Eur. Arch. Psychiat. &. Clin. Neurosci. 249, S90S98.
  • Ichikawa J. & Meltzer H. Y. (2000) The effect of serotonin1A receptors on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens. Brain Res. 858, 252263.DOI: 10.1016/s0006-8993(99)02346-x
  • Ichikawa J., Kuroki T., Dai J. & Meltzer H. Y. (1998) Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens. Eur. J. Pharmacol. 351, 171.
  • Khawaja X., Evans N., Reilly Y., Ennis C. & Minchin M. C. W. (1995) Characterization of the binding of [3H]WAY-100635, a novel 5-hydroxytryptamine1A receptor antagonist, to rat brain. J. Neurochem. 64, 27162726.
  • Kuroki T., Ichikawa J., Dai J. & Meltzer H. Y. (1996) R (+)-8-OH-DPAT, a 5-HT1A receptor agonist, inhibits amphetamine-induced serotonin and dopamine release in rat medial prefrontal cortex. Brain Res. 743, 357361.DOI: 10.1016/s0006-8993(96)01111-0
  • Kuroki T., Meltzer H. Y. & Ichikawa J. (1999) Effect of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J. Pharmacol. Exp. Ther. 288, 774781.
  • Lejeune F., Newman-Tancredi A., Audinot V. & Millan M. J. (1997) Interactions of (+)- and (-)-8- and 7-hydroxy-2-(di-n-propylamino) tetralin at human (h) D3, hD2 and h serotonin1A receptors and their modulation of the activity of serotonergic and dopaminergic neurons in rats. J. Pharmacol. Exp. Ther. 280, 12411249.
  • Li X.-M., Perry K. W., Wong D. T. & Bymaster F. P. (1998) Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology 136, 153161.DOI: 10.1007/s002130050551
  • Liégeois J. F., Ichikawa J., Bonaccorso S. & Meltzer H. Y. (2000) M100907, a 5-HT2A receptor antagonist, potentiates haloperidol-induced dopamine (DA) release in the medial prefrontal cortex (mPFC), but inhibits that in the nucleus accumbens (NAC). Soc. Neurosci. Abst. 26, 143.15.
  • Leysen J. E., Janssen P. M. F., Schotte A., Luyten W. H. M. L. & Megens A. A. H. P. (1993) Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacol. 112, S40S54.
  • Matsuda T., Yoshikawa T., Suzuki M., Asano S., Somboonthum P., Takuma K., Nakano Y., Morita T., Nakasu Y., Kim H. S., Egawa M., Tobe A. & Baba A. (1995) Novel benzodioxan derivative, 5-(3-[(2S)-1,4-benzodioxan-2- ylmethyl) amino]propoxy)-1,3-benzodioxole HCl (MKC-242), with a highly potent and selective agonist activity at rat central serotonin1A receptors. Jpn. J. Pharmacol. 69, 357366.
  • Matsuyama S., Nei K. & Tanaka C. (1996) Regulation of glutamate release via NMDA and 5-HT1A receptors in guinea pig dentate gyrus. Brain Res. 728, 175180.DOI: 10.1016/s0006-8993(96)00395-2
  • Meltzer H. Y. & McGurk S. R. (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr. Bull. 25, 233255.
  • Meltzer H. Y., Matsubara S. & Lee J.-C. (1989) Classification of typical and atypical antipsychotic drugs on the basis of D-1, D-2, and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 251, 238246.
  • Millan M. J., Canton H. & Lavielle G. (1992) Targeting multiple serotonin receptors: mixed 5-HT1A agonists/5-HT1C/2 antagonists as therapeutic agents. Drug News Perspective 5, 397406.
  • Millan M. J., Rivet J.-M., Audinot V., Gobert A., Lejeune F., Brocco M., Newman-Tancredi A., Maurel-Remy S. & Bervoets K. (1995) Antagonist properties of LY 165,163 at pre- and postsynaptic dopamine D2, D3 and D1 receptors: modulation of agonist actions at 5-HT1A receptors in vivo. J. Pharmacol. Exp. Ther. 273, 14181427.
  • Moghaddam B. & Bunney B. S. (1990) Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J. Neurochem. 54, 17551760.
  • Newman-Tancredi A., Gavaudan S., Conte C., Chaput C., Touzard M., Verriele L., Audinot V. & Millan M. J. (1998) Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPγS binding study. Eur. J. Pharmacol. 355, 245256.DOI: 10.1016/s0014-2999(98)00483-x
  • Paxinos G. & Watson C. (1986) The Rat Brain in Stereotaxic Coordinates. Academic Press, New York.
  • Pazos A., Cortes R. & Palacios J. M. (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res. 346, 231249.
  • Pompeiano M., Palacios J. M. & Mengod G. (1992) Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J. Neurosci. 12, 440453.
  • Prisco S., Pagannone S. & Esposito E. (1994) Classification of typical and atypical antipsychotic drugs on the basis of D-1, D-2, and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 271, 8390.
  • Rollema H., Lu Y., Schmidt A. W. & Zorn S. H. (1997) Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation. Eur. J. Pharmacol. 338, R3R5.DOI: 10.1016/s0014-2999(97)81951-6
  • Rollema H., Lu Y., Schmidt A. W., Sprouse J. & Zorn S. H. (2000) 5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in rat prefrontal cortex. Biol. Psychiatry 48, 229237.DOI: 10.1016/s0006-3223(00)00850-7
  • Sakaue M., Somboonthum P., Nishihara B., Koyama Y., Hashimoto H., Baba A. & Matsuda T. (2000) Postsynaptic 5-hydroxytryptamine1A receptor activation increases in vivo dopamine release in rat prefrontal cortex. Br. J. Pharmacol. 129, 10281034.
  • Santiago M. & Westerink B. H. C. (1991a) The regulation of dopamine release from nigrostriatal neurons in conscious rats: The role of somatodendritic autoreceptors. Eur. J. Pharmacol. 204, 7985.
  • Santiago M. & Westerink B. H. C. (1991b) Characterization and pharmacological responsiveness of dopamine release recorded by microdialysis in the substantia nigra of conscious rats. J. Neurochem. 57, 738747.
  • Schotte A., Janssen P. F. M., Gommeren W., Luyten W. H. M. L., Van Gompel P., De Lesage A. S., Loore K. & Leysen J. E. (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124, 5773.
  • Seeger T. F., Seymour P. A., Schmidt A. W., Zorn S. H., Schulz D. W., Lebel L. A., McLean S., Guanowsky V., Howard H. R., Lowe J. A. & Heym J. (1997) Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J. Pharmacol. Exp. Ther. 275, 113.
  • Shimizu H., Karai N., Hirose A., Tatsuno T., Tanaka H., Kumasaka Y. & Nakamura M. (1988) Interaction of SM-3997 with serotonin receptors in rat brain. Jpn. J. Pharmacol. 46, 311314.
  • Stockmeier C. A., DiCarlo J. J., Zhang Y., Thompson P. & Meltzer H. Y. (1993) Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors. J. Pharmacol. Exp. Ther. 266, 13741384.
  • Sumiyoshi T., Matsui M., Yamashita I., Nohara S., Uehara T., Kurachi M. & Meltzer H. Y. (2000) Effect of adjunctive treatment with serotonin-1A agonist tandospirone on memory functions in schizophrenia. J. Clin. Psychopharmacol. 20, 386388.
  • Tanda G., Caroni E., Frau R. & Di Chiara G. (1994) Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential? Psychopharmacology 115, 288.
  • Ugedo L., Grenhoff J. & Svensson T. H. (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology 98, 4550.
  • Volonté M., Monferini E., Cerutti M., Fodritto F. & Borsini F. (1997) BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex. J. Neurochem. 69, 182190.
  • Wadenberg M. L., Salmi P., Jimenez P., Svensson T. & Ahlenius S. (1996) Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat. Eur. J. Neuropsychopharmacol. 6, 305310.
  • Wadenberg M. L., Hicks P. B., Richter J. T. & Young K. A. (1998) Enhancement of antipsychotic-like properties of raclopride in rats using the selective serotonin2a receptor antagonist MDL 100,907. Biol. Psychiatry 44, 508515.DOI: 10.1016/s0006-3223(97)00424-1
  • Willins D. L. & Meltzer H. Y. (1997) Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J. Pharmacol. Exp. Ther. 282, 699706.
  • Zhang W. & Bymaster F. P. (1999) The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT2A and muscarinic receptors. Psychopharmacol. 141, 267278.