5-HT2A receptors modulate dopamine D2-mediated maternal effects

Abstract

Serotonin 5-HT_2A receptors are expressed throughout the mesolimbic and mesocortical dopamine pathways, and manipulation of this receptor system has a profound impact on dopamine functions and dopamine-mediated behaviors. It is highly likely that 5-HT_2A receptors may also modulate the D₂-mediated maternal effects. The present study investigated this issue and also explored the possible behavioral mechanisms. We tested the effects of two D₂ drugs (an agonist quinpirole: 0.5, 1.0 mg/kg, and a potent D₂ antagonist haloperidol: 0.05, 0.10 mg/kg, sc) and their combinations with two 5-HT_2A drugs (a selective 5-HT_2A agonist TCB-2: 2.5 mg/kg, and 5-HT_2A antagonist MDL100907, 1.0 mg/kg, sc) on maternal behavior in Sprague-Dawley postpartum females. Individually, TCB-2 (2.5 mg/kg, sc) and quinpirole (0.5 and 1.0 mg/kg, sc) reduced pup preference and disrupted home-cage maternal behavior. In contrast, haloperidol (0.10 mg/kg, sc) only disrupted home-cage maternal behavior, but did not suppress pup preference. MDL100907 (1.0 mg/kg, sc) by itself had no effect on either pup preference or maternal behavior. When administered in combination, pretreatment of TCB-2 did not alter quinpirole's disruption of pup preference and home-cage maternal behavior (possibly due to the floor effect), however, it did enhance haloperidol's disruption of pup retrieval in the home cage. MDL100907 had no effect both quinpirole's and haloperidol's disruption of pup preference and home-cage maternal behavior. Interestingly, haloperidol attenuated TCB-2's disruptive effect on pup preference. These findings suggest that activation of 5-HT_2A receptors tends to enhance D₂-mediated maternal disruption, whereas blockade of 5-HT_2A receptors is less effective. They also suggest that 5-HT_2A receptors may have a direct effect on maternal behavior independent of their interaction with D₂ receptors. The possible behavioral and neural mechanisms by which 5-HT_2A- and D2-mediated maternal effects and their interaction are discussed.

Keywords: Dopamine D(2) receptor; Emotional processing; Incentive motivation; Maternal behavior; Pup preference; Serotonin 2A receptor.

Fig. 1.

Comparison between mother rats and virgin females in the pup preference test on PPD 4. Duration of pup exploration time (A), object exploration time (B), pup preference ratio (C), and distance travelled (D) on PPD 4 are presented as mean ± SEM. *p < 0.05, **p < 0.01 significant difference between mother and virgin females; ##p < 0.01, +++p < 0.001 significant difference between two different test conditions (pup presence vs. pup absence).

Fig. 2.

Effects of individual drugs that stimulate or block D₂ or 5-HT_2A receptors on pup preference. Duration of pup exploration time (A), object exploration time (B), pup preference ratio (C), and distance travelled (D) in mother rats treated with TCB-2 (2.5 mg/kg), MDL100907 (1.0 mg/kg), quinpirole (QUIN, 0.5 or 1.0 mg/kg), or haloperidol (HAL, 0.05 or 0.10 mg/kg) on PPD 4 are presented as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 significant difference from VEH+VEH group.

Fig. 3.

Effects of individual drugs that stimulate or block D₂ or 5-HT_2A receptors on home-cage maternal behavior on PPD 9. Number of pups retrieved (A), duration of pup crouching (B), duration of pup licking (C), and duration of nest building (D) in mother rats treated with TCB-2 (2.5 mg/kg), MDL100907 (1.0 mg/kg), quinpirole (QUIN, 0.5 or 1.0 mg/kg), or haloperidol (HAL, 0.05 or 0.10 mg/kg) and tested in the home cage are presented as mean ± SEM. ***p < 0.001 significant difference from VEH+VEH group.

Fig. 4.

Modulation of activation or blockade of 5-HT_2A receptors on quinpirole’s effect on pup preference. Duration of pup exploration time (A), object exploration time (B), pup preference ratio (C), and distance travelled (D) in mother rats treated with quinpirole (QUIN, 1.0 mg/kg), or quinpirole together with TCB-2 (2.5 mg/kg) or MDL100907 (1.0 mg/kg) are expressed as mean ± SEM. **p < 0.01, ***p < 0.001 significant difference from VEH+VEH group; #p < 0.05, ##p < 0.01 significant difference from VEH+QUIN 1.0 group; +++p < 0.001 significant difference between TCB-2 and VEH treatment.

Fig. 5.

Modulation of activation or blockade of 5-HT_2A receptor on haloperidol’s effect on pup preference. Duration of pup exploration time (A), object exploration time (B), pup preference ratio (C), and distance travelled (D) in mother rats treated with haloperidol (HAL, 0.1 mg/kg), or haloperidol together with TCB-2 (2.5 mg/kg) or MDL100907 (1.0 mg/kg) are expressed as mean ± SEM. *p < 0.05, ***p < 0.001 significant difference from VEH+VEH group; #p < 0.05 significant difference from VEH+HAL 0.1 group; $ $p < 0.01, $ $ $p < 0.001 significant difference from TCB-2 2.5+VEH group; +++p < 0.001 significant difference between TCB-2 and VEH treatment.

Fig. 6.

Modulation of activation or blockade of 5-HT_2A receptor on haloperidol’s effect on home-cage maternal behavior. Number of pups retrieved (A), latency of first pup retrieval (B), latency of last pup retrieval (C), duration of pup crouching (D), duration of pup licking (E), and duration of nest building (F) in mother rats treated with haloperidol (0.1 mg/kg), or haloperidol together with TCB-2 (2.5 mg/kg) or MDL100907 (1.0 mg/kg) and tested in the home cage are presented as mean ± SEM. ***p < 0.001 significant difference from VEH+VEH group; #p < 0.05 significant difference from VEH+HAL 0.1 group; VEH+HAL 0.10 group. ++p < 0.01, +++p < 0.001 significant difference between TCB-2 or MDL100907 and VEH treatment.