Consistent with our previous study Gao et al b
Consistent with our previous study (Gao et al., 2018b; Wu et al., 2018), we found that TCB-2 disrupted both pup preference and home-cage maternal behavior. Based on the findings that 4-h pup fiin (a technique presumably increases maternal motivation) failed to attenuate the TCB-2-induced maternal disruption and TCB-2-treated dams showed an increased pup preference in a pup-male preference test, we suggested that TCB-2 is unlikely to have a disruptive effect on motivational and emotional processing of the rewarding property of pups (TCB-2 may actually have an enhancement effect on pup reward). Rather, we proposed that TCB-2 could disrupt pup preference and maternal behavior by disrupting the executive function (Wu et al., 2018), giving its well-known hallucinatory effect and its disruption of impulsive response and behavioral organization (Koskinen et al., 2000a; Koskinen et al., 2000b; Winstanley et al., 2004). TCB-2 is speculated to disrupt maternal behavior and pup preference by either diverting a mother rat's focused attention on pups towards other environmental cues, and by making her more easily distracted by irrelevant environmental stimuli, or by increasing behavioral fragmentation and premature, or ‘impulsive’ responding. This hallucinogenic behavioral effect of TCB-2 in rat maternal behavior is also supported by the finding that activation of 5-HT2A receptors in the mPFC is responsible for TCB-2's maternal effects (Gao et al., 2018b). This effect may be partially achieved through excessively stimulating dopamine release in the mesocortical and mesolimbic dopamine systems (Di Giovanni et al., 2000; Di Matteo et al., 2002), which in turn may cause a disruption of executive function. However, we do not have any direct evidence showing that activation of 5-HT2A receptors causes disorganized maternal responses, which should be examined in the future. MDL100907 at 1.0 mg/kg by itself did not alter pup preference or home-cage maternal behavior, a finding consistent with our previous report (Chen et al., 2014; Nie et al., 2018). It also did not change quinpirole's and haloperidol's effects in these two tests. Our finding on the MDL100907 and quinpirole interaction is consistent with a previous report showing that MDL100907 is ineffective in reducing contralateral rotational behavior induced quinpirole in adult rats with unilateral DA lesions (Taylor et al., 2006). The literature on the MDL100907 and haloperidol interaction is mixed, and three possible outcomes have been reported: a potentiation (Wadenberg et al., 2001b); a reduction (Benaliouad et al., 2007); and no effect (Creed-Carson et al., 2011; Gao et al., 2018a; Reavill et al., 1999). These findings, together with the present ones, suggest that the interactions between 5-HT2A and D2 receptors are much more complex than we originally thought, and may depend on specific D2-mediated behaviors. Indeed, we recently used a pup retrieval on an elevated plus maze test (a test of maternal anxiety, maternal motivation, executive function and their interactions) and found that MDL100907 exacerbated the quinpirole-induced disruption of pup retrieval (Nie et al., 2018), supporting the notion that 5-HT2A blockade's modulation on D2-mediated maternal effects also depends on the specific behavioral tests, which rely on different psychological processes with different degrees of sensitivity to the D2 × 5-HT2A interactions. In conclusion, the present study further demonstrates that the balanced dopamine D2-mediated neurotransmission is critically important for the normal expression of maternal behavior. Stimulation or blockade this receptor by quinpirole and haloperidol, respectively, induces a change in pup preference and home-cage maternal behavior likely through different behavioral mechanisms. Quinpirole may disrupt maternal behavior by causing a negative maternal affect or disrupting executive function; whereas haloperidol may do so by suppressing maternal motivation. Importantly, we found an important modulation of 5-HT2A on D2-mediated maternal effects: activation of 5-HT2A receptors by TCB-2 enhances D2-mediated suppression of maternal motivation, whereas blockade of 5-HT2A receptors by MDL100907 is less effective to alter D2-mediated maternal effects. Future work will examine the neural basis of the interactive actions between D2 and 5-HT2A receptors and further elucidate the relevant behavioral mechanisms.