D 2 -R Agonist Induced Locomotor Activity in D 2 -R Primed Rats: Life-Long D 2 -R Supersensitivity

In rats neonatally primed with quinpirole in the first week after birth, and with additional quinpirole treatments at one- to two-month intervals there was a 17-fold increase in quinpirole-induced locomotor time and ~75-fold increase in rearing at 18 months [17, 18]. This study also found that quinpirole-induced weekly quinpirole treatments in adult rats produced prominent rearing and locomotor activity in female rats versus that of saline controls [17]. Therefore, there is strong support that D 2 -R supersensitivity, while prominently displayed after neonatal quinpirole treatments, is able to be produced by adulthood treatments as well. Szechtman’s group has demonstrated long-lived D 2 -R supersensitivity following repeated adulthood quinpirole treatments of adult rats [19–22]. Significantly, D 2 -R supersensitization, once induced, may persist life-long.

D 2 -R Agonist Induction of Yawning in Rats with D 2 -R Supersensitivity

In the 1970s Mogilnicka and Klimek [23] showed that low-dose DA receptor agonists produced a yawning response with simultaneous penile erection in rats, and this effect was ultimately and definitively linked with D 2 -R action [24–27]. A bell-shaped dose–effect curve is observed, as high dose D 2 -R action induces excitatory effects that suppress or compete with the yawning response.

In rats treated with quinpirole HCl (3.0 mg/kg ip; controls received saline in place of quinpirole) from birth, once daily for the first 28 days, there was an approximate twofold increase in the acute quinpirole yawning response, versus controls, at 8 to 10 weeks after birth. This D 2 -R effect, however, was unaccompanied by a change in the number (B max ) or affinity (K d ) of D 2 -R in the striatum [28]. Notably, direct intrastriatal quinpirole administration produces the yawning response [29]. In a subsequent study it was shown that perinatal quinpirole-induction of D 2 -R supersensitivity was replicated by a low dose of quinpirole (50 µg/kg/day, salt form) administered prenatally (gestation day 10 to birth) or this same dose given perinatally for an 11 day period: 1–11 days post-birth, 12–22 days post-birth or 23–33 days post-birth [30]. In all groups tested at 6 weeks, quinpirole produced an enhanced yawning response, 70–300 % greater than controls, however several test doses were required at 6 weeks in the group that was quinpirole-treated in gestation [30]. This gradual induction of D 2 -R by repeated quinpirole treatments is termed a ‘priming’ process.

D 2 -R Agonist Induction of Vertical Jumping in Rats with D 2 -R Supersensitivity

In the initial study on quinpirole-priming we had observed that acute quinpirole treatment on postnatal day 18 was followed by intense gnawing on food pellets or intense suckling on the dam. At day 19 acute quinpirole treatment produced a darting response—rapid forward (horizontal) movement, akin to forward leaping, and the effect persisted for 15–30 min. When quinpirole-primed rats were placed in single plastic cages on the 20th day after birth, acute treatment with quinpirole (0.1–3.0 mg/kg) induced dose-related vertical jumping with forepaw treading in quinpirole-primed rats—with the maximal effect occurring between 30 and 150 min after acute quinpirole treatment. Quinpirole-induced vertical jumping was observable during the 3rd to 4th weeks after birth but was absent by the 34th day post-birth in rats that were quinpirole-primed postnatally (3.0 mg/kg P1–28). Vertical jumping was suppressed by pretreatment with either the D 2 -R antagonist spiperone or D 1 -R antagonist SCH 23390, thus reflecting cooperativity of D 1 -R and D 2 receptors in the D 2 -R supersensitivity effect. Quinpirole-induced vertical jumping was negligible in control rats. Also, if lids were placed on cages rats did not vertically jump, indicative of the ability of rats to self-suppress the jumping behavior [31]. These findings indicating a uniqueness of D 2 -R supersensitivity.

D 2 -R Sensitization and Stereotyped Activities

In rats ontogenetically primed with quinpirole (3.0 mg/kg for the first 28 days post-birth), an acute dose of quinpirole at 12 weeks produces profound sniffing and taffy pulling, while suppressing grooming. In these rats acute treatment with a D 1 -R agonist at 9 weeks produces prominent gnawing and eating [32].

D 2 -R Sensitization to Quinpirole Antinociception in Rats with D 2 -R Supersensitivity

DA D 2 -R agonists are associated with both nociceptive [33] and antinociceptive effects in rodents [34]. When quinpirole-primed rats (3.0 mg/kg/day for the first 28 days post-birth) were tested acutely with quinpirole HCl for antinociceptive action on a hot plate, quinpirole-primed rats displayed a greater response versus controls, and the antinociceptive effect was attenuated by pretreatment with the D 2 -R antagonist spiperone. The antinociceptive response to morphine was identical in quinpirole-primed and in control rats [35]. This action in conjunction with others described above, highlights the fact that D 2 -R supersensitization have an overlay in a spectrum of behaviors, some of which are not obvious unless specifically probed.

Active Avoidance in D 2 -R Primed Rats

Active avoidance responding was improved in rats primed with quinpirole (50 µg/kg/day) in the interval 1–11 days post-birth, 12–23 days post-birth, and 23–33 days post-birth [18].

Learning and Memory in D 2 -R Primed Rats

Rats, quinpirole primed during postnatal ontogeny, have discernable learning and memory deficits [17] in the Morris water task (MWT), on place and on match-to-place versions of the MWT [36], and the effect was correlated with an increase in hippocampal corticosterone and a reduction in nerve growth factor (NGF) [36]. Pretraining with the D 2 -R antagonist eticlopride prevented cognitive deficits in males and females on the place version of the MWT; and in males on the match-to-place version of the MWT [37]. Olanzapine administration over a 28 day period also reduced D 2 -R supersensitization and reversed deficits in the place version of the MWM, and its effect was associated with a reversal of reduced NGF, BDNF and CAT in the hippocampus of D 2 -R primed rats [38]. In D 2 -R primed rats there also was enhanced reaching accuracy in the Whishaw reaching task [36, 39].

Sex Differences in the Response to Ontogenetic Quinpirole Treatment

There have been several studies in which we have shown sex differences in the behavioral response to neonatal quinpirole treatment. This is especially relevant based on past work by Andersen and Teicher [40] that have shown sex differences in the development of both dopamine D 1 and D 2 receptors in both the striatum and nucleus accumbens, with males demonstrating higher levels of D 1 throughout adolescence and into adulthood, but level of striatal D 2 receptors differed depending on the day of assayed, with males demonstrating lower levels of D 2 receptors at P25, higher levels at P40 and leveling off to be equal relative to females at P60. Most of the work directed towards sex differences in this model has been performed using adolescent rats. In a previous study by Sheppard et al. [41], neonatal quinpirole resulted in more robust nicotine sensitization in male but not female rats. These animals were sensitized to nicotine every second day from P33–49, which represents a period of mid-adolescence in the rat. Based on past work in the dopamine receptor profile during this period these results seem to positively correlate with the increase in striatal dopamine D 2 receptors as well as the increase in the number dopamine D 1 receptors known to exist in males as compared to females [40]. In this same study, there was also a sexual dimorphism in a drug free nicotine-conditioned hyperactivity test administered at P50, 1 day after nicotine sensitization was complete. Adolescent females neonatally treated with saline and males neonatally treated with quinpirole demonstrated nicotine-conditioned hyperactivity, but this was not expressed in any other group. However, adolescent males neonatally treated with saline did not demonstrate nicotine-conditioned hyperactivity. In fact, the performance of control males was quite similar to females neonatally treated with quinpirole on the drug-free test, suggesting that the lack of associative effects of nicotine in females neonatally treated with quinpirole may have a mechanism similar to the lack of associative effects of nicotine in control males. It is also interesting that adolescent males, unlike adult males, did not express nicotine-conditioned hyperactivity [41]. We have more recently published results demonstrating that neonatal quinpirole enhanced nicotine place conditioning in adolescence, but there were no sex differences in this response, unlike the results with conditioned hyperactivity [42].

Finally, in one of the few studies we have analyzed sex differences in adulthood using this model, we have consistently found a sex difference in the yawning response, with males demonstrating a robust in increase in the number of yawns in response to acute quinpirole as compared to females, although the magnitude of the difference between neonatal quinpirole and saline females was greater than it was in males [38, 43]. In sum, it appears that neonatal quinpirole treatment enhances the associative effects of nicotine and there are sex differences in this response, which may also be related to methodological parameters and the type of associative conditioning analyzed.