Repeated treatment in ontogeny with the dopamine (DA) D2/D3 receptor agonist quinpirole is associated with enhanced quinpirole-induced yawning and other behaviors such as vacuous chewing, vertical jumping, and antinociception. To determine if the reputedly DA D3 agonist (±)-2-(dipropylamino)-7-hydroxy-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT) would prime for yawning in a manner analogous to that for quinpirole, rats were treated for the first 11 days after birth with an equimolar dose of either quinpirole or 7-OH-DPAT (195.4 nmol/kg/day) and tested for agonist-induced yawning in adulthood. While enhanced quinpirole-induced and 7-OH-DPAT-induced yawning was observed in quinpirole-primed rats, acute treatments with quinpirole and 7-OH-DPAT did not produce an enhanced yawing response in 7-OH-DPAT-'primed' rats. Our findings indicate that 7-OH-DPAT, unlike quinpirole, does not prime for quinpirole- or 7-OH-DPAT-induced yawning in rats.

Neonatal destruction of rat nigrostriatal dopaminergic fibers results in an enhanced oral activity response to both dopamine (DA) D1 and serotonin (5-HT) agonists. Because cholinergic systems represent another one of the neural circuits involved in oral behavior, it was of interest to determine whether muscarinic receptors might also be sensitized in the lesioned rats. At 3 days after birth, rats were pretreated with desipramine HCl (20 mg/kg, IP) 1 h before 6-hydroxydopamine (6-OHDA) HBr (100 μg in each lateral ventricle) or saline-ascorbic acid (0.1%) vehicle. Between 2 and 4 months, behavioral supersensitivity to a D1 agonist (SKandF 38393) and 5-HT agonist (m-chlorophenylpiperazine; m-CPP) was established before rats were challenged with the muscarinic receptor agonist, pilocarpine HCl (0.125 to 10.0 mg/kg, IP). The pilocarpine dose-effect curve was shifted to the left, with a maximal effect of 63.7 ± 8.6 oral movements being produced by a 1.0 mg/kg pilocarpine HCl dose in the 6-OHDA lesioned rats, versus 15.0 ± 2.4 oral movements in the control group (p < 0.001). The enhanced response to pilocarpine was attenuated by the muscarinic receptor antagonist, scopolamine HCl (0.1 mg/kg IP). These findings indicate that neonatal 6-OHDA treatment produces supersensitization of muscarinic receptors in rats.

It is known that dopamine (DA) receptors can be sensitized by repeated treatments with quinpirole during postnatal development. This study was undertaken to determine whether low-dose quinpirole treatments might sensitize receptors to quinpirole-induced yawning behavior. Rats were treated with quinpirole HCl (50 μg/kg per day) or saline at four different periods of ontogeny: a) the 10th day of gestation to day of birth; b) 1st-11th days after birth; c) 12th-22nd days from birth; or d) 23rd-33rd days from birth. The numbers of yawns occuring in 1 h after a challenge dose of quinpirole HCl (50 μg/kg, IP) was determined at 6 weeks. Rats exposed prenatally to quinpirole demonstrated increased numbers of yawns following the third dose of quinpirole (2-day interval between doses). In rats exposed postnatally to quinpirole, there was a 70-300% increase in the yawning response, with the greatest response occuring in the group treated with quinpirole from birth to 11 days from birth. The findings demonstrate that quinpirole receptors are sensitized by a low dose of quinpirole, 60-fold lower than previously shown. It is suggested that sensitized receptors are of the DA D3 subclass.

Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with supersensitization of the dopamine D1 agonist induction of oral activity. The present study was conducted to determine whether induced oral responses to serotonin (5-HT) agonists would be similarly altered in this rat model. At 3 days after birth, rats received desipramine HCl (20 mg/kg, IP) 1 h before 6-OHDA HBr (100 μg in each lateral ventricle) or saline-ascorbic acid (0.1%) vehicle. At approximately 9 mo, rats were challenged with the mixed 5-HT1C and 5-HT2 receptor agonist, m-chlorophenylpiperazine diHCl (m-CPP 2HCl; 0.30-6.0 mg/kg, IP) and were then observed for 1 min every 10 min over a 60-min period. m-CPP induced oral activity in both the vehicle and 6-OHDA groups, with the responses of the 6-OHDA group being much greater. An m-CPP dose of 3.0 mg/kg produced a maximal response of 63.6 ± 3.2 oral movements in the 6-OHDA group. A bell-shaped response curve was obtained, with lower and higher doses of m-CPP producing less of an effect. Attenuation of the m-CPP-induced response by the 5-HT receptor antagonist, mianserin HCl (1.0 mg/kg, IP, 30 min before m-CPP), indicates that the m-CPP effect is receptor mediated. These findings demonstrate that neonatal 6-OHDA treatment produces ontogenic long-lived supersensitization of a 5-HT receptor system in rats.

Yawning in male rats is a behavior that may be induced by a group of dopamine receptors when low doses of dopamine-receptor agonists are administered. To determine whether agonist treatments during postnatal development could produce a long-lived supersensitization of these dopamine receptors, rats were treated daily for the first 28 days from birth with quinpirole HCl (3.0 mg/kg/day, IP), an agonist that acts at D2 and D3 receptors. At 8 to 10 weeks from birth the dose-effect curve for quinpirole-induced yawning demonstrated that a supersensitization of dopamine receptors for yawning behavior had occurred. Yawning at the optimal dose of quinpirole HCl (100 μg/kg, IP) was increased 2-fold. The Bmax and Kd for D2 receptor binding in rat striatum were unaltered in this group of rats. These findings indicate that dopamine receptors can be ontogenically "primed" or supersensitized, and that the phenomenon apparently is not related to changes in striatal D2 receptor binding characteristics.

Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with supersensitization of the dopamine (DA) D1 agonist induction of stereotyped and locomotor behaviors. The present study was conducted to determine whether ontogenetic treatments of these rats with the DA D1 receptor agonist, SKF 38393, would produce a maximal DA D1 receptor supersensitivity, as measured by locomotor behavior in adulthood. Rat pups were treated daily with SKF 38393-HCl (3.0 mg/kg per day, i.p.) or saline vehicle for 28 consecutive days from birth. These animals were additionally treated at 3 days after birth with 6-OHDA-HBr (100 μg, in each lateral ventricle, salt form) or its vehicle. Between 6 and 9 weeks locomotor activity or stereotyped behaviors were observed after weekly challenge doses of SKF 38393-HCl (3.0 mg/kg, i.p.). In the neonatal 6-OHDA group, successive SKF 38393 treatments produced progressively greater locomotor activity. In the group of rats treated during postnatal ontogeny with both 6-OHDA and SKF 38393 daily treatments, the first adult challenge dose of SKF 38393 produced an enhanced locomotor response, greater than that seen in other groups (P < 0.01). Subsequent SKF 38393 treatments of this group produced increasingly greater locomotor responses. SKF 38393-induced stereotyped behavioral effects were greater in the 6-OHDA-lesioned groups, whether or not SKF 38393 was administered ontogenetically. Profound reductions (> 99%) of DA and its metabolites were found in the striatum of neonatal 6-OHDA treated rats, regardless of whether SKF 38393 was co-administered ontogenetically. A marked elevation in striatal 5-HT (> 50%) accompanied the DA depletion in the striatum. These findings indicate that neonatal 6-OHDA treatment produces the expected destruction of striatal DA fibers with associated sprouting of 5-HT fibers, while repeated ontogenetic treatments of these rats with a D1 agonist produces partial sensitization of the DA D1 receptors in adulthood.

Quinpirole-induced vertical jumping is a phenomenon first observed in rats treated from birth, once a day for 21 days or more, with the dopamine D 2 receptor agonist quinpirole. This quinpirole-induced behavioral sensitization is known as a priming process. To determine whether dopaminergic innervation influenced this priming phenomenon, groups of rats were lesioned at 3 days after birth with the neurotoxin 6-hydroxydopamine (6-OHDA; 67 μg in each lateral ventricle; desipramine pretreatment, 20 mg/kg ip, 1 h). Rats were additionally treated daily from birth with quinpirole HCl (3.0 mg/kg ip, salt form). Controls received saline vehicle in place of 6-OHDA and/or quinpirole. When rats were placed in individual observation cages (1 h acclimation) starting at 20 days after birth, acute quinpirole treatment produced vertical jumping in the quinpirole-primed group; and the effect persisted through the twenty-ninth day. In rats additionally lesioned with 6-OHDA, vertical jumping was enhanced at 20, 24, 26/27, and 28/29 day-with there being as much as a 32-fold increase in vertical jumping versus the group that was primed with quinpirole, but not lesioned with 6-OHDA. This finding indicates that an ontogenetic 6-OHDA lesion enhances quinpirole-induced vertical jumping in rats and that dopaminergic innervation may normally exert a suppressive effect on vertical jumping.

Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with concurrent supersensitization of dopamine (DA) D1 and serotonin 5-HT1C receptors, for agonist-induced oral activity. The present study was conducted to determine if graded reduction of striatal DA content and/or graded elevation of striatal 5-HT content by 6-OHDA would alter sensitivity of either receptor type, and thereby influence oral activity responses to DA and 5-HT agonists. At 3 days after birth, groups of rats were pretreated with desipramine (20 mg/kg i.p.), 1 h before administration of a range of doses of 6-OHDA HBr (15, 30, 60, 100, 150 and 200 μg, i.c.v., salt form; half in each lateral ventricle) or the vehicle, saline (0.85%)-ascorbic acid (0.1%). Between 2 and 4 months, a series of challenge doses of SKF 38393 HCl (0.30 to 3.0 mg/kg i.p.) and m-chlorophenylpiperazine 2HCl (0.30 to 6.0 mg/kg i.p.; m-CPP 2HCl) were administered to each group of rats and oral activity was observed. Oral activity was determined for 1 min every 10 min during a 60-min period, starting 10 min after injection of agonist or vehicle. SKF 38393 dose-response curves demonstrated enhanced oral activity responses in rats lesioned neonatally with 150 or 200 μg of 6-OHDA. m-CPP dose-response curves demonstrated enhanced oral activity responses in these 2 groups of rats, as well as those lesioned neonatally with 100 μg of 6-OHDA. Striatal DA content was reduced by > 97% in these 3 groups of rats. Striatal 5-HT content was elevated by > 80% in rats treated neonatally with 150- or 200-μg doses of 6-OHDA, and by 50% in rats treated neonatally with the 100-μg dose of 6-OHDA. Lower doses of 6-OHDA produced less of an effect on striatal DA and 5-HT content. Regression analysis determined that both SKF 38393- and m-CPP-induced oral activities were most closely correlated with the magnitude of change in striatal content of DA. These findings demonstrate that 5-HT agonist responses can be enhanced when DA agonist responses are not enhanced. Also, in neonatal 6-OHDA-lesioned rats the extent of DA depletion vs. the extent of 5-HT elevation seems to be a critical factor in the enhanced behavioral effects of DA and 5-HT agonists.

No description available.

To determine whether prolonged supersensitization of dopamine D-1 receptors could be produced during ontogeny, rats were treated daily, from birth, for 33 consecutive days with the D-1 receptor agonist, SKF 38393 HC1 (3.0 mg/kg per day i.p.). These rats were additionally treated at 3 days after birth with the neurotoxin, 6-hydroxydopamine HBr (6-OHDA; 200 μg, i.c.v., half in each lateral ventricle) or its vehicle. At 6 to 7 weeks from birth a challenge dose of SKF 38393 HCl (3.0 mg/kg i.p.) increased stereotypy scores for a number of behaviors in 6-OHDA-lesioned rats that were treated repeatedly during ontogeny with SKF 38393. These accentuated behaviors included licking, grooming, taffy pulling, jumping, paw treading and locomotion. Although the findings demonstrate an increased sensitivity of D-1 receptors to an agonist, there was no change in the Bmax or Kd for D-1 receptors in the striatum. In rats that were treated during postnatal development with SKF 38393, but not lesioned with 6-OHDA, SKF 38393-induced stereotyped behaviors were not substantially different from control. The neonatally primed rat model may be useful for probing mechanisms of receptor supersensitivity.