The ontogenic destruction of dopamine (DA) neurons in rat brain is associated with supersensitization of DA D1 receptors. This effect is attenuated when rats are cotreated in ontogeny with the serotonin (5-HT) neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). In an attempt to determine whether 5-HT fibers might have a similar modulatory role on the sensitivity of the DA D2 receptor complex, we pretreated rats with desipramine HCl (20 mg/kg IP, base), 1 h before the DA neurotoxin, 6-hydroxydopamine (6-OHDA; 134 μg ICV, base) and/or 5,7-DHT (75 μg ICV) and/or vehicle. At about 3 months after birth dose-effect curves for quinpirole-induced oral activity were constructed for each group of rats. We found that quinpirole, an agonist for the DA D2 receptor complex, produced a dose-related increase in oral activity in all groups of rats. After a 200 μg/kg dose of quinpirole HCl, however, neonatal 5,7-DHT-lesioned rats had a peak oral response of 54.4 ± 5.1 (mean and SEM) vs. 22.6 ± 4.8 for control rats (p < 0.01). In neonatal 6-OHDA-lesioned rats this dose of quinpirole increased oral activity to 36.8 ± 5.8 oral movements (p < 0.05 vs. control). In rats lesioned with both 5,7-DHT and 6-OHDA, the oral response was not different from control. The enhanced oral response to quinpirole in 5,7-DHT-lesioned rats was attenuated by spiperone, an antagonist for the DA D2 receptor complex. These findings are believed to be the first to demonstrate that receptors of the DA D2 complex become sensitized after ontogenic injury to 5-HT fibers. This effect is opposite to the attenuated sensitivity of DA D1 receptors in rats with a similar 5-HT lesion.

Enhanced oral responses have been observed in rats that are treated shortly after birth with 6-hydroxydopamine (6-OHDA). A series of studies was conducted to characterize this effect. A dose-response curve demonstrated that the dopamine D1 receptor agonist, SKF 38393, produced a maximal response in 6-OHDA-treated rats at a dose of 0.10 mg/kg (IP). With the D2 receptor antagonist, spiperone, a bell-shaped dose-response curve was seen, with a maximal effect in the 6-OHDA group occurring at 80 μg/kg. There were only slight increases in oral activity with different SKF 38393 or spiperone doses in the saline group, indicating that there was an overt supersensitization of D1 receptors in the 6-OHDA-treated rats. The D1 antagonist SCH 23390 (0.30 mg/kg, IP) attenuated the response to both SKF 38393 and spiperone. The oral response to the D2 agonist, quinpirole (0.10 mg/kg, IP) was not preferentially increased in the 6-OHDA group of rats. These findings indicate that the enhanced oral response in neonatal 6-OHDA-treated rats is mediated by supersensitive dopamine D1 receptors. The persistence of the enhanced oral ersponse in 6-OHDA-treated rats at 8 months demonstrates that this sensitization of D1 receptors is a long-lived phenomenon.

Neonatal 6-hydroxydopamine (6-OHDA) treatment is associated with destruction of dopamine (DA) fibers and subsequent sprouting of serotonin (5-HT) fibers in the striatum of rats. Enhanced oral activity responses to SKF 38393 and m-chlorophenylpiperazine (ifm-CPP), respective agonists for the DA D1 receptor complex and 5-HT2C receptor complex, ensue. To study the ontogenetic nature of this effect, rats were treated at birth, 3 days, 7 days, 10 days or 14 days with 6-OHDA-HBr (200 μg i.c.v.; salt form), following desipramine-HCl pretreatment (20 mg/kg i.p., 1 h; base form). Another group of rats was treated at 35 days and again at 42 days with 6-OHDA-HBr (300 γg i.c.v.), following desipramine-HCl (20 mg/kg i.p., 1 h) and pargyline-HCl (50 mg/kg i.p., 30 min). In rats treated from birth to 10 days, 6-OHDA reduced striatal DA content at 5 months by ≥ 94%. Striatal 5-HT content was elevated by 28% to 51%, but only in rats treated with 6-OHDA at 7 days from birth or earlier. An enhanced oral activity response to SKF 38393-HCl (0.03 to 1.0 mg/kg i.p.) was absent in rats treated 7 days or later, and the change in SKF 38393 effect was correlated with a change in striatal DA content. An enhanced response to m-CPP-2HCl (0.3 to 6.0 mg/kg i.p.) was absent after treatment at 14 or 35 days, when striatal DA content was reduced only 44% to 63% and 5-HT content was not changed. Loss of the enhanced m-CPP response was not directly correlated with the magnitude of change in striatal content of either DA or 5-HT. The findings indicate that SKF 38393 and m-CPP-enhanced oral activity responses are dependent on the age at which 6-OHDA is administered to rats, and that the enhanced response to m-CPP can persist when there is no enhanced response to SKF 38393.

Chronic surgical denervation of the rat vas deferens leads to an enhanced contractile response of the tissue to norepinephrine in vitro. Norepinephrine produces a higher rate of protein kinase C translocation to the particulate fraction of denervated tissues as compared with the paired, control vas deferens. Diacylglycerol generation in response to norepinephrine and contractile responses to phorbol diacetate were not altered by chronic denervation of the vas deferens. However, the contractile response to norepinephrine in these tissues was less susceptible to the inhibitory effects of the calcium channel blocker nifedipine. A potential role of protein kinase C in sensitizing the contractile apparatus to mobilized calcium in denervation supersensitivity is discussed.

Repeated treatments with a dopamine (DA) D2 receptor agonist result in the induction of DA D2 receptor supersensitivity, as evidenced by enhanced behavioral responses to subsequent D2 agonist treatments - a phenomenon known as priming of receptors. Priming of D2 receptors has been well-studied in otherwise intact (non-lesioned) rats. In contrast to D2 priming, repeated treatments with a DA D1 agonist are unable to prime D1 receptors unless nigrostriatal DA fibers are largely destroyed in early postnatal ontogeny. In order to determine if D2 receptors could be primed in rats in which nigrostriatal DA fibers were largely destroyed in early postnatal ontogeny, rats were (a) lesioned at 3 days after birth with 6-hydroxydopamine (67 μg in each lateral ventricle; desipramine, 20 mg/kg IP, 1 h; 6-OHDA), (b) treated daily for the first 28 days after birth with the D2 agonist quinpirole HCl (3.0 mg/kg IP), and (c) observed in adulthood for both quinpirole-induced and SKF 38393- (D1 agonist-) induced locomotor activity and stereotyped activities. In 6-OHDA-lesioned rats in which endogenous striatal DA was reduced by 99%, quinpirole did not produce enhanced locomotor or stereotyped activities. However, SKF 38393 produced increased locomotor and stereotyped activities even after the first dose of SKF 38393. These findings demonstrate that D2 receptors are not primed by ontogenetic quinpirole treatments of neonatally 6-OHDA-lesioned rats, although D2 agonist treatments do at least partially prime D1 receptors in 6-OHDA-lesioned rats.

The classic rodent model of Parkinson’s disease (PD) is produced by unilateral lesioning of pars compacta substantia nigra (SNpc) in adult rats, producing unilateral motor deficits which can be assessed by dopamine (DA) D2 receptor (D2-R) agonist induction of measurable unilateral rotations. Bilateral SNpc lesions in adult rats produce life-threatening aphagia, adipsia, and severe motor disability resembling paralysis-a PD model that is so compromised that it is seldom used. Described in this paper is a PD rodent model in which there is bilateral 99% loss of striatal dopaminergic innervation, produced by bilateral intracerebroventricular or intracisternal 6-hydroxydopamine (6-OHDA) administration to perinatal rats. This procedure produces no lethality and does not shorten the life span, while rat pups continue to suckle through the pre-weaning period; and eat without impairment post-weaning. There is no obvious motor deficit during or after weaning, except with special testing, so that parkinsonian rats are indistin-guishable from control and thus allow for behavioral assessments to be conducted in a blinded manner. L-DOPA (L-3,4-dihydroxyphenylalanine) treatment increases DA content in striatal tissue, also evokes a rise in extraneuronal (i.e.,in vivo microdialysate) DA, and is able to evoke dyskinesias. D2-R agonists produce effects similar to those of L-DOPA. In addition, effects of both D1-and D2-R agonist effects on overt or latent receptor supersensitization are amenable to study. Elevated basal levels of reactive oxygen species (ROS), namely hydroxyl radical, occurring in dopaminergic denervated striatum are suppressed by L-DOPA treatment. Striatal serotoninergic hyperinnervation ensuing after perinatal dopaminergic denervation does not appear to interfere with assessments of the dopaminergic system by L-DOPA or D1-or D2-R agonist challenge. Partial lesioning of serotonin fibers with a selective neurotoxin either at birth or in adulthood is able to eliminate sero-toninergic hyperinnervation and restore the normal level of serotoninergic innervation. Of all the animal models of PD, that produced by perinatal 6-OHDA lesioning provides the most pronounced destruction of nigrostriatal neurons, thus representing a model of severe PD, as the neurochemical outcome resembles the status of severe PD in humans but without obvious motor deficits.

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.

Repeated treatments of rats with the dopamine (DA) D2 receptor agonist quinpirole, consistently produce long-lived DA D2 receptor supersensitization, by the process that has been termed priming. Rats so-primed in ontogeny behaviorally demonstrate adulthood enhancement of low-dose quinpirole-induced yawning. Because 1) dopaminergic neurons originate in midbrain nuclei (substantia nigra and ventral tegmental area), and 2) noradrenergic neurons originate in pontine (locus coeruleus) and medullary areas, it might be presumed that these two monoaminergic systems are independent, not interdependent. However, in the present study we demonstrate that there was an attenuation of quinpirole-enhanced yawning at 8 weeks in rats that were 1) primed by repeated neonatal quinpirole HCl treatments (50 μg/kg per day SC) during the first ten days of postnatal ontogeny, and 2) lesioned at 3 days after birth with DSP-4 (N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride, 50 mg/kg SC). Dose-effect curves indicated a 23-45% reduction in yawning by DSP-4 treatment of quinpirole-primed rats, acutely treated as adults with quinpirole (25, 50, or 100 μg/kg). Effectiveness of DSP-4 is reflected by the 95% and 99% reductions in norepinephrine contents of frontal cortex and hippocampus, respectively (HPLC/ED method). The findings are supportive of a modulatory role of noradrenergic fibers on dopamine receptor priming (supersensitization) in rat brain.

Receptor priming is a recently discovered phenomenon by which receptor agonists produce abrupt and long-lived supersensitization of receptors. Induction of dopamine (DA) D2 receptor supersensitivity by the agonist quinpirole was discovered approximately 15 years ago, and was found to occur consistently if rats were treated repeatedly at daily or weekly or monthly intervals with low or high doses of quinpirole. In this review we summarize and discuss some of the major studies that underlie DA D2 receptor supersen-sitivity, describe behavioral processes that are known to be altered by DA D2 receptor supersensitivity, and discuss the importance of DA innervation on expression of enhanced behaviors. DA D2 receptor supersen-sitivity represents one of the neural mechanisms implicated in psychiatric disorders. Also, DA D2 receptor supersensitivity and increased DA D3 receptor expression are associated with motor dyskinesias, as in L-DOPA-treated Parkinson's disease patients. An understanding of receptor priming, a knowledge of the types of behavioral expression associated with DA D2 receptor supersensitivity, and an understanding of mechanisms associated with receptor supersen-sitization, can lead to improvements in the treatments of psychiatric and neurological disorders.

To explore associations of neostriatal (NST) endogenous levels of dopamine (DA) and serotonin (5-HT) with sensitivity of their receptors, graded doses of 6-hydroxydopamine HBr (0 to 400 μg, ICV; 6-OHDA; desipramine pretreatment, 20 mg/kg IP) were given to rats between birth (P 0) and P 42. Numbers of vacuous chewing movements (VCMs) induced by SKF 38393 or m-chlorophenylpiperazine (m-CPP), respective DA D1 and 5-HT2 agonists, were subsequently determined. Enhanced SKF 38393-induced VCMs occurred when NST DA was reduced 97%-98% by high dose 6-OHDA (100-134 μg) at P 0 or P 3, but not in rats with 95%-97% loss in DA produced by 6-OHDA at P7 (134 μg) or P3 (67 μg). Enhanced m-CPP-induced VCMs occurred even when NST 5-HT content was not elevated after 6-OHDA (134 μg at P 10). Accordingly, D1 and 5-HT receptor sensitivity is not correlated with respective NST DA and 5-HT contents. The stage of ontogeny at the time of DA denervation may be the governing influence on receptor sensitivity.