To study the role of dopamine D1 receptors in enhanced oral activity effects of SKF 38393 ((±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) in neonatal 6-hydroxydopamine-lesioned rats, SKF 38393 was compared to the full agonist, A77636 ((1R,3S)-3-(1′-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran). At 3 days after birth rats were treated with 6-hydroxydopamine HBr (200 μg, salt form, i.c.v.; desipramine (20 mg/kg i.p.), 1 h) or vehicle. At 6-8 months a 0.01 mg/kg dose of A77636 HCl increased oral activity in 6-hydroxydopamine vs. control rats (P < 0.01). A77636 and SKF 38393 produced identical maximal responses of 35-36 oral movements at 0.1 and 1.0 mg/kg, respectively. SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) HCl (0.3 mg/kg i.p.) attenuated the response to A77636. Neither A77636 HCl (0.01-1.0 mg/kg i.p.) nor SKF 38393 HCl (0.03-3.0 mg/kg i.p.) induced oral activity in intact rats. The findings demonstrate that A77636 is more potent than SKF 38393, and that supersensitized dopamine D1 receptors are involved in the induction of oral behavior in neonatal 6-hydroxydopamine-lesioned rats.

Dopamine (DA) receptor supersensitivity refers to the phenomenon of an enhanced physiological, behavioral or biochemical response to a DA agonist. Literature related to ontogenetic aspects of this process was reviewed. Neonatal 6-hydroxydopamine (6-OHDA) destruction of rat brain DA neurons produces overt sensitization to D1 agonist-induced oral activity, overt sensitization of some D2 agonist-induced stereotyped behaviors and latent sensitization of D1 agonist-induced locomotor and some stereotyped behaviors. This last process is unmasked by repeated treatments with D1 (homologous "priming") or D2 (heterologous "priming") agonists. A serotonin (5-HT) neurotoxin (5,7-dihydroxytryptamine) and 5-HT2C receptor antagonist (mianserin) attenuate some enhanced behavioral effects of D1 agonists, indicating that 5-HT neurochemical systems influence D1 receptor sensitization. Unlike the relative absence of change in brain D1 receptor number, DA D2 receptor proliferation accompanies D2 sensitization in neonatal 6-OHDA-lesioned rats. Robust D2 receptor supersensitization can also be induced in intact rats by repeated treatments in ontogeny with the D2 agonist quinpirole. In these rats quinpirole treatments produce vertical jumping at 3-5 wk after birth and subsequent enhanced quinpirole-induced antinociception and yawning. The latter is thought to represent D3 receptor sensitization. Except for enhanced D1 agonist-induced expression of c-fos, there are no changes in the receptor or receptor-mediated processes which account for receptor sensitization. Adaptive mechanisms by multiple "in series" neurons with different neurotransmitters may account for the phenomenon known as receptor supersensitivity.

Our laboratory has reported neonatal quinpirole (D2/D3 agonist) treatment to rats increases dopamine D2 receptor sensitivity that persists throughout the animal's lifetime. This model appears to have clinical relevance to schizophrenia, and smoking is common in this population. Male and female Sprague-dawley rats were neonatally treated with quinpirole from postnatal (P) days 1–21. After habituation from P30 to 32, animals were administered saline or nicotine (0.3, 0.5, or 0.7mg/kg free base) every other day from P33 to 49 and locomotor activity was assessed. Generally, animals neonatally treated with quinpirole and administered nicotine during adolescence demonstrated increased behavioral activity and/or sensitization compared to animals neonatally given saline and sensitized to nicotine as well as controls. However, animals neonatally treated with quinpirole and given the 0.7mg/kg dose of nicotine demonstrated elevated activity throughout testing but did not show sensitization, and only mild sex differences were reported. Therefore, microdialysis was performed on male rats sensitized to the 0.5mg/kg dose of nicotine, and results revealed that neonatal quinpirole sensitized dopamine overflow in response to nicotine to 500% above animals neonatally given saline and sensitized to nicotine at peak levels. In addition, neonatal quinpirole increased the accumbal BDNF in response to nicotine compared to all other groups, and nicotine alone also produced significant increases in striatal and accumbal BDNF. This study reveals that neonatal quinpirole enhanced adolescent nicotine sensitization, accumbal dopamine overflow, and BDNF protein in response to nicotine, which may be related to changes in the brain's reward system.

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.

Long-term postnatal treatment of rats with the dopamine D2 receptor antagonist, spiroperidol, results in the impaired development of striatal D2 receptors. Because the tripeptide prolyl-leucyl-glycinamide (MIF-1) attenuates haloperidol-induced up-regulation of striatal dopamine D2 receptors in adult rats, we studied the effect of MIF-1 on the spiroperidol-induced alteration of striatal D2 ontogeny. Postnatal treatment of rats with spiroperidol (1.0 mg/kg/day, IP, ×32 days from birth) resulted in a 74% decrease in the Bmax for [3H]spiroperidol binding with no change in the Kd at 5 weeks. When rats were studied at 8 weeks, in the absence of additional treatment, total specific [3H]spiroperidol binding was reduced by 59%. While MIF-1 alone (1.0 mg/kg/day, IP, ×32 days from birth) had no effect on [3H]spiroperidol binding, MIF-1 completely attenuated the ontogenic impairment of striatal D2 receptors that was produced by spiroperidol treatment. At 5 weeks the Bmax for [3H]spiroperidol binding was at the saline control level in the group of rats cotreated with spiroperidol and MIF-1. At 8 weeks, with no additional treatments, the specific binding of [3H]spiroperidol to striatum was also at control levels in the group cotreated with spiroperidol and MIF-1. These findings demonstrate that MIF-1 attenuates spiroperidol-induced impairment of development of striatal dopamine D2 receptors in rats.

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.

Abstract: To study potential biochemical correlates of dopamine (DA) and serotonin receptor supersensitivity, rats were lesioned at 3 days after birth with 6‐hydroxydopamine (6‐OHDA; 67 µg in each lateral ventricle; desipramine pretreatment, 20 mg/kg i.p., 1 h) and then sensitized with the DA D1 agonist, SKF 38393 HCl (3.0 mg/kg i.p. per day) either ontogenetically (daily, for 28 consecutive days from birth) and/or in adulthood (four weekly injections, 6–9 weeks from birth). Controls received vehicle in place of 6‐OHDA or SKF 38393. Enhanced locomotor responses were observed after SKF 38393 at 6 weeks, only in rats that received SKF 38393 + 6‐OHDA in ontogeny. Locomotor responses were further enhanced in this group after the last of four weekly SKF 38393 injections at the 9th week. These weekly SKF 38393 treatments also produced enhanced responses in 6‐OHDA rats that did not receive SKF 38393 in ontogeny. When striata were studied at 11 weeks, the percentages of high and low affinity DA D1 binding sites were not altered. Basal as well as DA‐, NaF‐, and forskolin‐stimulated adenylyl cyclase activities also were not changed. Dot blot analysis showed that there was a reduction of mRNA levels for DA D1, but not serotonin1C, receptors in the 6‐OHDA groups. However, SKF 38393 at 6–9 weeks eliminated this alteration. Based on these findings it can be proposed that supersensitization may be a consequence of altered neuronal cross talk rather than an imbalance of receptor elements per se.

Rationale and objective: The adenosine A(2A) receptor forms a mutually inhibitory heteromer with the dopamine D2 receptor, and A(2A) agonists decrease D2 signaling. This study analyzed whether an adenosine A(2A) agonist would alleviate deficits in sensorimotor gating and increases in cyclic-AMP response element binding protein (CREB) in the nucleus accumbens (NAc) in the neonatal quinpirole model of schizophrenia (SZ). Methods: Male and female Sprague-Dawley rats were neonatally treated with saline (NS) or quinpirole HCl (NQ; 1 mg/kg) from postnatal days (P) 1–21. Animals were raised to P44 and behaviorally tested on auditory sensorimotor gating as measured through prepulse inhibition (PPI) from P44 to P48. Approximately 15 min before each session, animals were given an ip administration of saline or the adenosine A(2A) agonist CGS 21680 (0.03 or 0.09 mg/kg). One day after PPI was complete on P49, animals were administered a locomotor activity test in the open field after saline or CGS 21680 treatment, respectively. On P50, the nucleus accumbens (NAc) was evaluated for CREB protein. Results: NQ-treated rats demonstrated a deficit in PPI that was alleviated to control levels by either dose of CGS 21680. The 0.03 mg/kg dose of CGS 21680 increased startle amplitude in males. The 0.09 mg/kg dose of CGS 21680 resulted in an overall decrease in locomotor activity. NQ treatment significantly increased NAc CREB that was attenuated to control levels by either dose of CGS 21680. Conclusions: This study revealed that an adenosine A(2A) receptor agonist was effective to alleviate PPI deficits in the NQ model of SZ in both male and female rats.

In rats lesioned neonatally with 6-hydroxydopamine (6-OHDA), repeated treatment with SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol), a dopamine D1/D5 receptor agonist, produces robust stereotyped and locomotor activities. The gradual induction of dopamine D1 receptor supersensitivity is known as a priming phenomenon, and this process is thought to underlie not only the appearance of vacuous chewing movements in humans with tardive dyskinesia, but also the onset of motor dyskinesias in l-dihydroxyphenylalanine (l-DOPA)-treated Parkinson's disease patients. The object of the present study was to determine the possible influence of the histaminergic system on dopamine D1 agonist-induced activities. We found that neither imetit (5.0 mg/kg i.p.), a histamine H3 receptor agonist, nor thioperamide (5.0 mg/kg i.p.), a histamine H3 receptor antagonist/inverse agonist, altered the numbers of vacuous chewing movements in non-primed-lesioned rats. However, in dopamine D1 agonist-primed rats, thioperamide alone produced a vacuous chewing movements response (i.e., P < 0.05 vs SKF 38393, 1.0 mg/kg i.p.), but did not modify the SKF 38393 effect. Notably, both imetit and thioperamide-induced catalepsy in both non-primed and primed 6-OHDA-lesioned rats, comparable in magnitude to the effect of the dopamine D1/D5 receptor antagonist SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.5 mg/kg i.p.). Furthermore, in primed animals both imetit and thioperamide intensified SCH 23390-evoked catalepsy. In vivo microdialysis established that neither imetit nor thioperamide altered extraneuronal levels of dopamine and its metabolites in the striatum of 6-OHDA-lesioned rats. On the basis of the present study, we believe that histaminergic systems may augment dyskinesias induced by dopamine receptor agonists, independent of direct actions on dopaminergic neurons.