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The effects of chronic continuous and intermittent administration of the dopamine D1 receptor agonist SKF 38393 or the D2 receptor agonist quinpirole on rotational behavior and dopamine receptor binding were examined in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. Continuous and intermittent SKF 38393 both decreased the rotational response to subsequent challenge with SKF 38393. Intermittent SKF 38393 increased quinpirole rotation, while continuous SKF 38393 had no effect. Continuous administration of quinpirole did not affect rotation elicited by either SKF 38393 or quinpirole. Intermittent quinpirole, however, increased both SKF 38393- and quinpirole-induced rotation. Autoradiographic techniques were used to measure D1 receptor binding in striatum and substantia nigra pars reticulata and D2 receptor binding in striatum and nucleus accumbens. Intermittent SKF 38393 reduced D1 receptor Bmax and increased D1 Kd in the striatum, while both continuous and intermittent treatment with the D1 agonist decreased D1 binding in the substantia nigra pars reticulata. Intermittent quinpirole decreased D1 receptor Kd in striatum, and continuous quinpirole reduced D1 binding slightly in substantia nigra pars reticulata. Striatal D2 receptor binding was unaffected by treatment with either SKF 38393 or quinpirole. Intermittent SKF 38393 and continuous quinpirole both reversed the lesioned-induced elevation in D2 binding in the nucleus accumbens, while intermittent quinpirole decreased D2 binding in the accumbens on both the intact and denervated sides. Thus, the effects of chronic treatment with D1 and D2 agonists on behavioral responses to D1 and D2 receptor stimulation differed considerably and were dependent on the treatment regimen employed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of selective dopamine D1 and D2 receptor agonists on chronic haloperidol-treated rats was studied. Haloperidol treatment produced a 77% increase in apomorphine-induced sterotypy. The administration of the selective dopamine D1 receptor agonist SKF38393 alone or in combination with the selective dopamine D2 receptor agonist quinpirole attenuated the effect of haloperidol. Treatment with quinpirole alone did not have a significant effect on the response to haloperidol. Haloperidol did not modify the number of dopamine D1 receptors but increased that of dopamine D2 receptors. SKF38393 reversed the effect of haloperidol on dopamine D2 receptor binding. Co-administration of SKF38393 and quinpirole did not modify the increase in the number of dopamine D2 receptors induced by chronic treatment haloperidol. The results confirm a dissociation between behavioral supersensitivity and dopamine receptor up-regulation, suggesting that other mechanisms may be involved in the expression of behavioral supersensitivity.

The effect of the selective K -opioid agonist, spiradoline, on rotational behavior induced by a dopamine d 1 or D 2 agonist was examined in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. Spiradoline reduced the rotational response to the d 1 agonist SKF 38393 in a dose-dependent manner. Spiradoline had no effect on the total number of turns elicited by the D 2 agonist quinpirole, but did alter the pattern of quinpirole-induced rotation at the highest dose tested. By itself, Spiradoline did not have any obvious effects on motor behavior and did not cause rotation in either the ipsilateral or contralateral direction. These data suggest that K receptor stimulation, possibly mediated by the endogenous agonist dynorphin under physiological conditions, may function to dampen striatal output through the D 1 receptor-regulated striatonigral pathway.

The ability of cannabinoid receptor stimulation or blockade to alter catalepsy produced by dopamine D1 and D2 receptor antagonists was studied in rats. The cannabinoid receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H- pyrazole-3-carboxamidehydrochloride) (0.5 and 2.5 mg/kg) reduced catalepsy elicited by the cannabinoid receptor agonist CP 55,940 (1 alpha,2-(R)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl ) cyclohexyl-phenol) (0.5 mg/kg). However, SR 141716A (0.5 and 2.5 mg/kg) did not decrease catalepsy produced by the dopamine D1 receptor antagonist SCH 23390 (R-(+)-7chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1-H-3-benzazepine) (0.5 mg/kg) or the dopamine D2 receptor antagonist raclopride (S(-)-3,5-dichloro-N-(1-ethyl-2-pyrrolidinyl)-methyl-6-methoxysalicylami de) (2.5 mg/kg), suggesting that, under these conditions, endogenous cannabinoid ligands do not modulate the cataleptic effects of dopamine D1 or D2 receptor antagonists. In contrast, CP 55,940 (0.025 and 0.1 mg/kg), at doses which do not produce catalepsy when administered alone, enhanced catalepsy produced by SCH 23390 and raclopride. These results suggest that stimulation, but not blockade, of brain cannabinoid receptors modifies catalepsy behavior produced by selective dopamine D1 and D2 receptor blockade.

Excitatory amino acid antagonists have been proposed as novel therapeutic agents for Parkinson's disease due to their ability to reverse akinesia in animal models of this disorder. To further evaluate this therapeutic potential, we examined the effects of a N-methyl-D-aspartate (NMDA) and an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist on catalepsy produced by dopamine D 1 or D 2 receptor antagonists in rats. Male Sprague-Dawley rats were injected with dizocilpine (MK-801 0.025, 0.05 or 0.1 mg/kg i.p.), 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX 12.5 mg/kg i.p.) or saline prior to administration of either raclopride (2.5 mg/kg i.p.) or SCH 23390 (0.5 mg/kg i.p.). Catalepsy was evaluated with both grid and bar tests every 20 min for 2.7 h. MK-801 (0.1 mg/kg) reversed the catalepsy produced by either raclopride or SCH 23390 but did not stimulate locomotion when given alone at this dose. At 0.05 mg/kg, MK-801 markedly decreased SCH 23390-induced catalepsy, but did not affect the catalepsy produced by raclopride. In contrast, NBQX increased raclopride-induced catalepsy, but had no effect on catalepsy elicited by SCH 23390. These findings suggest that blockade of NMDA receptors, but not non-NMDA receptors, may reverse the catalepsy produced by dopamine receptor antagonists.

The effect of G i protein modification produced by intrastriatal pertussis toxin injection on dopcmine (DA)-mediated behaviors was studied. Administration of the selective D 2 agonist quinpirole induced ipsilateral rotation but the selective D 1 agonist SKF 38393 did not. However, SKF 38393 was able to increase the rotation induced by quinpirole. The selective D 2 antagonist raclopride and the selective D 1 antagonist SCH 23390 both blocked the effect of quinpirole. Striatal levels of cAMP were measured in both intact and pertussis toxin injected striatum. SKF 38393 induced a significant increase in cAMP, but quinpirole had no effect. When both drugs were administered together, quinpirole attenuated the SKF 38393-induced increase in cAMP levels. Moreover, quinpirole-induced attenuation of SKF 38393 effect was greater in intact striatum. In pertussis toxin-injected striatum, quinpirole only attenuated SKF 38393-induced increase of cAMP to control levels. This imbalance between intact and injected striatum might be the cause of the rotation in pertussis toxin-injected rats suggesting an important role for G proteins in DA receptor interactions.

The effect of the selective dopamine-1 (D-1) antagonist, SCH 23390 and the selective D-1 agonist, SKF 38393 on plasma prolactin levels was investigated in conscious, freely moving male rats. Plasma prolactin was markedly increased by the intravenous injection of either SCH 23390 or SKF 38393 in a dose-related fashion. The maximal prolactin response was observed 15 min after drug injection. The d-isomer of SKF 38393 was significantly more potent than the l-isomer. In urethane-anesthetized rats, the two drugs produced similar effects on prolactin as those in the conscious animal preparation. Both SCH 23390 and SKF 38393 potentiated the sulpiride-induced prolactin as those in the These observations suggest that pharmacologic stimulation, or blockade of D-1 receptors in the living animal, can mimic the action of a D2 antagonist at the anterior pituitary lactotroph. We have speculated on the possible mechanisms in pituitary and higher in the central nervous system which might be responsible for the prolactin changes caused by either SCH 23390 of SKF 38393.

The effect of peripherally administered cholecystokinin-octapeptide (CCK8) was tested on signaled-avoidance behavior, apomorphine-induced stereotypy, and catalepsy. Rats were trained to avoid shock in a signaled shuttle-box avoidance task, and then given CCK8, tetragastrin, or haloperidol. CCK8 (20-3840 micrograms/kg i.p.) reduced avoidance in a dose-dependent manner. The impairment at maximal dose levels was approximately 25% from its predrug level compared to 50% with haloperidol (100 micrograms/kg i.p.). Combined injection of CCK8 (320 micrograms/kg i.p.) and haloperidol (75 micrograms/kg i.p.) reduced avoidance significantly more than either drug alone. The effects of CCK8 were relatively brief in that active avoidance was impaired if CCK8 was injected up to 15 min before the avoidance test. CCK8 also facilitated the extinction of avoidance. Tetragastrin (177 micrograms/kg i.p.), which elicits gastrointestinal effects resembling CCK8, did not affect avoidance. In addition, CCK8 diminished apomorphine-induced stereotypy up to 5 min after CCK8 injection. CCK8 (20-1280 micrograms/kg i.p. and s.c.) failed to produce catalepsy in vertical grip tests. These data suggest that peripherally administered CCK8 has sedative and certain neuroleptic-like effects on behavior.

The effect of selective D-1 and D-2 dopamine receptor agonists (SKF 38393 and LY 171555, respectively) on motor function was studied in rats with unilateral, quinolinic acid-induced striatal lesions. Dose-dependent turning ipsilateral to the side of the lesion was elicited by LY 171555, but not by SKF 38393. When the drugs were given together, however, SKF 38393 was able to increase the total number (but not the duration) of turning induced by LY 171555 in a dose-dependent fashion. Furthermore, either α-methyl-paratyrosine pretreatment, a DA-depleting agent, or SCH 23390, a D-1 antagonist, inhibited the LY 171555-induced rotation, which would be restored by SKF 38393. These observations suggest that both the D-1 and D-2 dopamine receptor systems participate in the regulation of rotational behaviors in striatally lesioned rats with normosensitive DA receptors.

The effects of continuous and intermittent levodopa treatment on rotational behavior induced by dopamine agonists were examined in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. Chronic administration of levodopa by continuous infusion (90–100 mg/kg per day i.p. by osmotic pump for 19 days with a 3 day washout) enhanced the rotational response to the D-2 dopamine receptor agonist quinpirole, but had no effect on rotation induced by the D-1 agonist SKF 38393 or that due to the non-selective dopamine agonist apomorphine. The rotational responses to the selective dopamine agonists differed dramatically in rats treated with levodopa by intermittent injection (45–50 mg/kg i.p., b.i.d. for 19 days with a 3 day washout): they showed a markedly increased response to quinpirole, a greatly diminished response to SKF 38393, and a modestly enhanced response to apomorphine. Continuous and intermittent treatment resulted in equivalent daily plasma levodopa levels. These findings suggest that the intermittence of central dopamine receptor stimulation may be an important factor in determining the subsequent responses of the dopamine system. The dissociation between the effects of both continuous and intermittent levodopa on D-1 and D-2 agonist-induced rotation indicates that D-1 and D-2 dopamine receptor-mediated mechanisms respond differently to chronic levodopa treatment.

The effect of chronic D-1 dopamine (DA) receptor blockade on D-1 DA receptors and DA-mediated behaviors was studied in rats with unilateral, quinolinic acid-induced striatal lesions. Administration of the selective D-1 antagonist SCH 23390 for 15 days increased D-1 receptor numbers in the unlesioned striatum as indicated by [125I]SCH 23982 binding; ipsilateral turning initiated by the D-2 receptor agonist LY 171555 decreased, while grooming produced by the D-1 receptor agonist SKF 38393 intensified. There was, however, no change in the ability of the D-1 agonist to potentiate D-2 agonist-mediated rotation. The observed behavioral subsensitivity in response to a D-2 agonist may reflect D-1 receptor upregulation and the consequent imbalance of D-1/D-2 receptor interactions in the striatum where these two receptor subtypes appear to play opposite functional roles; potentiation of grooming, primarily a D-1 receptor-mediated behavior, may also reflect the increase in D-1 receptor numbers.

Cholecystokinin octapeptide was administered intraventricularly to laboratory rats in a behaviorally active dose. Quantitative regional glucose utilization was assessed as a measure of neuronal activity using [14C]2-deoxyglucose. CCK-8 reduced glucose utilization in selected subcortical nuclei, but left most areas of cortex unaffected. The subcortical nuclei were chiefly extrapyramidal systems. The diminutive pharmacologic action on cortical neuronal activity implies CCK-8 may act here as a neuronal modulator, in concert with other central transmitters, rather than having prominent singular actions.

Chronic treatment with the selective D-1 agonist SKF 38393 induced behavioral supersensitivity (increased stereotypy and decreased locomotor activity) in response to apomorphine. In contrast, chronic treatment with the selective D-2 agonist LY 171555 resulted in a subsensitive behavioral response to apomorphine challenge. Chronic treatment with the combination of these drugs augmented apomorphine-induced stereotypic behaviors, but these were different in nature from those observed in animals treated with SKF 38393 alone. Chronic SKF 38393 treatment resulted in an enhanced behavioral response to SKF 38393 itself. Behavioral response to LY 171555 was affected only by chronic treatment with the combination of selective agonists. These results suggest that chronic D-1 receptor stimulation may be necessary and sufficient for the development of dopamine agonist-induced behavioral sensitization in the intact rat; the mechanism may involve increased sensitivity of D-1 receptor-associated mechanisms. Chronic D-2 receptor stimulation appears to have the opposite effect. These results also provide evidence that a synergistic interaction between receptor subtypes may underlie certain behavioral effects of chronic agonist exposure.

Systemic administration of cholecystokinin-octapeptide (CCK8) suppresses operant responding in water deprived rats, but it is unclear whether this effect is centrally or peripherally mediated. Rats were trained to press a lever for water in an operant conditioning chamber under a variable-interval schedule of reinforcement. After response rate stabilized injections were administered, and response suppression was measured by comparing injection response rate to baseline rate. Intracerebroventricular injections of CCK8 reduced lever pressing at relatively high doses (20 and 50 micrograms/rat). But in a direct comparison, the same dose of CCK8 (20 micrograms/rat) given intraperitoneally reduced responding significantly more than when given into the lateral ventricle. The suppressive effects of CCK8 (30 and 300 micrograms/kg i.p.) were significantly reduced by complete abdominal vagotomy. The effects of CCK8 (30 micrograms/kg i.p.) were blocked by pretreatment with the specific competitive CCK8 antagonist dibutyryl cyclic GMP (70 and 140 mg/kg i.p.), but not by the acetylcholine antagonist atropine (0.1 to 10 mg/kg i.p.). These data suggest that suppression by CCK8 of operant lever pressing in water-deprived rats is primarily mediated by vagal afferent fibers.

Regional changes in the distribution of D-1 dopamine receptors produced by unilateral striatal lesions were evaluated in rat brain by quantitative autoradiography. Lesions were induced by local infusion of quinolinic acid, an endogenous excitotoxin that destroys intrinsic neurons, but spares fibers of passage. D-1 receptor density, as determined by [125I]SCH 23982 binding, was reduced in caudate-putamen, globus pallidus, substantia nigra, nucleus entopeduncularis on the lesioned side. These results confirm the presence of D-1 receptors on striatal cell bodies and provide direct evidence for the existence of presynaptic D-1 receptors on the terminals of striatal projections.

Administered independently, the selective D-1 and D-2 agonists SKF 38393 and LY 171555 elicited dose dependent increases in complex motor behaviors such as locomotion or grooming. Typical stereotypic behaviors were observed only when these agents were combined and only at the higher doses of the D-1 agonist. AMPT pretreatment blocked the effects of the agonists administered independently, but all classes of behavior could be induced when they were administered in combination. Thus, expression of dopamine agonist induced behaviors requires concurrent activation of D-1 and D-2 receptors; the nature of the behavior appears to depend upon the ratio of D-1 to D-2 receptor activation.