D-2 but not D-1 dopamine agonists produce augmented behavioral response in rats after subchronic treatment with methamphetamine or cocaine

A study was performed to examine behavioral response to a challenge of selective dopamine D-1 and D-2 agonists in rats previously sensitized by subchronic administration of methamphetamine or cocaine. Rats in three groups received repeated injections (IP) of saline, methamphetamine (4 mg/kg/day) or cocaine (20 mg/kg/day), respectively, for 14 days. After an abstinence period of 7–13 days, all groups were challenged with either a selective D-1 agonist (SKF 38393) or D-2 agonists (quinpirole or RU 24213). The ability of SKF 38393 (6 mg/kg or 18 mg/kg) to produce grooming behavior did not differ significantly among the saline-, methamphetamine-and cocaine-treated groups. In contrast, quinpirole (1 mg/kg) and RU 24213 (3 mg/kg) produced more intense stereotypy consisting of rearing, sniffing and repetitive head movement in the two psychostimulant-treated groups than in the saline-treated group. Such augmented response to selective D-2 agonists was observed even after a 1-month abstinence period. These results suggest that the enduring behavioral sensitization induced by two pharmacologically distinct psychostimulant agents, methamphetamine and cocaine, occurs through a common neurobiological mechanism of lasting supersensitivity in postsynaptic D-2, but not D-1 dopamine receptors.     

Dopaminergic control of locomotion,mouthing, snout contact,and grooming: opposing roles of D1 and D2 receptors

The study compares the behavioral profiles induced in rats (N=118) by the D₂-dopaminergic receptor agonist quinpirole (0.03 and 0.5 mg/kg), and the D₁-agonist SKF38393 (1.25–40 mg/kg), and both agonists administered together. Locomotion and snout contact frequency were reduced by the low but increased by the high dose of quinpirole; SKF38393 also reduced these behaviors and attenuated the effect of the high quinpirole dose. Only the high dose of quinpirole increased the duration of snout contact bouts and the frequency of mouthing; SKF38393 had no effect but in combination with the high dose of quinpirole, it enhanced the performance of these behaviors greatly. The duration of mouthing bouts was not affected by either agonist but was greatly extended when SKF38393 was administered together with the high dose of quinpirole. Grooming was inhibited by both the low and the high dose of quinpirole, and stimulated by the injection of SKF38393 or its addition to the low dose of quinpirole. These findings suggest that snout contact is controlled by modulating the frequency of episodes whereas mouthing is controlled by modulating the duration of episodes. Moreover, although they do not disprove the prevailing notion of D₁–D₂ receptor synergism, the present data are consistent also with an oppositional model of D₁–D₂ receptor interaction in the regulation of locomotion, snout contact, mouthing, and grooming in intact animals.     

Selective attenuation of the antinociceptive effects of μ opioids by the putative dopamine D3 agonist 7-OH-DPAT

Rationale: The purpose of the present investigation was to evaluate the effects of the D₃ agonist (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), various dopamine (DA) agonists and DA antagonists on the antinociceptive effects of μ opioids. Methods: Antinociception was assessed using a warm-water tail-withdrawal procedure in rats. Results: The μ opioids morphine (0.3–10 mg/kg) and dezocine (0.03–3.0 mg/kg) produced dose-dependent increases in antinociception with maximal effects obtained at the higher doses tested. Pretreatment with the putative D₃ agonist 7-OH-DPAT (1.0–10 mg/kg) produced a dose-dependent attenuation of the antinociceptive effects of morphine and dezocine. At the highest dose of 7-OH-DPAT tested, the morphine dose-effect curve was shifted rightward by approximately 1.5 log units and the dezocine curve by greater than 2.3 log units. The (+)-isomer of 7-OH-DPAT (1.0 and 3.0 mg/kg) also shifted the morphine dose-effect curve to the right in a dose-dependent manner. The DA D₃/D₂ agonist (−)-quinpirole (0.1–10 mg/kg) attenuated the effects of morphine, but these effects were small in magnitude, not dose-dependent and observed only under a limited set of conditions. The DA D₂/D₃ antagonist spiperone failed to alter the morphine dose-effect curve, but reversed the effects of 7-OH-DPAT on morphine antinociception. Pretreatment with the DA D₁ agonist (±)-SKF38393 (1.0 and 10 mg/kg) and the D₁ antagonist (+)-SCH23390 (0.1 and 1.0 mg/kg) failed to alter the morphine dose-effect curve. Conclusion: The finding that 7-OH-DPAT markedly attenuated the effects of morphine and that these effects were reversed with spiperone suggests that activity at the D₃, and possibly the D₂, receptor can modulate μ agonist-induced antinociception. Received: 30 June 1998/Final version: 12 January 1999     

Role of dopamine receptors in the dual effect of naloxone on quinpirole-induced yawning in morphine pretreated rats

Summary The present study was undertaken to determine the state of sensitivity of dopamine D2/133 receptors involved in the mediation of yawning behaviour at various times following acute morphine administration to rats. Morphine (3.0 mg/kg, s.c.) induced a biphasic effect on locomotor activity: an initial inhibitory phase lasting for about 30 min was after about an hour followed by a phase of locomotor activation lasting for about 60 min. Dopamine D2/D3 receptor agonist quinpirole (0.01–0.1 mg/kg, s.c.) induced yawning behaviour in rats. Morphine given at 15 or 60 min before (inhibitory phase) inhibited the yawning response to quinpirole (0.1 mg/kg) but not when given at 90 or 120 min before (stimulatory phase). Naloxone (1.0 mg/kg) given 10 min before quinpirole restored yawning inhibited by morphine pretreatment during the inhibitory phase (15–60 min after morphine). However, during the morphine-induced stimulatory phase naloxone strongly inhibited the yawning response to quinpirole. D 1 receptor antagonist SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hemimaleate] at 0.01 mg/ kg did not affect quinpirole-induced yawning or its inhibition by morphine. However, in rats which received morphine 90 min prior to testing yawning, SCH 23390 enhanced quinpirole-induced yawning behaviour as compared with morphine- or saline-pretreated animals. The data obtained in the present study indicate that morphine pretreatment initially induces a lack of responsiveness of the D2/D3 receptors mediating yawning behaviour and subsequently increases their sensitivity. However, the behavioural expression of hypersensitivity of these receptors seems to be attenuated by the concomitant activation of D1 receptors after morphine pretreatment, and thus the enhanced response to quinpirole is first seen after blockade of D1 receptors. Correspondence to L. Ahtee at the above address     

Dopamine D-2 receptor agonist-induced behavioural depression: critical dependence upon postsynaptic dopamine D-1 function

Summary The dopamine (DA) D-2 receptor agonists quinpirole (threshold dose, 0.01 mg/kg IP), pergolide (0.025 mg/kg), B-HT 920 (0.003 mg/kg) and (–)-3-PPP (4 mg/kg) produced dose-dependent locomotor depression (immobility) in mice as assessed by a subjective scoring system, with the immobility being characterized by a frozen posture. The animals were still but had their eyes open. The immobility was accompanied by reductions in sniffing, rearing and grooming. The depression (and the associated reduction in the various behaviours) produced by quinpirole (0.1 mg/kg), pergolide (0.1 mg/kg) and B-HT 920 (0.1 mg/kg) was substantially (but not always completely) reversed by the selective D-1 receptor agonist SKF38393 (up to 12 mg/kg) and the non-selective D-1 receptor agonist CY208243 (up to 3 mg/kg). The immobility induced by (–)-3-PPP (16 mg/kg) was also reversed by CY208243 and SKF38393, but the reversal was due to an increase in grooming behaviour in mice challenged with the D-1 receptor agonists, whether or not the animals had also received (–)-3-PPP. There was no reversal of the depression of rearing or sniffing. In contrast, CY208243 and SKF38393 also antagonized the immobility induced by B-HT 920, but the reversal was accompanied by at least partial reversals of the depression of sniffing, rearing and grooming. The reversal of quinpirole-induced immobility by SKF38393 and CY208243 was antagonized by SCH23390 (0.1 mg/kg). The selective D-2 receptor antagonist raclopride (0.025 to 0.4 mg/kg) could not reverse quinpirole-induced immobility. High doses of either raclopride (0.4 mg/kg) or SCH23390 (> 0.1 mg/kg) significantly increased immobility. Although raclopride itself (0.2 mg/kg) produced a substantial increase in DOPAC and homovanillic acid (HVA) levels in the striatum, it did not antagonize the autoreceptor mediated effects of quinpirole (0.1 mg/kg) in reducing the striatal dihydroxyphenylacetic acid (DOPAC) to DA ratio. However, the same dose of raclopride was partly effective in reducing the effects of lower doses of quinpirole (0.01 and 0.03 mg/kg) on the striatal DOPAC to DA ratio. Raclopride (0.2 mg/kg) also partially but significantly reduced the locomotor stimulant effects of d-amphetamine in reserpinized mice. Biochemical analyses in the striata indicated that CY208243 slightly retarded DA turnover (as assessed by the DOPAC/DA ratio). SKF38393 itself also slightly reduced DA turnover. In automated activity cages, using mice depleted of DA with reserpine and a-methyltyrosine, all the D-2 receptor agonists tested, in combination with SKF38393, produced an increase in activity. It is concluded that the depression induced by D-2 receptor agonists is due substantially to a deprivation of DA at postsynaptic D-1 receptors and that, at the doses tested, the D-2 receptor agonists were able to exert measurable stimulation of the postsynaptic receptors. The ability of D-1 receptor agonists to reverse the D-2-mediated depression is due to the stimulation of the postsynaptic D-1 receptors with the injected D-1 receptor agonist (replacing the endogenous transmitter) and the stimulation of the postsynaptic D-2 receptors by the injected D-2 receptor agonist.     

Behavioral effects of dopaminergic agonists and antagonists alone and in combination in the squirrel monkey

The effects on schedule-controlled operant behavior of the D₂ receptor agonist, quinpirole, and the D₁ agonist, SKF 38393, were assessed alone and in combination with selective dopamine-receptor antagonists. Squirrel monkeys (Saimiri sciureus) were trained to press a response key under fixed-interval and fixed-ratio schedules of food reinforcement. The fixed-interval schedule maintained relatively low rates of responding that increased up to food presentation. The fixed-ratio schedule maintained relatively constant high rates of responding. Quinpirole increased rates and disrupted the temporal pattern of responding under the fixed-interval schedule at doses (0.1–1.0 mg/kg) that decreased rates of responding under the fixed-ratio schedule. Under the fixed-interval schedule, the D₂ antagonists, spiperone (0.003–0.006 mg/kg) and haloperidol (0.003–0.01 mg/kg), and the D₁ antagonist, SCH 23390 (0.03 mg/kg), shifted the quinpirole dose-effect curve to the right. The maximal effects of quinpirole were decreased at the highest doses of the antagonists. However, only spiperone antagonized effects of quinpirole on the rates of responding under the fixed-ratio schedule. The D₁ agonist, SKF 38393, dose-dependently (1.0–10.0 mg/kg) decreased rates of responding under both schedules. Those effects were not antagonized by any doses studied of either spiperone (0.003 mg/kg) or SCH 23390 (0.003–0.3 mg/kg). Rather, both antagonists enhanced the effects of SKF 38393. The present study suggests significant differences between the effects of D₁ and D₂ agonists on schedule-controlled behavior, and differences in the antagonist actions of the D₂ antagonists haloperidol and spiperone. Further, the selective dopamine D₁ agonist, SKF 38393, has behavioral effects that cannot be antagonized by either a D₁ or D₂ antagonist, suggesting that some other mechanism has a significant role in mediating its behavioral effects.     

Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists andd-amphetamine

The effects of local injections of dopamine receptor agonists into various areas within the nucleus accumbens or the medial caudate-putamen on the generation of locomotor activity were examined. Combinations of 0.32 µg/side of the dopamine receptor agonists SKF 38393 (D₁) and quinpirole (D₂) produced increases in locomotor activity that varied according to the rostral-caudal placement of the cannulae within the nucleus accumbens. The greatest levels of locomotion were generated by injections into a region in the caudal-central nucleus accumbens, with lower levels of activity elicited by injections into more rostral or caudal regions. A similar pattern of responses was produced by administration of the indirect dopamine agonistd-amphetamine. These results indicate that there is marked heterogeneity in the response of discrete sub-regions of the nucleus accumbens to dopamine receptor stimulation and that this heterogeneity is functionally expressed in the mediation of the locomotor effects of dopaminergic agonists.     

Chronic treatment with MK-801 affects the behavioral response to both D1 and D2 dopamine agonist in the one-trial inhibitory avoidance

Post-training administration of theN-methyl-d-aspartate (NMDA) antagonists CPP (0.5 and 1.0 mg/kg) and MK-801 (0.25 and 0.5 mg/kg) impaired, in a dose dependent fashion, the one-trial inhibitory avoidance response in NMRI mice. The D₁ dopamine (DA) agonist SKF 38393 (10 and 20 mg/kg) and the D₂ agonist quinpirole (0.5 and 1.0 mg/kg) instead facilitate the response in the same behavioral paradigm. Sub-chronic blockade of NMDA receptors with MK-801 (0.25 mg/kg once a day for 14 days) did not change the response to both competitive (CPP) and non-competitive (MK-801) NMDA antagonists. The same chronic treatment with MK-801 induced an increased response to both SKF 38393 and quinpirole. These data suggest that repeated administration of MK-801 induce an upregulation of both D₁ and D₂ DA receptors without affecting NMDA receptors.     

Effects of cocaine and quinpirole on perceptual and motor functions in baboons

 The effects of cocaine and quinpirole were studied in baboons to determine whether quinpirole, a relatively selective D₂/D₃ dopamine agonist, produced effects similar to those of cocaine on perceptual and motor processes. To measure perceptual and motor function, three baboons were trained to discriminate differences between a standard vowel and four other synthetic vowels; response accuracy as well as response latencies, or ”reaction times”, were measured following drug administrations. Cocaine reduced reaction times in two baboons, and did not affect reaction times in a third; on the other hand, quinpirole lengthened reaction times in a dose-dependent manner in all baboons. Cocaine and quinpirole also differed in the time course to produce the maximal reaction time effect following drug administration. Cocaine and quinpirole did not differ consistently in their perceptual effects, as indicated by similar changes in d′, a signal-detection index of discriminability. These distinct profiles of effects for cocaine and quinpirole suggest differing neurochemical actions for these two drugs. Received: 10 August 1996 /Final version: 16 May 1997     

Enhanced stimulus-reward learning by intra-amygdala administration of a D3 dopamine receptor agonist

The amygdala is considered to be a critical neural substrate underlying the formation of stimulus-reward associations, and is known to receive substantial innervation from dopaminergic neurons located within the ventral mesencephalon. However, relat- ively little is known about the function of the mesoamygdaloid dopamine projection in stimulus-reward learning. Recently, we have found post-session intra-amygdala microinjections of d-amphetamine to enhance appetitive Pavlovian conditioning as assessed in a discriminative approach task. In the present study, we have examined the effects of dopamine receptor agonists possessing relative selectivity for the D₁, D₂ and D₃ receptor subtypes in order to examine more fully the role of the mesoamygdaloid dopamine projection in stimulus-reward learning. Thus, subjects were trained to associate an initially neutral stimulus (CS⁺) with 10% sucrose reward (US). A second, control stimulus (CS⁻) was also presented but never paired with sucrose reward. In order to measure specifically the conditioned response to CS⁺/CS⁻ presentation, responding during CS and US presentations was measured separately. Immediately following each training session, subjects received bilateral intra-amygdala infusion of 0.1, 1 or 10 nmol/side of SKF-38393, quinpirole or 7-OH-DPAT. Infusions of SKF-38393 or quinpirole were without effect on CS⁺ approach. However, post-session intra-amygdala infusions of 7-OH-DPAT enhanced selectively CS⁺ approach in a dose-dependent fashion. No dose of any drug affected CS⁻approach, US behaviours, or measures of extraneous behaviour. Subsequent acquisition of a novel conditioned instrumental response was also unaffected. Thus, the present data indicate a selective involvement of the D₃ dopamine receptor subtype in the modulation of stimulus-reward learning by the mesoamygdaloid dopamine projection. Received: 12 December 1996 / Final version: 9 April 1997