Selective antagonism of dopamine D1 and D2 receptors does not block the development of behavioral sensitization to cocaine

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D₁ or D₂ selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D₁ dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D₂ dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D₁ or D₂ dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor.Portions of this paper were presented at the 1992 Society for Neuroscience meetings, Anaheim, Cal., USA     

Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats

There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D₃ versus D₂ dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01–0.1 mg/kg), the preferential D₂ agonist, bromocriptine (1–10 mg/kg) and the selective D₃ agonists, 7-OH-DPAT (0.003–0.1 mg/kg), PD 128907 (0.1–3 mg/kg), (+)3PPP (0.3–3 mg/kg), quinelorane (0.0001–0.003 mg/kg) and quinpirole (0.003–0.03 mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D₃ but not D₂ responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D₂/D₃ dopamine antagonists, haloperidol (0.1–0.4 mg/kg) and tiapride (10–60 mg/ kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission. Received: 25 January 1998/Final version: 24 April 1998     

Effects of selective D1 and D2 dopamine antagonists on the development of behavioral sensitization to apomorphine

The objective of the present study was to determine whether the development of behavioral sensitization to apomorphine could be blocked by either D₁ or D₂ selective dopamine antagonists. In three experiments, male rats received 10–21 daily injections of a selective D₁ (SCH 23390; 0 or 0.5 mg/kg IP) or D₂ (sulpiride; 0, 30, or 100 mg/kg IP) antagonist followed by an apomorphine (0 or 1.0 mg/kg SC) injection. In two experiments, the rats were tested for locomotor activity in photocell arenas after the daily injections. In all experiments, the rats were tested for sensitization to apomorphine following the training phase. The results indicated that apomorphine produced a progressively greater increase in locomotor activity with each injection, and this apomorphine-induced increase in activity was completely blocked by both sulpiride and SCH 23390 treatments. However, although both sulpiride and SCH 23390 blocked apomorphine-induced activity, only SCH 23390 injections prevented the development of sensitization to apomorphine. That is, rats pretreated with sulpiride and apomorphine displayed significant sensitization when subsequently tested with a challenge dose of apomorphine alone. These findings suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine D₁ receptors.Portions of this paper were presented at the 1990 Society for Neuroscience meetings, St. Louis, MO, USA     

Effects of SCH 23390 and eticlopride on cocaine-seeking produced by cocaine and WIN 35,428 in rats

Rationale. Exposure to a small amount of cocaine can trigger relapse, and so an understanding of the mechanisms underlying cocaine-seeking are important for the development of effective anti-relapse treatments. Objectives. The present study sought to compare the contributions of dopamine D₁- and D₂-like receptors in drug-seeking produced by cocaine and WIN 35,428. Methods. Reinstatement of extinguished cocaine self-administration was measured for rats that received injections of cocaine (5.0–20.0 mg/kg) or WIN 35,428 (0.1–1.0 mg/kg) following extinction. Prior to the injection of cocaine or WIN 35,428, rats received an injection of the D₁-like antagonist, SCH 23390 (0.001–0.010 mg/kg) or the D₂-like antagonist, eticlopride (0.01–0.30 mg/kg). Effects of SCH 23390 (0.01 mg/kg) on cocaine-produced locomotor activation were also measured in separate groups of rats. Results. The ability of both cocaine and WIN 35,428 to produce cocaine-seeking was dose-dependent. Within the range of doses tested, SCH 23390 failed significantly to attenuate the ability of either cocaine or WIN 35,428 to reinstate extinguished cocaine self-administration, although cocaine-produced locomotor activation was significantly attenuated by pretreatment with the highest dose of SCH 23390. Eticlopride attenuated both cocaine and WIN 35,428 produced cocaine-seeking but lower doses were required to decrease WIN 35,428-produced cocaine-seeking. Conclusions. These results suggest that dopamine D₂ mechanisms are involved in cocaine-seeking produced by both cocaine and WIN 35,428. The lower potency of eticlopride in attenuating cocaine-produced cocaine-seeking suggest that cocaine's effects at sites other than the dopamine transporter contribute to its ability to elicit drug-seeking.     

D1 and D2 dopamine receptor antagonists reverse prepulse inhibition deficits in an animal model of schizophrenia

The amplitude of the acoustic startle response is decreased if the startle stimulus is preceded by a nonstartle eliciting stimulus. This sensorimotor gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the dopamine agonist apomorphine disrupts prepulse inhibition and this disruption is reversed by classical and atypical antipsychotics. Furthermore, the ability of antipsychotics to reverse the apomorphine disruption is correlated with clinical potency and D₂ receptor affinity. In the present study, the role of the D₁ receptor in prepulse inhibition of the acoustic startle response was studied; the effects of the D₁ receptor antagonist SCH 23390 were examined and compared to the effects of the D₂ receptor antagonist eticlopride. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB noise bursts presented alone or preceded by a 75 dB noise burst. Trials consisting of no stimulus and the 75 dB prepulse stimulus alone were also included. These six trial types (ten each) were randomly presented within a 35-min session. Rats treated with 2.0 mg/kg apomorphine (SC) demonstrated a significant disruption of prepulse inhibition compared to vehicle controls. Pretreatment with the D₁ antagonist SCH 23390 (0.01, 0.05, 0.1 mg/kg SC) or the D₂ antagonist eticlopride (0.01, 0.05, 0.1 mg/kg SC) attenuated the disruptive effects of apomorphine. These results indicate that selective blockade of either the D₁ or D₂ receptor subtype is sufficient in reversing the sensorimotor gating deficits produced by apomorphine. The effects of eticlopride and SCH 23390 on prepulse inhibition in saline-treated rats were also examined. Each antagonist produced a dose-related facilitation of prepulse inhibition, suggesting that endogenous DA acting at either receptor subtype plays a role in the tonic modulation of sensorimotor gating.     

Effects of daily SKF 38393, quinpirole,and SCH 23390 treatments on locomotor activity and subsequent sensitivity to apomorphine

In three experiments, male Wistar rats (250–350 g) were injected (SC) daily with the D₁-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D₂-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D₁-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8–10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D₁ receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D₂ receptor stimulation also contributes to the effect.Portions of this paper were presented at the 1991 Society for Neuroscience meetings, New Orleans, La, USA.     

Repeated 7-OH-DPAT treatments: behavioral sensitization,dopamine synthesis and subsequent sensitivity to apomorphine and cocaine

Male Wistar rats (250–350 g) were injected (SC) daily with the putative selective dopamine D₃ receptor agonist, 7-OH-DPAT (0.01, 0.10, or 1.0 g/kg) or vehicle for 10 days. Fifteen minutes after each injection, the rats were tested for locomotor activity in photocell arenas for 20 min or 2 h. In two experiments, following this subchronic treatment, all rats received a challenge injection of apomorphine (1.0 mg/kg, SC), or cocaine (10 mg/kg, IP) on day 11, and were tested for locomotor activity. In a third experiment, dopamine synthesis in striatal and mesolimbic (nucleus accumbens-olfactory turbercle) tissue was assessed following acute or chronic 7-OH-DPAT treatments by measuring the accumulation of dihydroxyphenylalanine (DOPA) after treatment with a DOPA decarboxylase inhibitor. Major findings were as follows: a) acute 7-OH-DPAT treatment produced a dose-dependent decrease in locomotor activity; b) when tested for 2 h, the 1.0 mg/kg dose of 7-OH-DPAT produced a progressively greater increase in activity across the 10 test days (i.e., behavioral sensitization); c) subchronic treatment with 7-OH-DPAT did not result in cross-sensitization to either apomorphine or cocaine; d) acute treatment with the 1.0 mg/kg dose of 7-OH-DPAT significantly decreased dopamine synthesis in both striatal and mesolimbic regions; and e) chronic 7-OH-DPAT treatments did not affect basal dopamine synthesis in either brain region. Although the behavioral effects of 7-OH-DPAT were similar to the reported effects of the D₂/D₃ dopamine agonist quinpirole, the effects of repeated 7-OH-DPAT treatments differed from those of quinpirole in terms of cross-sensitization and basal dopamine synthesis. These results suggest that locomotor inhibition produced by low doses of 7-OH-DPAT is not related to dopamine autoreceptor stimulation, and the development of behavioral sensitization to high doses of 7-OH-DPAT is not due to the development of dopamine autoreceptor subsensitivity.     

Enhancement of dopamine-mediated behaviour by the NMDA antagonists MK-801 and CPP: similarities with repeated electroconvulsive shock

The behavioural effect of dopamine D₁-like receptor agonists (SKF 38393, SKF 81297) and a D₂-like receptor agonist (quinpirole), administered alone and in combination, was tested in rats pretreated with a single injection of an NMDA antagonist (MK-801, CPP) or vehicle. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Pretreatment with MK-801 (0.05 mg/kg, SC, 30 min) had no significant effect (compared to controls) on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC) or quinpirole (0.1 and 0.25 mg/ kg SC) administered alone. In contrast, MK-801 markedly increased locomotion (activity counts and scores) induced by co-administration of a D₁-like plus a D₂-like agonist [SKF 38393 (7.5 mg/kg) plus quinpirole (0.25 mg/kg), SKF 81297 (0.2 mg/kg) plus quinpirole (0.1 mg/kg)]. The behavioural response to the non-selective dopamine agonist apomorphine (0.5 mg/ kg SC) was also enhanced by MK-801. Pretreatment with CPP (0.1 mg/kg SC, 30 min) also significantly increased the locomotor response to co-administration of SKF 38393 plus quinpirole administered alone, but had no effect on the behavioural response to separate injection of these agonists. MK-801 (0.05 mg/kg SC, 30 min) also enhanced the behavioural response to bilateral injection into the nucleus accumbens of SKF 38393 plus quinpirole (1.0 plus 0.4 μg/side, respectively). These data suggest that in the intact rat, the enhancement of dopamine-mediated behaviour by either MK-801 or CPP requires concomitant stimulation of D₁-like and D₂-like receptors, possibly located within the nucleus accumbens. The effect of these NMDA antagonists on dopamine function is similar to that of repeated electroconvulsive shock (ECS), indicating that one of the actions of ECS may be to reduce NMDA receptor function. Received: 24 January 1997/Final version: 21 March 1997     

Effects of dopamine D1- or D2-like receptor antagonists on the hypermotive and discriminative stimulus effects of (+)-MDMA

Rationale Both dopamine (DA) and serotonin (5-HT) release are evoked by (+)-MDMA; however, little is known of the contribution of DA D₁- and D₂-like receptors (D₁R and D₂R, respectively) in the behavioral effects of (+)-MDMA.Objectives To test the hypothesis that a D₁R or D₂R antagonist would attenuate the hypermotive or discriminative stimulus effects of (+)-MDMA.Methods Male Sprague-Dawley rats (n=164) were pretreated with the D₁R antagonist SCH 23390 (3.125–50 g/kg, SC) or the D₂R antagonist eticlopride (12.5–50 g/kg, SC) prior to treatment with (+)-MDMA (3 mg/kg, SC) and locomotor activity was recorded using photobeam monitors. Twelve additional rats trained to discriminate (+)-MDMA (1 mg/kg, IP) from saline in a two-lever water-reinforced FR20 task were administered SCH 23390 (6.25 g/kg, IP) or eticlopride (12.5 g/kg, IP) prior to (+)-MDMA (0.375–1.0 mg/kg, IP). Rats were then placed in the drug discrimination chambers and the percent (+)-MDMA appropriate responding and response rate were measured.Results Both SCH 23390 and eticlopride blocked (+)-MDMA-evoked hyperactivity in a dose-related manner; the highest doses of the antagonists also effectively suppressed basal locomotor activity. In rats trained to discriminate (+)-MDMA from saline, SCH 23390 (6.25 g/kg), but not eticlopride (12.5 g/kg), blocked the stimulus effects of (+)-MDMA without altering response rate.Conclusion These data indicate that DA released indirectly by (+)-MDMA administration results in stimulation of D₁R and D₂R to enhance locomotor activity. Furthermore, the D₁R appears to play a more prominent role than the D₂R in the discriminative stimulus properties of (+)-MDMA.     

7-OH-DPAT,a dopamine D3-selective receptor agonist,produces contralateral rotation in 6-hydroxydopamine-lesioned rats

The purpose of the present study was to characterize the rotational behavior in unilateral 6-OHDA-lesioned rats produced by the high affinity and selective dopamine D₃ receptor ligand 7-OH-DPAT. Qualitatively similar to the direct-acting DA agonist apomorphine, 7-OH-DPAT causes rats to rotate in a direction contralateral to the side of the nigrostriatal DA pathway lesion. This effect is dose-dependent and the minimum effective dose is 0.03 mg (0.12 m?mol)/kg. 7-OH-DPAT-induced rotation is blocked in a dose-dependent manner by oral pretreatment with the “D₂-like” receptor antagonists haloperidol, eticlopride, or clozapine, but not by the “D₁-like” antagonist SCH 23390. The rank order potency for inhibition of 7-OH-DPAT rotation for haloperidol [ID₅₀ = 0.067 mg (0.18 m?mol)/kg], eticlopride [ID₅₀ = 0.41 mg (1.2 m?mol)/kg], clozapine [ID₅₀ = 13 mg (40 m?mol)/kg], and SCH 23390 [ID₅₀ > 90 mg (313 m?mol)/kg] closely parallels their rank order affinity for binding to either the D₂ or the D₃ receptor. Pretreatment with the non-DA receptor antagonists ritanserin (serotonin 5HT₂), scopolamine (muscarinic cholinergic), propranolol (betaadrenergic), or naltrexone (opiate), each at relevant pharmacological doses, failed to reduce 7-OH-DPAT rotation. Taken together, these results are consistent with mediation of 7-OH-DPAT-induced rotational behavior via an agonist interaction with one or more DA receptors. ©1995 Wiley-Liss, Inc.     

Inhibition of methamphetamine sensitization by post-methamphetamine treatment with SCH 23390 or haloperidol

Methamphetamine (2 mg/kg SC) increased ambulation in mice for about 3 h, with a peak effect at around 40 min after the administration, and its repeated administration induced sensitization. Both SCH 23390 (0.03 mg/kg SC) and haloperidol (0.4 mg/kg SC), dopamine D₁ and D₂ receptor antagonists, respectively, completely inhibited not only the acute stimulant effect of methamphetamine but also its sensitization when repeated methamphetamine was repeatedly combined with either of these drugs. Moreover, treatment with SCH 23390 2–5 h or haloperidol 1–5 h after each methamphetamine administration significantly antagonized methamphetamine sensitization. The maximal inhibitory effect was observed in the schedules of 3-h post-methamphetamine treatment for both drugs. However, treatments with SCH 23390 or haloperidol at 0.5 h, 6 h and 24 h after methamphetamine had no such inhibitory effect. The mice treated with SCH 23390 or haloperidol after each saline administration (the control administration for methamphetamine) did not show significant change in the sensitivity to methamphetamine. These results suggest that methamphetamine has an effect on both dopamine D₁ and D₂ receptors for several hours even after cessation of its acute stimulant effect, and that such an effect is involved in the induction of sensitization to the stimulant effect of methamphetamine on ambulation in mice.     

Involvement of dopamine D<Subscript>1</Subscript> and D<Subscript>2</Subscript> receptors in the nucleus accumbens core and shell in inhibitory response control

Rationale Impaired inhibitory control over behavior is a key feature in various psychiatric disorders, and recent studies indicated an important role for dopamine D₁ and D₂ receptors and the nucleus accumbens (Acb) in this respect. Objective The present experiments were designed to study the role of dopamine D₁ and D₂ receptors in the Acb in inhibitory response control. Methods Rats were trained in a five-choice serial reaction time task and received bilateral infusions into the Acb core or shell of either SCH 23390 or eticlopride (representing selective dopamine D₁ and D₂ receptor antagonists, respectively). Subsequently, the effects of systemic amphetamine on inhibitory response control were examined. Results Eticlopride into either the Acb core or shell did not affect premature responding, a measure for inhibitory response control, but increased reaction time and errors of omission. In contrast, SCH 23390 into both regions reduced premature responding, slightly improved attentional performance in the core and increased errors of omission in the shell. Amphetamine robustly increased premature responding which was dose-dependently blocked by eticlopride in the Acb core and attenuated by eticlopride in the shell. In addition, amphetamine slightly decreased accuracy and reaction time, and these effects were inhibited by eticlopride in both regions. SCH 23390 infusion into the Acb core or shell did not alter amphetamine’s effects. Conclusion Our data provide evidence for the involvement of dopamine D₁ and D₂ receptors in the Acb core and shell in inhibitory response control and attentional performance.     

Discriminative stimulus effects of apomorphine and 7-OH-DPAT: a potential role for dopamine D3 receptors

Previous studies have reported that the non-selective dopamine agonist, apomorphine, can serve effectively as a discriminative stimulus in experimental animals, and evidence has been presented that this effect is mediated by dopamine D₂ receptors. More recently, it has been found that another dopamine agonist, 7-OH-DPAT, which has some selectivity for D₃ receptors, also produces a discriminative cue in rats. The present study set out to make a direct comparison of the discriminative stimulus effects of these two compounds. Rats were trained to discriminate either apomorphine (0.05 mg/kg, SC) or 7-OH-DPAT (0.1 mg/kg, IP) from saline. Both discriminations were acquired but extended training was necessary. Cross generalisation occurred between the two compounds and both cues generalised to the dopamine agonists, quinpirole, quinelorane, PD 128207, and bromocriptine. When the potencies of these compounds to produce the apomorphine or 7-OH-DPAT cues were correlated with their potencies to produce D₂ or D₃ functional responses in vitro (mitogenesis in transfected cells–results taken from the literature) stronger correlations with D₃ than with D₂ responses were observed. Both the cueing and the response rate-decreasing effects of apomorphine and 7-OH-DPAT were antagonised by the autoreceptor selective dopamine antagonist amisulpride, and sulpiride also antagonised the cues but without affecting response rates. In contrast, haloperidol blocked the cues but potentiated the response rate decreases. These results suggest that, at the doses used, apomorphine and 7-OH-DPAT produce similar discriminative stimuli, which may be mediated by presynaptically located dopamine D₃ receptors. Received: 5 October 1996 / Final version: 15 November 1996     

Evidence that the enhancement of dopamine function by repeated electroconvulsive shock requires concomitant activation of D1-like and D2-like dopamine receptors

In this study, the behavioural response to dopamine D₁-like receptor agonists (SKF 38393, SKF 81297 and SKF 77434) and D₂-like receptor agonists (quinpirole and RU 24213), administered alone and in combination to rats treated repeatedly with electroconvulsive shock (five ECS over 10 days) or sham, was tested. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Repeated ECS (compared to sham controls) had no significant effect on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC), SKF 77434 (0.1 mg/kg SC), quinpirole (0.1 and 0.25 mg/kg SC) or RU 24213 (0.3 mg/kg SC), when administered alone. In contrast, repeated ECS markedly increased locomotion (activity counts and scores) induced by the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) and by co-administration of a D₁-like agonist plus a D₂-like agonist [SKF 38393 (7.5 mg/kg SC) plus quinpirole (0.25 mg/kg SC), SKF 81297 (0.2 mg/kg SC) plus quinpirole (0.1 mg/kg SC), and SKF 77434 (0.1 mg/ kg SC) plus RU 24213 (0.3 mg/kg SC)]. This ECS-induced enhancement of dopamine-mediated behaviour was observed for up to 3 weeks after cessation of ECS treatment. In addition, ECS also enhanced the locomotor response to intra-accumbens SKF 38393 plus quinpirole (0.4 and 1.0 μg/side, respectively). These results provide evidence that the enhancement of dopamine function by repeated ECS requires concomitant stimulation of both D₁-like and D₂-like receptors, and that this effect is long-lasting. Received: 24 January 1997 /Final version: 5 March 1997     

Behavioral interactions produced by co-administration of 7-OH-DPAT with cocaine or apomorphine in the rat

 Previous research from our laboratory suggests that low doses (<0.1 mg/kg) of the dopamine (DA) D₃-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) attenuate conditioned place preference (CPP) produced by the indirect DA agonist d-amphetamine, but enhance d-amphetamine-induced stereotypic behaviors. This study further examined the effects of 7-OH-DPAT on behaviors produced by the indirect DA agonist, cocaine, and the non-selective direct DA agonist, apomorphine. To examine whether 7-OH-DPAT would alter cocaine and apomorphine dose-response curves for motor behaviors and CPP, 0.1 mg/kg 7-OH-DPAT was co-administered with 0–30 mg/kg cocaine and 0–3 mg/kg apomorphine. To establish place conditioning, drug injections were paired with one of two distinctly different compartments, whereas saline injections were paired with the other compartment. Locomotion, sniffing, oral stereotypy, and headbobbing were measured following acute and repeated drug administration during conditioning, and place conditioning was assessed 24 h following the last conditioning day.7-OH-DPAT enhanced cocaine- and apomorphine-induced stereotypies following repeated administration. 7-OH-DPAT also attenuated cocaine-CPP, but potentiated apomorphine-CPP. Furthermore, 7-OH-DPAT attenuated locomotion produced by high doses of apomorphine. The attenuation of cocaine-CPP by 7-OH-DPAT likely involves stimulation of D₂/D₃ autoreceptors in the mesolimbic pathway, whereas the potentiation of apomorphine-CPP likely involves stimulation of D₂/D₃ postsynaptic receptors. Furthermore, it is suggested that attenuation of apomorphine-induced locomotion by 7-OH-DPAT likely involves stimulation of postsynaptic D₃ receptors in the mesolimbic pathway. Thus, if postsynaptic D₃ receptors are involved in mediating CPP and locomotion, then stimulation of D₃ receptors may facilitate CPP but inhibit locomotion. Received: 20 May 1998 / Final version: 17 September 1998     

Differential effects of 7-OH-DPAT on amphetamine-induced stereotypy and conditioned place preference

 Low doses of the dopamine D₃-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) produce a behavioral profile that is opposite to that produced by the psychomotor stimulants cocaine and amphetamine. For example, low doses of 7-OH-DPAT produce conditioned place aversion and hypolocomotion, whereas psychomotor stimulants produce conditioned place preference (CPP) and hyperlocomotion. In experiment 1, the effects of low doses of 7-OH-DPAT (0.01–0.1 mg/kg) on d-amphetamine-induced (1 mg/kg) motor behaviors and CPP were assessed. In experiment 2, the effects of 0.1 mg/kg 7-OH-DPAT on d-amphetamine (0–10 mg/kg) dose-response curves for the same behaviors were examined. During conditioning, drug injections were paired with a distinct compartment, whereas saline injections were paired with another compartment. Locomotion and headbobbing were measured following acute and repeated drug administration during conditioning and place conditioning was assessed 24 h following the last conditioning day. In experiment 1, d-amphetamine-induced locomotion was dose-dependently decreased by 7-OH-DPAT following repeated administration, which was probably due to the emergence of headbobbing, a behavior not observed with d-amphetamine alone. d-Amphetamine-CPP was not altered by co-administration of 0–0.03 mg/kg 7-OH-DPAT, but was attenuated by co-administration of 0.1 mg/kg 7-OH-DPAT. In experiment 2, 7-OH-DPAT co-administered with low doses of d-amphetamine (0–0.5 mg/kg) produced a decrease in locomotion following acute administration. However, 7-OH-DPAT produced sensitization of locomotion at the 0.5 mg/kg dose of d-amphetamine and an increase in headbobbing at the 0.5–10 mg/kg doses of d-amphetamine following repeated administration. In contrast, d-amphetamine-CPP was attenuated by co-administration of 7-OH-DPAT. These findings suggest that 0.1 mg/kg 7-OH-DPAT attenuates the reinforcing effects of d-amphetamine despite enhancing stereotypic behaviors. Received: 14 May 1997 / Final version: 22 January 1998     

Striatal and nigral D1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

  Rationale: Previous work has demonstrated that cholinomimetic-induced tremulous jaw movements in rats have temporal and pharmacological characteristics similar to parkinsonian tremor. Objective: This rodent model was used to characterize the putative antiparkinsonian effects of the full D₁ dopamine receptor agonist, SKF 82958. Methods: Jaw movement activity was induced by the muscarine agonist pilocarpine (4.0 mg/kg IP), and a series of experiments studied the pharmacological characteristics of the reversal of pilocarpine-induced jaw movements by SKF 82958. Results: SKF 82958 (0.5–2.0 mg/kg IP) reduced the tremulous jaw movements induced by pilocarpine. The suppressive effects of SKF 82958 on jaw movements were dose-dependently reversed by systemic pretreatment with the selective D₁ dopamine receptor antagonist SCH 23390 (0.025–0.2 mg/kg IP); SCH 23390 was about 16 times more potent than the D₂ antagonist raclopride at reversing the effects of SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the ventrolateral striatum, the rodent homologue of the human ventral putamen, dose-dependently reversed the reduction of pilocarpine-induced jaw movements produced by SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the substantia nigra pars reticulata also dose-dependently reversed the reduction by SKF 82958 of pilocarpine-induced jaw movements. Injections of SCH 23390 (2.0 μg/side) into control sites dorsal to the striatum or substantia nigra had no effects on the action of SKF 82958. Intranigral (SNr) injections of the GABA-A antagonist bicuculline blocked the suppressive effect of systemically administered SKF 82958 on jaw movement activity. Conclusions: These data suggest that the antiparkinsonian actions of SKF 82958 may be due to stimulation of D₁ receptors in the ventrolateral striatum and substantia nigra pars reticulata. In addition, these results indicate that GABA mechanisms in the substantia nigra pars reticulata may be important for the antiparkinsonian effects of D₁ agonists. Received: 9 June 1998 / Final version: 10 October 1998     

Repeated treatments with 7-OH-DPAT: context-independent behavioral sensitization and conditioned hyperactivity

The primary objective of this study was to determine whether the expression of behavioral sensitization to the putative dopamine D3 receptor agonist 7-OH-DPAT is context dependent. Three groups (n = 8 each) of male Wistar rats (250-350 g) were given nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle 15 min before and after activity testing. The paired group received 7-OH-DPAT before activity testing and vehicle after testing. The unpaired group received vehicle before and 7-OH-DPAT after testing, and the vehicle control group received two vehicle injections. Locomotor activity was measured in photocell arenas for 2 h. After the first seven sessions, all rats were tested for activity following a vehicle injection to test for possible conditioning effects. Prior to the 11th session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) to test for sensitization. Major findings were as follows: (a) the 7-OH-DPAT/paired group displayed a progressively greater increase in locomotor activity with repeated treatments; (b) the 7-OH-DPAT/paired group was significantly more active than either the vehicle control group or the 7-OH-DPAT/unpaired group during the vehicle test session; and (c) after the 7-OH-DPAT challenge injection, the paired and unpaired 7-OH-DPAT groups were significantly, and equally, more active than the vehicle control group. In contrast to previous findings with the D2-type dopamine agonists bromocriptine and quinpirole, these results suggest that the expression of behavioral sensitization to 7-OH-DPAT is not context dependent. Moreover, these results suggest that the apparent conditioned hyperactivity and context dependency often observed after repeated dopamine agonist treatments may not be related to the same associative and/or nonassociative mechanisms.     

D1 dopamine receptor blockade prevents the facilitation of amphetamine self-administration induced by prior exposure to the drug

 Prior exposure to amphetamine leads to sensitized locomotor responding to subsequent injections and an enhanced predisposition to self-administer low doses of the drug. Because D₁ dopamine (DA) receptors have been shown to play an important role in the development of sensitized locomotor responding to amphetamine, the present experiment assessed their contribution to the development of facilitated amphetamine self-administration produced by prior exposure to the drug. During a pre-exposure phase, rats were administered two injections on each of 10 consecutive days. The first injection (saline, 1 ml/kg, IP, or the D₁ DA receptor antagonist SCH23390, 0.04 mg/kg, SC) preceded the second (saline or amphetamine, 1.5 mg/kg, IP) by 30 min. Starting 10 days after the last injection, animals were given the opportunity to lever press for a low dose of amphetamine (10 μg/kg per infusion) in a two-lever (active versus inactive) continuous reinforcement operant task, in each of seven daily sessions. Consistent with previous reports, prior exposure to amphetamine resulted in an increase in active versus inactive lever pressing. Blocking D₁ DA receptors with SCH23390 prior to each of the amphetamine pre-exposure injections prevented the development of this enhanced self-administration of amphetamine. When animals were grouped according to their locomotor response to a novel environment (assessed prior to the experiment), it was found, again in agreement with previous reports, that enhanced drug self-administration (as indicated by increased active versus inactive lever pressing as well as shorter latencies to emit the first active lever press, shorter inter-response times and more time-out responses on this lever) was observed only in amphetamine pre-exposed rats that had shown a locomotor response to novelty above the median of the subject sample (high responders). Preceding the amphetamine pre-exposure injections with SCH23390 blocked the development of enhanced drug self-administration observed in these animals. These findings, indicating that manipulations known to block the induction of locomotor and dopaminergic sensitization by amphetamine also block the facilitation of drug self-administration, suggest an important and common role for D₁ DA receptor activation in the development of enhanced responding to and for drug. Received: 19 June 1997 / Final version: 15 January 1998     

Effects of intranucleus accumbens shell administration of dopamine agonists and antagonists on cocaine-taking and cocaine-seeking behaviors in the rat

Rationale Dopamine signaling in the nucleus accumbens (NAc) plays an important role in regulating drug-taking and drug-seeking behaviors, but the role of D₁- and D₂-like receptors in this regulation remains unclear.Objectives Our objective was to study the role of NAc D₁- and D₂-like receptors in the reinstatement of cocaine-seeking behavior and the regulation of stabilized cocaine intake in rats.Methods Using a within-session reinstatement procedure, whereby animals self-administer cocaine (90 min) and extinguish responding (150 min) in a single session, we assessed the ability of NAc microinfusions of the D₁ agonist SKF 81297 and the D₂ agonist 7-OH-DPAT to reinstate extinguished cocaine seeking. The effects of the D₁ antagonist SCH 23390 and the D₂ antagonist eticlopride pretreatment on agonist- and cocaine-primed reinstatement were also measured. Similar agonist and antagonist treatments were tested for their ability to modulate stabilized cocaine and sucrose self-administration.Results Intra-NAc infusions of either SKF 81297 (0.3–3.0 μg) or 7-OH-DPAT (1.0–10.0 μg) dose-dependently reinstated cocaine seeking with greater efficacy in the medial core than in the shell subregion and at doses that also stimulated locomotor behavior. Intra-NAc shell infusions of SCH 23390 (1.0 μg) and eticlopride (3.0–10.0 μg) blocked cocaine-primed reinstatement (2.0 mg/kg, i.v.) and indiscriminately blocked reinstatement induced by either intra-NAc D₁ or D₂ agonists. Doses of agonists that triggered reinstatement failed to alter stabilized cocaine intake, whereas doses of antagonists that blocked reinstatement increased cocaine intake in the shell.Conclusions Both D₁ and D₂ receptors in the NAc play a prominent, and perhaps cooperative, role in regulating cocaine-taking and cocaine-seeking behaviors.