Differential modulation of the D1-like- and D2-like dopamine receptor-induced locomotor responses by group II metabotropic glutamate receptors in the rat nucleus accumbens.

There is strong evidence for the existence of functional interactions between metabotropic glutamate receptors and dopamine transmission in the nucleus accumbens. In the present study, we investigated the interactions between group II mGlu receptors and D1-like- and D2-like receptors in the rat nucleus accumbens. Administration of the selective group II metabotropic glutamate receptor agonist APDC, which had no effect when injected alone, potentiated the locomotor response produced by the selective D1-like receptor agonist SKF 38393 but had no effect on those induced by the selective D2-like receptor agonist quinpirole (also known as LY 171555)--a compound believed to act only at D2-like presynaptic receptors when injected alone--or co-administration of SKF 38393+quinpirole--a pharmacological condition thought to stimulate both D1-like receptors and presynaptic and postsynaptic D2-like receptors. In contrast, the selective group II mGlu receptor antagonist LY 341495, which induced an increase in basal locomotor activity, showed no effect on the SKF 38393-induced locomotor response, but abolished that produced by quinpirole or SKF 38393+quinpirole. The present findings demonstrate that stimulation of group II mGlu receptors has a cooperative and potentiating action on the locomotor response induced by D1-like receptor activation, whereas blockade of group II mGlu receptors has an antagonist action on the locomotor responses induced by activation of D2-like receptors. Although these data are consistent from a pharmacological point of view, as the effects of the group II mGlu receptor antagonist LY 341495 were blocked by the group II mGlu receptor agonist APDC and conversely, the subtle neurochemical crosstalks underlying such a differential effect of group II mGlu receptors on D1-like- and D2-like DA receptors remain to be elucidated.     

The actions of (-)N-n-propylnorapomorphine and selective dopamine D1 and D2 receptor agonists to modify the release of [3H]dopamine from the rat nucleus accumbens

The ability of (-)N-n-propylnorapomorphine and selective D1 and D2 dopamine receptor agonists and antagonists to modify the release of [3H]dopamine, induced by potassium from the nucleus accumbens, was studied using an in vitro superfusion technique. (-)N-n-Propylnorapomorphine, in picomolar concentrations, inhibited the release of [3H]dopamine, the inhibition being antagonised by fluphenazine and the selective D2 receptor antagonist sulpiride; the selective D1 receptor antagonist SCH 23390 was ineffective. The selective D1 receptor agonist SKF 38393 and the selective D2 agonist quinpirole, both inhibited the potassium-induced release of [3H]dopamine; no synergistic effect was observed to a combined treatment with SKF 38393 and quinpirole. The effects of SKF 38393 and quinpirole were selectively antagonised by SCH 23390 and sulpiride, respectively, although both antagonists failed to modify the release of [3H]dopamine when administered alone. Receptor antagonists for other transmitter sites, e.g. noradrenaline, 5-hydroxytryptamine and acetylcholine, failed to modify potassium-induced release of [3H]dopamine, when administered alone or to prevent the inhibition of the release caused by (-)N-n-propylnorapomorphine. It is concluded that the action of dopamine agonists on both dopamine D1 and D2 receptors in the nucleus accumbens can reduce the release of [3H]dopamine in the in vitro system. Comparable actions in vivo may contribute to the ability of dopamine agonists to moderate locomotor responding.     

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.     

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.     

Gz proteins are functionally coupled to dopamine D2-like receptors in vivo

The receptors that couple to the G protein Gz in vivo are still relatively unknown. In this study, we investigated the effects of various dopamine receptor agonists in a mouse deficient in the alpha subunit of Gz. The dopamine D1-like receptor agonist SKF38393 stimulated comparable locomotor activity in both wildtype mice and mice lacking Galphaz. In contrast, the dopamine D2-like receptor agonist quinpirole suppressed locomotor activity in both groups of mice, but this suppression was significantly smaller in Galphaz knockout mice. Consistent with these behavioural observations, quinpirole inhibition of dopamine release in the forebrain nucleus accumbens evoked by electrical stimulation of dopamine axons was significantly attenuated in mice lacking Galphaz. In addition, hypothermia and adrenocorticotropic hormone release resulting from activation of dopamine D2-like receptors were also significantly reduced in Galphaz knockout mice. However, adrenocorticotropic hormone secretion induced by corticotrophin releasing hormone and the serotonin 1A receptor agonist 8-hydroxy-dipropylamino-tetralin were similar between wildtype and Galphaz knockout mice. Western blot analysis showed that the expression levels of Galphai, Galphao, Galphas, Galphaq and Gbeta were the same in the brains of mice of both genotypes. Overall, our data suggest that Gz proteins are functionally coupled to dopamine D2-like receptors in vivo.     

Morphine alters the locomotor responses to a D2/D3 dopamine receptor agonist differentially in adolescent and adult mice

The D2-like dopamine receptors mediate the emotional/aversive state during morphine withdrawal. Given age-dependent differences in the affective responses to withdrawal, this study examined whether the response to dopamine receptor agonists is altered differentially across ages following morphine administration. Adolescent and adult mice were injected with morphine (twice daily, 10-40 mg/kg, s.c.) or saline for 6 days. Subsequently, they were examined for their locomotor response to quinpirole, a D2/D3 receptor agonist, and SKF 38393, a D1 receptor agonist. Quinpirole dose-dependently reduced locomotion in drug-na?ve animals. Initial suppression was also observed in morphine-treated animals, but was followed by enhanced locomotion. Notably, this enhanced locomotion was markedly greater in adolescents than adults. Quinpirole-induced hypo-locomotion is thought to be mediated by the presynaptic D2Short receptors, whereas its activating effect is mediated by postsynaptic D2Long/D3 receptors. This suggests that following morphine administration, the postsynaptic, but not the presynaptic, dopaminergic signaling is differentially modulated across ages. This locomotor supersensitivity was not observed for SKF 38393, a D1 dopamine receptor agonist. The D2/D3 receptors are involved in the pathophysiology of many mental illnesses. Thus, this study offers a potential explanation for the increased psychiatric disorder co-morbidities when drug use begins during adolescence.     

Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis

In vitro results show the ability of the CB(1) receptor agonist CP 55,940 to reduce the affinity of D(2) receptor agonist binding sites in both the dorsal and ventral striatum including the nucleus accumbens shell. This antagonistic modulation of D(2) receptor agonist affinity was found to remain and even be enhanced after G-protein activation by Gpp(NH)p. Using the FRET technique in living HEK-293T cells, the formation of CB(1)-D(2) receptor heteromers, independent of receptor occupancy, was demonstrated. These data thereby indicate that the antagonistic intramembrane CB(1)/D(2) receptor-receptor interactions may occur in CB(1)/D(2) formed heteromers. Antagonistic CB(1)/D(2) interactions were also discovered at the behavioral level through an analysis of quinpirole-induced locomotor hyperactivity in rats. The CB(1) receptor agonist CP 55,940 at a dose that did not change basal locomotion was able to block quinpirole-induced increases in locomotor activity. In addition, not only the CB(1) receptor antagonist rimonobant but also the specific A(2A) receptor antagonist MSX-3 blocked the inhibitory effect of CB(1) receptor agonist on D(2)-like receptor agonist-induced hyperlocomotion. Taken together, these results give evidence for the existence of antagonistic CB(1)/D(2) receptor-receptor interactions within CB(1)/D(2) heteromers in which A(2A) receptors may also participate.     

Inhibition of jaw opening reflex and single neurons in the trigeminal subnucleus caudalis by activation of striatal D2 dopamine receptors

The influence of striatal dopaminergic receptors on the inhibitory action of the striatum on the jaw opening reflex (JOR) was studied in anesthetized rats. Single unit activity was recorded at the subnucleus caudalis of the trigeminal nerve. Dopamine agonists and antagonists were microinjectd into the striatum. The striatal administration of apomorphine inhibits the JOR evoked by dental pulp stimulation. Similar results were observed by microinjections of quinpirole, an agonist of D2 receptors, but not by microinjection of SKF 38393, a D1 agonist. The effect of quinpirole was only inhibited by intrastriatal microinjection of haloperidol, a blocker of D2 receptors and reversed by systemic administration of 1 mg/kg of naloxone. The evoked neuronal responses in subnucleus caudalis, by tooth pulp stimulation, were also suppressed by microinjection of quinpirole into the striatum and reversed by naloxone (1 mg/kg, i.v.). Based on the above results, we conclude that the activation of striatal D2 dopamine receptors is responsible for the inhibition of the JOR possibly by action on the subnucleus caudalis of the trigeminal nerve.     

Acute reserpine treatment induces down regulation of D-1 dopamine receptor associated adenylyl cyclase activity in rat striatum.

Behavioural studies suggest a functional interaction between D-1 and D-2 systems in normal rat striatum to alter motor behaviour and which is disrupted by dopamine depletion induced by acute reserpine treatment. Consequently, we have investigated the effect of acute reserpine treatment on the biochemical interaction between D-1 and D-2 receptors present in rat striatal slices. Twenty-four hours following the administration of reserpine (5 mg/kg i.p.), striatal dopamine content was depleted by more than 73%; the density (B(max)) of D-1 receptor sites measured by the in vitro binding of [3H]SCH 23390 to striatal membranes was increased while the binding of [3H]spiperone to D-2 receptor sites was unaltered. Reserpine treatment had no effect on the affinity (Kd) of [3H]SCH 23390 or [3H]spiperone for D-1 and D-2 sites. Basal levels of cyclic AMP accumulation in striatal slices prepared from reserpine-treated rats were lower than those observed in control slices. In striatal slices prepared from normal rats, dopamine (10-320 microM) and the D-1 agonist SKF 38393 (0.1-3.2 microM) induced concentration-dependent increases in cyclic AMP accumulation. The D-1 antagonist SCH 23390 (10 microM) abolished the accumulation of cyclic AMP produced by dopamine or SKF 38393. The D-2 antagonist (+/-)-sulpiride (50 microM) enhanced the response to dopamine (10-320 microM) while the D-2 agonist quinpirole (10 microM) abolished the response to SKF 38393 (0.1-3.2 microM). However, 24 hr after reserpine treatment the ability of dopamine (10-320 microM) and SKF 38393 (0.1-3.2 microM) to elicit an increase in cyclic AMP accumulation was markedly reduced in striatal slices. SCH 23390 (10 microM) did not enhance the trend for an increase in cyclic AMP accumulation produced by dopamine. Also, quinpirole (10 microM) did not affect the response to SKF 38393 (0.1-3.2 microM) in striatal slices from reserpine pretreated rats. The data confirm the positive linkage between D-1 receptors and adenylyl cyclase and the inhibitory coupling to D-2 sites in striatal slices from normal, rats. Acute reserpine treatment appears to cause an uncoupling of D-1 receptors associated with adenylyl cyclase.     

Activation of dopamine D4 receptors modulates [3H]GABA release in slices of the rat thalamic reticular nucleus

The thalamic reticular nucleus (nRt) is innervated by dopaminergic projections from the sustantia nigra compacta (SNc) and is rich in dopamine D4 receptors, however, the functional effects of dopamine on this structure are unknown. We examined whether the D1 receptor agonist SKF 38393, or the D2 class receptor agonist quinpirole, modify depolarization evoked Ca(2+)-dependent [3H]GABA release. SKF 38393 was without effects, whereas quinpirole inhibited [3H]GABA release with an IC50 of 81 +/- 33 nM. Dose-dependence determinations of agonists (quinpirole and PD 168, 077) and antagonists (L-745,870, U-101958, clozapine and raclopride) with different affinities for different D2 class subtype receptors showed that a D4 receptor mediates quinpirole inhibition. We used methylphenidate, an agent that acts by increasing interstitial dopamine, to determine whether endogenous dopamine modulates [3H]GABA release. Methylphenidate inhibited [3H]GABA release showing that the nRt contains sufficient endogenous dopamine to activate D4 receptors. This inhibition was completely reversed by selectively blocking D4 receptors with L-745,870 or U-101958 indicating that the catecholamine receptors that modulate GABA release are D4 receptors. Given the importance of the nRt in the control of attention, sensory processing and the generation of rhythmic activity during slow wave sleep, it is possible that abnormal nRt function may generate some of the manifestations of the disorders of dopaminergic transmission.     

Histamine H3 receptor agonist- and antagonist-evoked vacuous chewing movements in 6-OHDA-lesioned rats occurs in an absence of change in microdialysate dopamine levels

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 D(1)/D(5) receptor agonist, produces robust stereotyped and locomotor activities. The gradual induction of dopamine D(1) 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 D(1) agonist-induced activities. We found that neither imetit (5.0 mg/kg i.p.), a histamine H(3) receptor agonist, nor thioperamide (5.0 mg/kg i.p.), a histamine H(3) receptor antagonist/inverse agonist, altered the numbers of vacuous chewing movements in non-primed-lesioned rats. However, in dopamine D(1) 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 D(1)/D(5) 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.     

Decreased postsynaptic dopaminergic and cholinergic functions in the ventrolateral striatum of spontaneously hypertensive rat

Dopamine and acetylcholine receptor functions in spontaneously hypertensive rats (SHR) and in control progenitor Wistar-Kyoto (WKY) rats were assessed, using dopamine D1-like/D2-like receptor-mediated and acetylcholine receptor-mediated jaw movements as readout parameters. Spontaneous behaviours such as locomotor activity, vacuous chewing, grooming, sniffing and rearing occurred significantly more in SHR than in WKY rats. In the anaesthetised rats, a mixture of SKF 38393 (5 micrograms), a dopamine D1-like receptor agonist, and quinpirole (10 micrograms), a dopamine D2-like receptor agonist, readily produced repetitive jaw movements in WKY rats, but not SHR, when bilaterally injected into the ventrolateral striatum; such injections into the nucleus accumbens shell were ineffective in each strain. Bilateral injections of carbachol (2.5 micrograms each side), an acetylcholine receptor agonist, into the ventrolateral striatum elicited repetitive jaw movements in both SHR and WKY rats, but to a far less degree in SHR. The present study demonstrates that spontaneous behaviours are enhanced in SHR, and that postsynaptic dopamine D1-like/D2-like receptors and acetylcholine receptors in the ventrolateral striatum of SHR are hyposensitive when compared to those of WKY rats.     

"Priming" to dopamine agonist-induced contralateral turning as a model of non-associative sensitization to the expression of the post-synaptic dopamine message

In adult rats bearing unilateral 6-hydroxydopamine (6-OHDA) lesions of the ascending dopaminergic neurons, a single administration of a dopamine (DA) receptor agonist results in strong sensitization ("priming") of contralateral turning in response to D2 and particularly D1 receptor agonists. In order to investigate the role of distinct environmental cues associated with the effect of the agonist during exposure to the primer, rats bearing 15-day-old unilateral 6-OHDA lesions were primed in their home cage with L-dopa or with saline. L-Dopa but not saline induced medium to low but steady contralateral turning. Three days later, challenge with the D1 agonist SKF 38393 in the home cage also resulted in contralateral turning in the rats previously primed with L-dopa, but not in those primed with saline. In a second experiment rats lesioned with 6-OHDA were primed in two different contexts (hemispheres versus cylinders) with a single administration of the D2/D3 agonist quinpirole (LY 171555: 0.2mg/kg s.c.) or saline. Three days later the rats were placed in hemispheres and tested for contraversive turning in response to saline or to SKF 38393. SKF 38393 elicited high rate contraversive turning independently of the environment where priming with quinpirole took place; on the other hand no conditioned contraversive turning was observed after saline. In a third experiment, the possibility of priming SKF 38393-induced turning by stimulation of nigral or striatal DA receptors was investigated. Rats lesioned unilaterally with 6-OHDA were locally infused on the lesioned side in the substantia nigra with SKF 38393 or in the striatum with quinpirole. Both these treatments elicited contralateral turning, the intranigral injection of SKF 38393 eliciting a stronger and longer lasting contraversive turning than intrastriatal quinpirole. Challenge with SKF 38393 (3mg/kg s.c.) 3 days later induced contralateral turning only in rats previously primed with intrastriatal quinpirole. The results of these studies are consistent with the idea that "priming" is an example of non-associative sensitization induced by stimulation of denervated striatal DA receptors and expressed as an increased efficiency of post-synaptic dopaminergic transduction in the striatum.     

Effect of the D1 receptor agonist SKF 38393 on some behavioural effects of apomorphine in rats

Summary The dopamine receptor agonist apomorphine in experiments on rats in low doses (0.025–0.2 mg/kg, s.c.) induced yawning which reflected a selective activation of presynaptic dopamine receptors. In high doses (0.25–1.0 mg/kg) apomorphine induced stereotyped sniffing and yawning in consequence of postsynaptic D 2 receptor activation. Dopamine D 1 receptor agonist SKF 38393 inhibited yawning induced by low doses of apomorphine. The inhibitory effect of SKF 38393 on apomorphine-induced yawning was attenuated by pretreatment with specific D I receptor antagonist SCH 23390 [2-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol]. On the other hand however, SKF 38393 potentiated sniffing induced by the high doses of apomorphine without affecting gnawing. These data indicate that D 1 receptor activation modulates both pre- and postsynaptic effects of apomorphine in opposite directions.     

Role of dopamine and GABA in the control of motor activity elicited from the rat nucleus accumbens.

The application of 1.2 and 12.0 micrograms/side of the GABAA receptor agonist 3-aminopropane sulphonic acid bilaterally into the nucleus accumbens (Acb) of rats nonsignificantly depressed locomotor activity as assessed in automated Animex activity cages, while the highest dose (60 micrograms/side) significantly stimulated activity. The GABAA receptor antagonists picrotoxinin (0.0625 and 0.125 micrograms/saide) and bicuculline (0.895 micrograms/side) produced forward locomotion around the cage accompanied by a number of other behaviours. The GABAB agonist baclofen (0.023 and 0.092 micrograms/side) induced a short-lasting (18 min) locomotor depression. None of the GABAB antagonists tested (2-hydroxysaclofen 2.6 micrograms/side, two novel beta-(benzo[b]furan) analogues of baclofen 9G or 9H each 6.8 micrograms/side, 4-aminobutylphosphonic acid 1.32 micrograms/side and phaclofen 0.535 and 2 micrograms/side) significantly affected locomotor activity. In rats pretreated with reserpine and alpha-methyl-p-tyrosine, picrotoxinin (0.0625 and 0.125 micrograms/side) did not significantly alter locomotor activity. Furthermore, when picrotoxinin (0.0625 micrograms/side) was combined with either the selective dopamine (DA) D1 agonist SKF38393 or the selective D2 agonist quinpirole, no significant alteration in locomotor function occurred. When SKF38393 and quinpirole were coadministered, significant stimulation occurred which was further enhanced by the addition of picrotoxinin. It is concluded that GABAA receptors, together with D1 and D2 receptors, play a major role in modulating the control of motor function by the Acb of rats.     

Antagonistic interaction between adenosine A2A and dopamine D2 receptors modulates the social recognition memory in reserpine-treated rats

Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the control of motor activity. However, there are few studies investigating this interaction in other brain regions and its role in additional functions. In the present study, we evaluated whether reserpine-treated rats (1.0 mg/kg, i.p.) exhibit altered social recognition memory abilities. The effects of acute administration of the dopamine receptor agonists 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine (SKF 38393, dopamine D(1) receptor agonist) and quinpirole (dopamine D(2) receptor agonist), together with the adenosine receptor antagonists caffeine (non-selective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A(1) receptor antagonist) and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A(2A) receptor antagonist), were also investigated. Twenty-four hours after treatment, reserpine-treated rats exhibited a significant disruption in the ability to recognize a juvenile rat after a short period of time. These animals did not show any motor deficit. The social recognition disruption induced by reserpine was reversed by acute treatment with quinpirole (0.05-0.1 mg/kg, i.p.), caffeine (10.0-30.0 mg/kg, i.p.) or ZM241385 (0.5-1.0 mg/kg, i.p.), but not with SKF 38393 (0.5-3.0 mg/kg, i.p.) or DPCPX (0.5-3.0 mg/kg, i.p.). Moreover, a synergistic response was observed following the co-administration of 'non-effective' doses of ZM241385 (0.1 mg/kg, i.p.) and quinpirole (0.01 mg/kg, i.p.). These results reinforce and extend the notion of antagonistic interactions between adenosine and dopamine receptors, and demonstrate, for the first time, that the blockade of adenosine A(2A) receptors and the activation of dopamine D(2) receptors can reverse the social recognition deficits induced by reserpine in rats.     

Effects of selective drugs for dopaminergic D1 and D2 receptors on conditioned locomotion in rats

Classically conditioned locomotor activity has been demonstrated by pairing injections of dopamine agonists or antagonists with specific environmental stimuli. The present studies investigated conditioning using drugs with varying selectivity for the dopamine D1 or D2 receptor. Experiment 1 assessed conditioning in groups of rats using the indirect acting agonist (+)-amphetamine (2.0 mg/kg), and the D1 agonist SKF 38393 (10.0 mg/kg), the D2 agonist quinpirole (2.5 mg/kg), the D1 and D2 antagonists, SCH 23390 (0.05 mg/kg) and metoclopramide (25.0 mg/kg), respectively. Paired groups received nine 2-h drug-environment (automated activity monitoring chambers) pairings whereas Unpaired groups received the stimuli explicitly unpaired. Test revealed conditioned hyperactivity with each agonist and metoclopramide whereas conditioned hypoactivity was seen with SCH 23390. Experiment 2 assessed the interaction of these agonists and antagonists on the establishment of conditioned activity. Paired groups received an agonist and antagonist during conditioning sessions. SCH 23390 blocked conditioning based on (+)-amphetamine and SKF 38393 but not quinpirole. Metoclopramide (10.0 mg/kg) blocked conditioning based on quinpirole but not SKF 38393. Metoclopramide (25.0 mg/kg) also did not block (+)-amphetamine-induced conditioning. These studies suggested that drug-induced alterations at either D1 or D2 receptors may be involved in conditioned locomotion.     

Behavioral effects of selective and nonselective dopamine agonists on young rats after irreversible antagonism of D1 and/or D2 receptors

In general, preweanling and adult rats respond similarly when challenged with competitive dopamine (DA) agonists or antagonists. In contrast, results using a noncompetitive antagonist suggest that the D₁ and D₂ receptor systems of preweanling and adult rats differ in some critical way. To further assess this phenomenon, the behavioral effects of irreversible receptor blockade were assessed across 8 days in NPA (a nonselective DA agonist), quinpirole (a D₂ agonist), or SKF 38393 (a D₁ agonist) treated 17-day-old rat pups. The irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) did not block the locomotor activity and rearing of NPA- or quinpirole-treated rat pups, nor did EEDQ reduce SKF 38393-induced grooming. Moreover, pretreatment with EEDQ appeared to potentiate the normal increases in locomotor activity and rearing produced by NPA, but only when D₂ receptors were not protected by a previous injection of sulpiride (a D₂ antagonist). Taken together, these results are consistent with the presence of large reserves of D₁ and D₂ receptors in the preweanling rat pup.     

Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice

The locomotor stimulatory effects of the dopamine D₁ receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3–300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100–300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D₁ receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D₁ receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D₁ agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D₁ receptor subtype.     

Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, the effects of bilateral intrahippocampal CA1 injections of dopamine receptor agonists and antagonists on the acquisition and expression of morphine-induced place preference were examined in male Wistar rats. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a conditioned place preference (CPP) dose-dependently. Using a 3-day schedule of conditioning, it was found that dopamine D1 receptor agonist, SKF 38393 (0.01-1 microg/rat), dopamine D1 receptor antagonist, SCH 23390 (0.25-1 microg/rat), dopamine D(2/3) receptor agonist, quinpirole (0.3-3 microg/rat) or dopamine D2 receptor antagonist, sulpiride (0.04-5 microg/rat) did not produce significant place preference. The administration of SKF 38393 (1 microg/rat) significantly potentiated the acquisition of morphine (0.5 and 2.5 mg/kg)-induced place preference. This potentiation was reversed by SCH 23390 (1 microg/rat) pretreatment. Quinpirole injection (0.3 microg/rat) induced CPP in combination with the lower doses of morphine but decreased the response of the higher doses of morphine. These responses of quinpirole were reversed by sulpiride (5 microg/rat) pretreatment. SCH 23390 or sulpiride reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of sulpiride, but not other drugs, during acquisition showed an increase in the locomotor activity on the testing days. SKF 38393, SCH 23390 or sulpiride, but not quinpirole when used before testing, reduced the expression of morphine-induced place preference. Sulpiride, but not other drugs, increased locomotion when used before testing. It is concluded that dorsal hippocampal dopamine receptors may play an active role in morphine reward.