The influence of repeated treatment with imipramine, (+)- and (−)-oxaprotiline on behavioural effects of dopamine D-1 and D-2 agonists

Summary The paper examined the action of imipramine, (+)- and (–)-oxaprotiline, administered repeatedly to rats, on the behavioural effects of the dopamine D-1 and D-2 agonists, SKF 38393 and quinpirole, respectively. The three antidepressants studied, given in the single dose or repeatedly, attenuate the enhanced grooming evoked by SKF 38393. The locomotor hyperactivity, evoked by quinpirole administered s.c., is increased by repeated but not single-dose treatment with imipramine and (+)-oxaprotiline [but not with (–)-oxaprotiline]. Quinpirole at a low dose produces the locomotor hypoactivity which is attenuated by repeated, but not single-dose, treatment with the antidepressants studied here. Repeated imipramine and (+)-oxaprotiline [but not (–)-oxaprotiline] increase the locomotor activity effect of quinpirole injected into the nucleus accumbens.The results indicate that the enhanced responsiveness of the dopamine system, observed previously after repeated treatment with antidepressants, may be mediated by the dopamine D-2 receptors.     

Quinpirole-induced 50 kHz ultrasonic vocalization in the rat: role of D2 and D3 dopamine receptors

The goal of the present investigation was to study a full dose-response of quinpirole in production of species-specific 50 kHz ultrasonic vocalizations in rats, and to study involvement of D2 and D3 dopamine receptors in this response. Quinpirole, a D2/D3 dopamine agonist with high selectivity for D2 dopamine receptors, was injected into the shell of the nucleus accumbens. Quinpirole induced species-specific 50 kHz ultrasonic vocalizations at a wide range of doses as compared to saline. The dose-response study showed a triphasic effect of quinpirole and reached two comparable peak responses in the number of emitted vocalizations at 0.25 μg and 6 μg, respectively (a 24-fold dose difference). These two peaks were separated by a decreased phase. A medium dose range (0.5-1.0 μg) of quinpirole consistently depressed production of calls to the control level. Application of antagonists of D2 dopamine receptors (raclopride) and D3 dopamine receptors (U-99194A) before quinpirole revealed that quinpirole activates differentially the D2 and D3 dopamine receptors at different doses. The vocalization response induced by the low dose of quinpirole (0.25 μg) was antagonized by local pretreatment with the D3 receptor antagonist but not by the D2 receptor antagonist. On the other hand, the response induced by the high dose of quinpirole (6 μg) was antagonized by a similar local pretreatment with the D2 receptor antagonist but not by the D3 receptor antagonist. In conclusion, the results indicated that quinpirole can induce 50 kHz vocalizations after its direct intra-accumbens application in rats, and both D2 and D3 dopamine receptors are involved in the response. They play, however, different functional roles, as revealed by the triphasic effect of increasing doses of quinpirole.     

Quantitative autoradiography of Gpp(NH)p sensitive and insensitive [3H]quinpirole binding sites in the rat brain

Recent advances in the cloning of dopamine receptor subtypes have resulted in the detection of at least 5 genetically distinct subtypes of the dopamine receptor. The dopaminergic agonist, quinpirole, has relatively high affinity for the cloned D-2, D-3, and D-4 receptor subtypes. The D-3 receptor is unique within these 3 subtypes in that it does not appear to have sensitivity to guanine nucleotides. In order to localize the brain regions containing these subtypes of the dopamine receptor, the distribution of [³H]quinpirole binding sites in the rat brain was mapped by autoradiography. Labelling in the absence and presence of the nonhydrolyzable GTP analog, guanylyl-5′-imidodiphosphate (Gpp(NH)p) allowed differentiation between the high affinity agonist conformation of the D-2 receptor and the D-3 receptor. The highest densities of [³H]quinpirole binding were found in the caudate-putamen, nucleus accumbens, islands of Calleja, and olfactory tubercle which is consistent with the distribution of dopamine receptors seen with “classical D-2” receptor agonist and antagonist radioligands. In the presence of 10 μM Gpp(NH)p, binding was reduced in all these areas with the exception of the islands of Calleja. Additional areas which exhibited no change in binding when incubated with Gpp(NH)p included the nodulus and floculus of the cerebellum. Several areas exhibited a partial reduction in binding including the glomerular layer of the olfactory bulb, nucleus accumbens, and the superior colliculus. The distribution of these subtypes is consistent with the distribution of mRNA for the D-2 and D-3 receptor in the brain. Therefore, [³H]quinpirole binds to the high affinity agonist conformation of the D-2 and the D-3 receptor. © 1993 Wiley-Liss, Inc.     

Neurophysiological investigation of effects of the D-1 agonist SKF 38393 on tonic activity of substantia nigra dopamine neurons

The effects of the D-1 agonist SKF 38393 on tonic activity of rat substantia nigra pars compacta dopamine neurons were studied using extracellular, single-unit recording techniques. Unlike nonselective D-1/D-2 dopamine agonists or the D-2 agonist quinpirole, SKF 38393 did not inhibit dopamine neuronal activity when applied iontophoretically or when administered intravenously in doses up to 20 mg/kg to chloral hydrate-anesthetized rats. Moreover, pretreatment with SKF 38393 did not alter the inhibitory response of these neurons to apomorphine or the D-2 agonist quinpirole. However, in locally anesthetized, gallamine-treated, artificially respired rats, dopamine cell activity was significantly altered by i.v. administration of SKF 38393; firing rate increases and decreases were observed. Administration of the inactive enantiomer of SKF 38393, S-SKF 38393, did not induce similar changes in parallel experiments. These results support the idea that unlike D-2 autoreceptor stimulation, D-1 receptor stimulation does not exert a direct local effect on dopamine neurons in the substantia nigra pars compacta and suggest that D-1 receptor stimulation at sites postsynaptic to the dopamine cells may indirectly affect the activity of some dopamine neurons through long-loop feedback mechanisms.     

Comparison of effects of D-1 and D-2 dopamine receptor agonists on neurons in the rat caudate putamen: an electrophysiological study

Extracellular single-unit recording and microiontophoretic techniques were used to characterize the pharmacological properties of dopamine (DA) receptor subtypes within the rat caudate putamen (CPu), a striatal structure that receives a dense innervation from DA neurons originating from the substantia nigra pars compacta (A9 DA neurons). Similar to the action of DA, the DA D-1 receptor agonist (+)SKF-38393 generally potentiated the activation produced by glutamate (GLU) at low ejection currents (less than or equal to 5 nA); at higher ejection currents, it depressed 97% of the CPu neurons tested. By contrast, the D-2 receptor agonist LY-171555 (quinpirole) was much less effective in affecting the firing rate of CPu cells. The selective D-1 antagonist SCH-23390, administered either intravenously or iontophoretically, completely blocked the (+)SKF-38393-induced effects on CPu cells but failed to change the depressant effects produced by either quinpirole or 5-HT. On the other hand, the selective D-2 antagonist I-sulpiride, blocked the effects induced by quinpirole but not (+)SKF-38393. These observations suggest that the D-1 and D-2 DA receptor agonists elicit their effects via distinct DA receptor subtypes. A comparison of these results with our previous results obtained from the nucleus accumbens (NAc) indicates that NAc cells are more responsive to DA D-2 agonist, whereas CPu cells are more sensitive to D-1 agonist. Therefore, D-1 receptors in the CPu may have a critical role in mediating the effect produced by DA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Repeated trimipramine induces dopamine D2/D3 and α1-adrenergic up-regulation

Summary. Trimipramine (TRI), which shows a clinical antidepressant activity, is chemically related to imipramine but does not inhibit the reuptake of noradrenaline and 5-hydroxytryptamine, nor does it induce β-adrenergic down-regulation. The mechanism of its antidepressant activity is still unknown. The aim of the present study was to find out whether TRI given repeatedly was able to induce adaptive changes in the dopaminergic and α₁-adrenergic systems, demonstrated by us previously for various antidepressants. TRI was given to male Wistar rats and male Albino Swiss mice perorally twice daily for 14 days. In the acute experiment TRI (given i.p.) does not antagonize the reserpine hypothermia in mice and does not potentiate the 5-hydroxytryptophan head twitches in rats. TRI given repeatedly to rats increases the locomotor hyperactivity induced by d-amphetamine, quinpirole and (±)-7-hydroxy-dipropylo-aminotetralin (dopamine D₂ and D₃ effects). The stereotypies induced by d-amphetamine or apomorphine are not potentiated by TRI. It increases the behaviour stimulation evoked by phenylephrine (given intraventricularly) in rats, evaluated in the open field test as well as the aggressiveness evoked by clonidine in mice, both these effects being mediated by an α₁-adrenergic receptor. It may be concluded that, like other tricyclic antidepressants studied previously, TRI given repeatedly increases the responsiveness of brain dopamine D₂ and D₃ (locomotor activity but not stereotypy) as well as α₁-adrenergic receptors to their agonists. A question arises whether the re-uptake inhibition is of any importance to the adaptive changes induced by repeated antidepressants, suggested to be responsible for the antidepressant activity. Accepted January 21, 1998; received November 3, 1997     

On the roles of dopamine D-1 vs. D-2 receptors for the hyperactivity response elicited by MK-801

Summary The present study was aimed at clarifying to what extent the hypermotility induced by the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 depends on dopamine (DA) D-1 compared to D-2 receptor tone. The D-1 receptor antagonist SCH 23390 was found to reduce locomotion to a greater extent in MK-801-treated than in vehicle-treated mice, whereas the reverse appeared to be the case for the DA D-2 receptor antagonist raclopride. In other words, MK-801-induced hyperactivity was more readily antagonized by SCH 23390 than by raclopride and, thus, DA D-1 receptors seem to be more important than D-2 receptors for MK-801-induced hyperactivity. These results are in line with our previous observation that MK-801 generally interacts synergistically with a DA D-1 but not with a D-2 receptor agonist in monoamine-depleted mice. In view of the possible role of deficient glutamatergic neurotransmission in schizophrenia, our findings underline the importance of investigating the efficacy of selective DA D-1 antagonists in this disorder.     

Pharmacological effects of venlafaxine, a new antidepressant, given repeatedly, on the α1-adrenergic, dopamine and serotonin systems

Summary. Venlafaxine (VEN) is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the uptake of serotonin and noradrenaline, but – in contrast to tricyclics – show no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated VEN (given twice daily for 14 days) induced adaptive changes in the α₁-adrenergic, dopamine and serotonin systems, similar to those reported by us earlier for tricyclic antidepressants. The results indicate that VEN potentiates the clonidine-induced aggressiveness and the methoxamine-induced exploratory hyperactivity, both these effects being mediated by α₁-adrenoceptors. VEN increased the hyperlocomotion induced by D-amphetamine and (±)-7-OH-DPAT. Neither the apomorphine and quinpirole hyperlocomotion, nor the apomorphine and D-amphetamine stereotypies were changed. VEN did not affect the behavioural syndrome induced by 8-OH-DPAT (a 5-HT_1A effect), and decreased both the head twitch reaction induced by L-5-HTP or (±)DOI and the hyperthermia induced by trifluoromethylphenylpiperazine, all those effects being mediated by 5-HT₂ receptors. Repeated VEN did not change the hypothermia evoked by oxotremorine (a central cholinergic agonist). The above results indicate that repeated VEN increases – as do tricyclics – the responsiveness of α₁-adrenergic and dopaminergic (mainly D₃) systems and decreases the responsiveness of the 5-HT₂ system. It may be concluded that the lack of affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment. Received April 20, 1998; accepted July 22, 1998     

Independent in vitro regulation by the D-2 dopamine receptor of dopamine-stimulated efflux of cyclic AMP and K-stimulated release of acetylcholine from rat neostriatum

Two types of dopamine receptors whose stimulation affect cAMP efflux (and by inference formation) could be identified in rat neostriatum. One type of receptor, called D-1 receptor, increased cAMP efflux whereas stimulation of a second type of dopamine receptor, called D-2 receptor, was followed by a reduction in cAMP efflux induced by stimulation with a D-1 receptor agonist. D-2 receptor agonists inhibited the effects of D-1 receptor agonists on cAMP efflux in a non-competitive way. These inhibiting effects of D-2 receptor agonists occured also in the absence of Ca²⁺-ions which could imply that some of the D-2 receptors are located on cells possessing D-1 receptors.

The dopamine receptor mediating inhibition of the release of radiolabeled acetylcholine (ACh) in the neostriatum appeared to have the same pharmacological characteristics as the D-2 dopamine receptor mediating the inhibition of the D-1 receptor agonist induced cAMP efflux. Selective D-2 receptor agonists like LY 141865 and RU 24926 stimulated this receptor while the D-1 receptor agonist SKF 38393 was inactive. Effects of the selective D-2 receptor agonists could be antagonized by (—)-sulpiride, a selective D-2 receptor antagonist. Although the pharmacological characteristics of the dopamine receptors mediating inhibition of both ACh release and (D-1 dopamine receptor agonist induced) cAMP efflux appeared to be similar, drugs stimulating cAMP efflux did not affect ACh release or LY 141865 induced inhibition of ACh release from rat neostriatum. Therefore it is still questionable whether the dopamine receptor mediating inhibition of both ACh release and cAMP efflux is one and the same functional entity.     

Evidence for an increased catecholamine synthesis in rat adrenal glands following stimulation of peripheral dopamine receptors

Summary In studies on peripheral dopamine (DA) turnover in our department evidence has accumulated that changes in adrenal DA levels induced by varying degrees of neurogenic stimulation roughly reflect changes in the catecholamine (CA) synthesis rate. The question arises if changes in DA levels in rat adrenals induced by different DA D-2 receptor agonists and previously reported from our laboratory, also indicate changes in CA synthesis. After various periods of drug administration rats were killed by decapitation and tissue CA levels in adrenals and forebrain were determined by HPLC-EC. The potent inhibitor of DA--hydroxylase FLA 63 (40 mg/kg i.p.) increased adrenal DA by 186% after 1 h and by 423% after 3 h. The DA D-2 agonist quinpirole (0.2 mg/kg s.c, 30 min) itself increased adrenal DA by 55–60% compared to control. In FLA 63 pretreated rats quinpirole increased adrenal DA levels by further 127% (FLA 63 — 1 h), resp. 122% (FLA 63 — 3h) than did FLA 63 itself. The DA D-2 receptor antagonist domperidone (3 mg/kg s.c, 150 min) blocked the quinpirole effect both in saline and FLA 63 (3 h) pretreated rats. Adrenal DOP AC was changed in similar manner as adrenal DA in FLA 63 pretreated rats. No significant changes either in adrenal NA or A were observed after FLA 63 pretreatment.Under the present experimental conditions adreanal DA may thus mainly be looked upon as an intermediate in the synthesis of NA and A, and the elevation of DA induced by DA D-2 receptor stimulation as a consequence of increased catecholamine synthesis.     

The effect of (+)- and (−)-oxaprotiline administered repeatedly on the dopamine system

Summary The behavioural and biochemical effects of repeated (14 and 28 days) treatment with (+)-oxaprotiline (a noradrenaline uptake inhibitor) and (–)-oxaprotiline (levoprotiline, without influence on noradrenaline uptake; the clinically active antidepressant) were studied in rats. Both those enantiomers given repeatedly increased the locomotor and exploratory activity and reduced the immobility time in Porsolt's test. The D-amphetamine-induced locomotor hyperactivity, as well as the stereotypies induced by D-amphetamine and apomorphine, were increased by the oxaprotilines. Single-dose treatment with both the oxaprotilines was not effective in the tests mentioned above. Repeated (+)-oxaprotiline administration reduced the binding (B_max but not K_D) to dopamine D-1 receptors in the striatum and limbic system; levoprotiline was inactive. The binding to dopamine D-2 receptors was not changed by either drug. Both the enantiomers showed only low affinity for brain dopamine D-1 and D-2 receptors in vitro. The obtained results indicate that chronic treatment with (+)- and (–)-oxaprotiline increases behavioural responsiveness of the dopamine mesolimbic and striatal systems.     

Repeated quinpirole treatment: Locomotor activity,dopamine synthesis,and effects of selective dopamine antagonists

Repeated treatment with the non-selective dopamine agonist apomorphine results in behavioral sensitization and enhanced dopamine synthesis in dopamine projection fields. To examine the role of D₂-type dopamine receptors in modulating these effects, the present experiment assessed the effects of repeated treatment with the D₂-type agonist quinpirole on locomotor activity and dopamine synthesis. In the first experiment, rats were treated with vehicle or one of two doses (0.3 or 3.0 mg/kg) of quinpirole for 8 days. Daily measures of locomotor activity revealed an initial suppression of activity produced by quinpirole which dissipated over the 8 days of treatment. A trend for an increase in activity for 3.0 mg/kg quinpirole compared to vehicle was obtained on day 8. Twenty-four hours after cessation of treatment, dopamine synthesis, measured as accumulation of 3,4-dihydroxyphenylalanine (DOPA) after treatment with the DOPA decarboxylase inhibitor NSD-1015, was enhanced in the striatum, but not nucleus accumbensolfactory tubercle (NAOT) or ventral mesencephalon (VM). In Experiment 2, rats were treated for 8 days with vehicle, 3.0 mg/kg quinpirole or the D₁ antagonist SCH 23390 (0.5 mg/kg) in a two (vehicle or quinpirole) × two (vehicle or SCH 23390) design. Quinpirolealone treatment resulted in a reduction of the locomotor suppressant effects of the drug. SCH 23390-alone and quinpirole-SCH 23390 combined treatment resulted in decreased activity compared to the vehicle control group that did not change across days. DOPA accumulation was enhanced in the striatum and NAOT after quinpirole treatment; however, SCH 23390 had no effect. In Experiment 3, rats were treated for 10 days with vehicle, 3.0 mg/kg quinpirole or the D₂ antagonist eticlopride (1.0 mg/kg) in a two (vehicle or quinpirole) × two (vehicle or eticlopride) design. As in the first two experiments, repeated quinpirolealone treatment resulted in a reduction of the locomotor suppressant effects of the drug; however, locomotor activity in this group was enhanced compared to vehicle controls on day 10. Eticlopridealone and eticlopride-quinpirole treated rats had suppressed locomotor activity across the 10 days. DOPA accumulation was enhanced by both repeated quinpirole and repeated eticlopride treatment in the striatum and NAOT. DOPA accumulation in eticlopride-quinpirole treated rats was not different from vehicle control levels in the NAOT, while no significant difference was obtained between the eticlopridealone and eticlopride-quinpirole groups in the striatum. The locomotor activity data suggest that repeated quinpirole treatment results in tolerance to the locomotor suppressant effect of the drug. Evidence for sensitization was obtained in two out of three of the experiments. These results suggest that enhanced dopamine synthesis after repeated non-selective dopamine agonist treatment is modulated by D₂-type dopamine receptors. © 1995 Wiley-Liss, Inc.     

Adolescent exposure to methylphenidate alters the activity of rat midbrain dopamine neurons.

BACKGROUND: Methylphenidate is commonly used to treat children and adolescents with attention-deficit/hyperactivity disorder. A health concern is its long-term effects with respect to later stimulant exposure. We reported that repeated exposure to a low dose of methylphenidate during adolescence increases self-administration of a low, typically nonreinforcing dose of cocaine in adult rats. We also showed that enhanced vulnerability to cocaine is associated with elevated impulse and bursting activity of midbrain dopamine neurons in drug-na?ve adult rats and might constitute a substrate critically associated with abuse liability. Thus we sought to determine whether repeated exposure to low-dose methylphenidate in adolescence alters dopamine neuronal excitability in adulthood. METHODS: After 3-day and 2-week withdrawal from repeated low-dose adolescent exposure to methylphenidate, we used extracellular single-unit recording in chloral hydrate-anesthetized rats to determine basal firing and bursting activity of midbrain dopamine neurons and dopamine autoreceptor sensitivity to the D2-class direct receptor agonist quinpirole. RESULTS: Dopamine neuronal impulse activity was increased after 3 days and decreased after 2 weeks' withdrawal from methylphenidate given in adolescence. No difference between groups was evident with respect to autoreceptor sensitivity to quinpirole. CONCLUSIONS: Adolescent exposure to methylphenidate induces neuronal changes associated with increased addiction liability in rats.     

Differential effects of D1 and D2 dopamine agonists on stereotyped locomotion in rats.

The study examines the effect of selective D1 dopamine stimulation with SKF38393 (1.25-10 mg/kg), on stereotyped locomotion induced by the D2 agonist, quinpirole (0.5 mg/kg). Quinpirole induces repeated travel along a few routes in a limited portion of the environment. Co-administration of low doses of SKF38393 (1.25-2.5 mg/kg) produces the following results: the rate of route perseveration is not affected; the area explored expands to encompass the entire periphery of the open field; and, spatial distribution of locomotion is transformed from routes that cross the center under quinpirole to travel only along the edge. Under higher doses of SKF38393, locomotion ceases. These findings suggest that D1 and D2 stimulation may control the spatial organization of locomotion in oppositional rather than synergistic manner.     

Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatum

It has been shown that striatal adenosine A2A receptors can antagonistically interact with dopamine D2 receptors at the membrane level leading to a decrease in the affinity and efficacy of D2 receptors. Extracellular recordings and rotational behaviour were employed to obtain a correlate to these findings in an animal model of Parkinson's disease (PD). The recordings were performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced catecholamine depletion. While recording in the dopamine-depleted striatum, local applications of the dopamine D2 agonist quinpirole reduced neuronal activity. However, when the adenosine A2A antagonist MSX-3 was applied simultaneously with quinpirole, the inhibition of neuronal firing seen after quinpirole alone was significantly potentiated (P< 0.001, n = 11). In contrast, local application of CGS 21680 attenuated the effect of quinpirole. The doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal firing. Furthermore, rotational behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole while no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX-3 alone did not induce rotational behaviour. In conclusion, this study shows that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal firing rate, while the A2A agonist exerts the opposite action. This mechanism gives a therapeutic potential to A2A antagonists in the treatment of PD by enhancing D2 receptor function.     

Dynamic dopamine receptor interactions in the core and shell of nucleus accumbens differentially coordinate the expression of unconditioned motor behaviors

Many neurochemical and behavioral functions mediated by dopamine require the dynamic interaction between dopamine receptors. We examined the behavioral effects evoked by microinjections of drugs with relative selectivity for specific dopamine receptors into the nucleus accumbens (Acb). The results showed that, at behaviorally inactive doses, the dopamine D1-class receptor agonist SKF 38393 switched the behavioral profile induced by injections of the dopamine D2-class receptor agonist quinpirole into the Acb, from sedation, yawning, and motor inhibition to hyperactive-like behavior. Further, the effects of injections of the dopamine D2-class receptor agonist (+)-PD 128907 into the shell of Acb, including suppression of rearing, locomotion, and grooming, and induction of oral dyskinesia, yawning, and sedation, could not be distinguished from those elicited by (+)-PD 128907 following infusions into the core of Acb. However, the behavioral effects elicited by coadministration of SKF 38393 and (+)-PD 128907 into the core or the shell of Acb showed a striking anatomical specificity. The infusion of SKF 38393 plus (+)-PD 128907 into the core, but not into the shell, of Acb modified the pattern of responses induced by (+)-PD 128907, inducing behavioral hyperactivity. These results suggest critical differences in the functional interaction between dopamine receptors in the core and the shell of the Acb and reveal a mechanism of behavioral switching in the core of Acb by virtue of which dopamine D1-class receptors regulate the transition from states of behavioral suppression to states of heightened psychomotor arousal.     

Differential interaction of competitive NMDA and AMPA antagonists with selective dopamine D-1 and D-2 agonists in a rat model of Parkinson's disease

Stimulation of the dopamine (DA) D-2 and D-1 receptors results in behavioural activation (i.e., induction of contralateral rotations) in 6-hydroxydopamine (6-OHDA) substantia nigra lesioned rats. Competitive N-methyl-D-aspartate (NMDA) antagonists as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists potentiate the stimulatory responses to threshold doses of L-DOPA or the mixed dopamine D-1/D-2 agonist apomorphine in this model, indicating the potential of such combinations for the management of Parkinson's disease. Neuroanatomic and electrophysiologic data indicate a differential distribution of DA D-1 and DA D-2 receptors within motor loops of the basal ganglia. DA D-1 receptors are preferentially located on GABAergic neurones projecting to the substantia nigra compacta (SNc) and to the substantia nigra reticulata (SNr), whereas DA D-2 receptors are preferentially located on neurones that innervate the external pallidum. NMDA receptors are present in high densities within the striatum, whereas AMPA receptors are enriched in the entopeduncular nucleus/internal pallidum and the SNr. To further characterise the functional interaction between DA and glutamate receptors, we tested the competitive NMDA antagonist 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) following systemic administration in combination with the DA D-2 selective agonist quinpirole or the DA D-1 selective agonist A 68 930 (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman) in rats with chronic 6-OHDA lesions of the SNc. CPP potentiated quinpirole-induced rotations and did not affect those induced by the D-1 agonist A 68930. By contrast, NBQX had no effect on quinpirole-induced rotations, whereas synergism was seen with A 68930. These results suggest that rotations induced by combined treatment with glutamate antagonists and DA agonists are mediated by different pathways within the basal ganglia, depending on which subtype of receptor is involved. AMPA antagonists could act preferentially by activating the direct motor pathway, whereas NMDA antagonists could modulate the indirect loop. Synapse 26: 381–391, 1997. © 1997 Wiley-Liss Inc.     

Effects of low,autoreceptor selective doses of dopamine agonists on the discriminative cue and locomotor hyperactivity produced by d-amphetamine

Summary The ability of low doses of the dopamine (DA) agonists quinpirole and (+)-3-PPP to reduce the discriminative stimulus properties and locomotor hyperactivity produced by d-amphetamine (0.5 mg/kg) was assessed in two groups of rats. Quinpirole (0.0125–0.05mg/kg) and (+)-3-PPP (1.0–2.0 mg/kg) completely antagonized d-amphetamine-induced locomotor hyperactivity. In contrast, only single doses of quinpirole (0.025 mg/kg) and (+)-3-PPP (2.0 mg/ kg) were effective in the drug discrimination paradigm; the antagonisms were small (18–47%), but significant. The inhibitory effects of quinpirole and (+)-3-PPP in these behavioural models are probably due to their ability to selectively stimulate DA autoreceptors in the nucleus accumbens and reduce the increase in DA release produced by d-amphetamine. It is suggested that the much weaker effects of the drugs in the discrimination paradigm are due to changes produced by the long-term periodic administration of d-amphetamine to these animals, such as a down-regulation in the sensitivity of DA autoreceptors.     

Striatal dopamine D2 receptors attenuate neuropathic hypersensitivity in the rat

Earlier studies indicate that striatal dopamine D(2) receptors are involved in pain regulation in non-neuropathic conditions. We assessed whether striatal dopamine D(2) receptors contribute to pain regulation also in neuropathic conditions. The spared nerve injury model of neuropathy was induced by unilateral ligation of the tibial and common peroneal nerves in the rat. In awake nerve-injured animals, pain-related withdrawal responses to calibrated monofilaments or noxious heating were attenuated following striatal administration of a dopamine D(2) receptor agonist quinpirole. Pain-related responses were attenuated only in the nerve-injured limb ipsilateral to the injection and in the midline (tail). In unoperated controls, striatal administration of quinpirole at an antihypersensitive dose did not influence withdrawal responses to mechanical stimulation. Attenuation of pain-related responses induced by striatal administration of quinpirole was reversed by intrathecal administration of a dopamine D(2) receptor antagonist (eticlopride) or a non-selective 5-HT receptor antagonist (methysergide), but not by an alpha(2)-adrenoceptor antagonist (atipamezole). In the rostroventromedial medulla of lightly anesthetized neuropathic animals, striatal administration of quinpirole significantly decreased the activity of presumably pronociceptive cells that are activated by noxious stimulation. The innocuous H-reflex in lightly anesthetized control animals was not suppressed by striatal administration of quinpirole at an antihypersensitive dose. The results indicate that striatal dopamine D(2) receptors attenuate neuropathic hypersensitivity. The antihypersensitive effect induced by striatal dopamine D(2) receptors in peripheral neuropathy involves suppression of impulse discharge of presumably pronociceptive neurons in the rostroventromedial medulla, and a descending influence acting on spinal 5-HT and dopamine D(2) receptors.     

Changes in dopaminergic and glutamatergic excitatory mechanisms of micturition reflex after middle cerebral artery occlusion in conscious rats

Previous reports have shown that N-methyl-d-aspartate (NMDA) glutamatergic and D2 dopaminergic mechanisms have independent excitatory effects on bladder activity in normal and cerebral infarcted (CI) rats under urethane anesthesia. The study presented here was undertaken to investigate the interaction between these two mechanisms on bladder activity in conscious Sprague-Dawley female rats with or without cerebral infarction. Occlusion of the left middle cerebral artery or a sham operation (SO) was performed under halothane anesthesia. After recovery from the anesthesia, bladder activity was monitored continuously by means of infusion cystometrography in awake rats. The effects of cumulative intravenous doses of quinpirole (0.001-1 mg/kg), a D2 dopamine receptor agonist, were studied in awake SO and CI rats with or without dizocilpine (10 mg/kg) pretreatment. The effects of dizocilpine (1 or 10 mg/kg) were also examined in other SO or CI rats pretreated with 1 mg/kg of quinpirole. Bladder capacity in CI rats was significantly smaller (0.18 ml) than that in SO rats (0.48 ml). Quinpirole (0.1 and 1 mg/kg) further reduced bladder capacity in both types of rats, an effect blocked by sulpiride (20 mg/kg), a D2 dopamine receptor antagonist. The effect of quinpirole was also antagonized by dizocilpine (1 mg/kg) to a significantly (P < 0.01) greater degree in CI than in SO rats. In SO rats pretreated with 1 mg/kg of quinpirole, dizocilpine significantly increased bladder capacity in a dose-dependent manner. After the maximum dose (10 mg/kg) of dizocilpine, sulpiride did not produce any changes in bladder activity. In CI rats pretreated with 1 mg/kg of quinpirole, 1 mg/kg of dizocilpine increased bladder capacity. After administration of the maximum dose of dizocilpine (10 mg/kg), which did not produce an additional effect, sulpiride (20 mg/kg) increased bladder capacity by 58.3%. These results indicate that in awake rats D2 dopaminergic excitatory effects on the urinary bladder are mediated in part by NMDA glutamatergic mechanisms and in part by non-NMDA mechanisms. The latter type was more prominent in CI rats, indicating that the bladder hyperactivity induced by cerebral infarction may be mediated by an alteration in dopaminergic-glutamatergic interactions in the brain.