Morris water maze learning in Long-Evans rats is differentially affected by blockade of D1-like and D2-like dopamine receptors

Dopaminergic neurotransmission is involved in several brain functions including spatial cognition. In the present study we examine the effects of systemic administration of D1-like receptor antagonist SCH23390 and D2-like receptor antagonist sulpiride on the acquisition of the Morris water maze task. We used visible versus hidden platform versions of the MWM in order to distinguish between the effects of the drugs on the procedural versus cognitive aspects of the task. SCH23390 was found to prolong escape latencies to the visible platform at a higher dose (0.05mg/kg), whilst the lower dose (0.02mg/kg) left both procedural and cognitive functions almost unchanged. SCH23390 was also found to reduce swimming speed. Sulpiride did not affect the visible platform learning at any of three doses studied (30, 60 and 100mg/kg); the highest dose of sulpiride (100mg/kg) impaired place navigation to the hidden platform, without affecting the swim speed. The results of the present study show a difference in the involvement of D1-like and D2-like receptors in the MWM acquisition.     

Mapping quantitative trait loci that regulate sensitivity and tolerance to quinpirole, a dopamine mimetic selective for D(2)/D(3) receptors

Acute sensitivity and tolerance to quinpirole (a dopamine mimetic with selectivity for D(2)/D(3) dopamine receptors) were evaluated in the C57BL/6J and DBA/2J inbred strains of mice, 24 of their BXD recombinant inbred strains, and 233 F(2) mice. Baseline locomotor activity, locomotor activity following 0.03 mg/kg quinpirole (and 0. 01 mg/kg in BXD mice), body temperature following 1 mg/kg quinpirole, and hypothermic tolerance following 2 or 3 days of quinpirole administration were evaluated. Quantitative trait locus (QTL) analysis was employed to identify genetic determinants of baseline locomotor activity and five behavioral responses to quinpirole. We examined correlated allelic variation in genetic markers of known chromosomal location with variation in each of these phenotypes. We definitively mapped a QTL on Chromosome (Chr) 9 linked to the D(2) dopamine receptor gene, Drd2, for hypothermic sensitivity to quinpirole, and identify a suggestive QTL in the same chromosomal region for tolerance to quinpirole after repeated treatments. Suggestive QTLs were also identified on Chr 19 for sensitivity and tolerance to quinpirole-induced hypothermia and for baseline locomotor activity; on Chr 15 for locomotor sensitivity to quinpirole; and on Chr 13 and 5 for baseline locomotor activity. Our results indicate that genetic differences in quinpirole sensitivity and tolerance are associated with QTLs near Drd2, and that baseline locomotor activity is associated with a suggestive QTL in proximity to the dopamine transporter gene Dat1. These data suggest that the genes influencing locomotor activity, dopamine mimetic sensitivity, and tolerance do not overlap completely.     

Role of alpha1- and alpha2-adrenoceptors in the regulation of locomotion and spatial behavior in the active place avoidance task: a dose-response study

Studies on the neurotransmitter substrate of locomotion and place navigation occupy a central position in behavioral neuroscience. Active allothetic place avoidance (AAPA) is a task, in which animals are trained to avoid a room frame defined stable sector on a continuously rotating arena. The aim of the present study was to test the effect of the blockage of alpha1- and alpha2-adrenoceptors, using specific antagonists prazosin and idazoxan, on the locomotor activity and spatial behavior in the AAPA task. Both prazosin and idazoxan at the highest doses (4 and 6 mg/kg, respectively) were found to decrease the locomotor activity in the AAPA and they also impaired navigational performance. The results suggest that antagonizing alpha-adrenoceptors with systemically administered drugs affects locomotor activity together with avoidance behavior and does not cause a purely cognitive deficit in the AAPA task.     

Characterization of the role of medial prefrontal cortex dopamine receptors in cocaine-induced locomotor activity

Medial prefrontal cortex (mPFC) dopamine (DA) modulates the motor-stimulant response to cocaine. The present study examined the specific mPFC DA receptor subtypes that mediate this behavioral response. Intra-mPFC injection of the DA D2-like receptor agonist quinpirole blocked cocaine-induced motor activity, an effect that was prevented by coadministration of the D2 receptor antagonist sulpiride. Intra-mPFC injection of the selective D4 receptor agonist PD 168,077 or the selective D1 receptor agonist SKF 81297 did not alter the motor-stimulant response to cocaine. Finally, it was found that an intermediate dose of quinpirole, which only attenuated cocaine-induced motor activity, was not altered by SKF 81297 coadministration, suggesting a lack of synergy between mPFC D1 and D2 receptors. These results suggest that D2 receptor mechanisms in the mPFC are at least partly responsible for mediating the acute motor-stimulant effects of cocaine.     

Prior D1 dopamine receptor stimulation is required to prime D2-mediated striatal Fos expression in 6-hydroxydopamine-lesioned rats

Repeated dopamine agonist administration to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway potentiates behavioral and neuronal activation in response to subsequent dopamine agonist treatment. This response sensitization has been termed "priming" or "reverse-tolerance". Our prior work has shown that three pretreatment injections of the mixed D1/D2 agonist apomorphine (0.5 mg/kg) into 6-hydroxydopamine-lesioned rats permits a previously inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to induce robust contralateral rotation and striatal Fos expression in striatoentopeduncular "direct" pathway neurons. These striatal neurons typically express D1 but not D2 receptors. Because apomorphine acts as an agonist at both D1 and D2 receptors, the present study sought to determine whether D1, D2, or concomitant D1/D2 receptor stimulation was required to prime D2-mediated contralateral rotation and striatal Fos expression. Twenty-one days following unilateral stereotaxic injection of 6-hydroxydopamine into the medial forebrain bundle, rats received three pretreatment injections, at three- to six-day intervals, with either: the mixed D1/D2 agonist apomorphine, the D1 agonist SKF38393, the D2 agonist quinpirole, or a combination of SKF38393 + quinpirole. Ten days following the third pretreatment injection, 6-hydroxydopamine-lesioned rats were challenged with the D2 agonist quinpirole (0.25 mg/kg). Pretreatment with SKF38393 (10 mg/kg), quinpirole (1 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to induce robust contralateral rotation which was similar in magnitude to that observed following apomorphine priming. However, only pretreatment with SKF38393 (10 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted the same dose of quinpirole (0.25 mg/kg) to induce striatal Fos expression. These results demonstrate that while prior stimulation of D1, D2 or D1/D2 receptors can effectively prime D2-mediated contralateral rotation, prior stimulation of D1 receptors is required to prime D2-mediated striatal Fos expression. This study demonstrates that priming of 6-hydroxydopamine-lesioned rats with a D1 agonist permits a subsequent challenge with a D2 agonist to produce robust rotational behavior that is accompanied by induction of immediate-early gene expression in neurons that comprise the "direct" striatal output pathway. These responses are equivalent to the changes observed in apomorphine-primed 6-hydroxydopamine-lesioned rats challenged with D2 agonist. In contrast, D2 agonist priming was not associated with D2-mediated induction of striatal immediate-early gene expression even though priming of D2-mediated rotational behavior was not different from that observed following priming with apomorphine or D1 agonist. Therefore, while priming-induced alterations in D2-mediated immediate early gene expression in the "direct" striatal output pathway may contribute to the enhanced motor behavior observed, such changes in striatal gene expression do not appear to be required for this potentiated motor response in dopamine-depleted rats.     

Dopamine receptors modulate ethanol's locomotor‐activating effects in preweanling rats

Near the end of the second postnatal week motor activity is increased soon after ethanol administration (2.5 g/kg) while sedation‐like effects prevail when blood ethanol levels reach peak values. This time course coincides with biphasic reinforcement (appetitive and aversive) effects of ethanol determined at the same age. The present experiments tested the hypothesis that ethanol‐induced activity during early development in the rat depends on the dopamine system, which is functional in modulating motor activity early in ontogeny. Experiments 1a and 1b tested ethanol‐induced activity (0 or 2.5 g/kg) after a D1‐like (SCH23390; 0, .015, .030, or .060 mg/kg) or a D2‐like (sulpiride; 0, 5, 10, or 20 mg/kg) receptor antagonist, respectively. Ethanol‐induced stimulation was suppressed by SCH23390 or sulpiride. The dopaminergic antagonists had no effect on blood ethanol concentration (Experiments 2a and 2b). In Experiment 3, 2.5 g/kg ethanol increased dopamine concentration in striatal tissue as well as locomotor activity in infant Wistar rats. Adding to our previous results showing a reduction in ethanol induced activity by a GABA B agonist or a nonspecific opioid antagonist, the present experiments implicate both D1‐like and D2‐like dopamine receptors in ethanol‐induced locomotor stimulation during early development. According to these results, the same mechanisms that modulate ethanol‐mediated locomotor stimulation in adult rodents seem to regulate this particular ethanol effect in the infant rat. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 52: 13–23, 2010     

Dopamine D1/D2 agonists injected into nucleus accumbens and ventral pallidum differentially affect locomotor activity depending on site.

Ventral pallidal dopamine has been recently shown to play an important role in psychostimulant reward and locomotor activation. The aim of the present study was to compare the roles of ventral pallidal D1 and D2 receptors in evoking locomotor activity with those in the nucleus accumbens. The D1 agonist SKF 38393 and the D2 agonist quinpirole hydrochloride (0.3-3 microg/ 0.5 microl) were bilaterally injected into ventral pallidum or nucleus accumbens through pre-implanted cannulae. In the ventral pallidum, 0.3-1 microg SKF 38393 increased locomotor activity while 3 microg had no effect; 3 microg quinpirole suppressed locomotion while 0.3-1 microg had no effect. Locomotor activity induced by an equigram (0.3 microg) mixture of SKF 38393 and quinpirole, while significantly higher than that induced by 0.3 microg quinpirole was not significantly higher than that induced by 0.3 microg SKF 38393 alone. At the 3 microg dose, SKF 38393 injections into anterior ventral pallidum increased activity; injections into posterior ventral pallidum decreased activity. In the nucleus accumbens, 0.3-3 microg SKF 38393 dramatically increased locomotor activity while quinpirole moderately increased locomotion. In the group that had previously received the full quinpirole dose range, injection of the equigram (0.3 microg) mixture of SKF 38393 and quinpirole induced locomotor activation which was higher than that induced by either drug alone or by the addition of the effect of each drug alone, i.e. synergy occurred. Moreover, rats that had previously received SKF 38393 developed a sensitized locomotor response to subsequent SKF 38393, quinpirole or the mixture of these two drugs. The difference in locomotor response to dopamine agonists between the ventral pallidum and nucleus accumbens is consistent with electrophysiological evidence collected at these two sites. These findings suggest that, unlike the nucleus accumbens, where D1 and D2 receptor activation may facilitate each other to induce a synergistic effect on locomotor activity, ventral pallidal D1 and D2 receptors may be located on different neurons and coupled with different, if not opposite, behavioral output.     

Dopamine D-2 receptor mediation of response suppression learning of young rats

In three experiments, the effects of augmenting or blocking dopamine (DA) D-2 receptor activity on the ontogeny of response suppression learning of preweanling rat pups were determined. In the initial experiment, rat pups were trained to traverse a straight alley for nipple attachment to an anesthetized dam. When footshock (0.2 mA, 0.5 sec) was made contingent on responding, younger (11- and 13-day-olds) rat pups were deficient to older (17- and 19-day-olds) pups at withholding punished responding. In the subsequent experiments, response suppression learning was assessed after injecting 11- and 17-day-old rat pups with the specific DA D-2 agonist, LY 171555 (0.005-, 0.01-, and 0.1-mg/kg, i.p.), or the specific DA D-2 antagonist, sulpiride (5.0-, 15.0-, and 50.0-mg/kg, i.p.). LY 171555 enhanced the punished responding of both the 11- and 17-day-old rat pups; whereas, sulpiride increased the punished responding of the 17-, but not the 11-day-olds. In four additional experiments, the effects of LY 171555 and sulpiride on the locomotor activity, nociception, and reinforcement processes of 17-day-old rat pups was assessed. Rat pups given LY 171555 (0.01 mg/kg, i.p.) exhibited enhanced locomotor activity and a trend towards hyperanalgesia using a hot plate task. Sulpiride (15.0 mg/kg, i.p.) completely antagonized LY 171555's activity enhancing effects and had hyperalgesic properties. In two experiments, sulpiride did not affect the nonpunished appetitive responding of the 17-day-olds; whereas, haloperidol-treated pups responded on fewer reinforced trials than did saline-treated pups. Therefore, these results indicate that the response suppression learning of 17-day-old rat pups is mediated, at least partially, by a DAD-2 receptor system, and that D-2 receptors are also involved in the locomotor activity and nociceptive responses of young rat pups.     

Opposing effects of D1 and D2 receptor activation on odor discrimination learning

Dopaminergic modulation of cortical activity has been implicated in the formation of reward associations. There is abundant evidence for dopaminergic effects on olfactory processing. Using an olfactory discrimination task, the authors show that D1 and D2 dopamine receptors can regulate rats' olfactory discrimination capacities and that the effects of receptor activation functionally oppose one another. Injection of either the D1 agonist SKF 38393 (10 mg/kg) or the D2 antagonist spiperone (0.62 mg/kg) facilitated the discrimination of similar odorants but had no effect on the discrimination of dissimilar odorants, whereas both the D, antagonist SCH 23390 (0.025 mg/kg) and the D2 agonist quinpirole (0.2 mg/kg) significantly impaired rats' ability to discriminate similar and dissimilar odorants.     

Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole

Locomotor sensitization induced by the dopamine agonist quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to quinpirole. Rats were co-treated with 0.5 mg/kg quinpirole and either salvinorin A (0.04, 0.4 or 2.0 mg/kg) or U69593 (0.3 mg/kg). Control groups were co-treated with vehicle and saline, vehicle and quinpirole (0.5 mg/kg), or saline and salvinorin A (0.4 mg/kg). Rats were injected biweekly for a total of 10 injections and locomotor activity measured after each treatment. Results showed that the highest dose of salvinorin A potentiated sensitization to quinpirole as did U69593, the middle salvinorin A dose had no effect on quinpirole sensitization, and the lowest dose of salvinorin A attenuated sensitization to quinpirole. These findings indicate that structural differences between salvinorin A and U69593 do not affect the potentiation of quinpirole sensitization. Moreover, the opposite effects of high and low salvinorin A doses suggest that salvinorin A can produce bidirectional modulation of sensitization to dopamine agonists.     

Behavioral responsitivity to dopamine receptor agonists after extensive striatal dopamine lesions during development

Dopamine (DA) receptor responsitivity was investigated in adult rats that received intrastriatal (i.s.) injections of 6-OHDA (20 μg per striatum) on day of birth or postnatal Day 1 (Day 0/Day 1). Neonatally lesioned rats exhibited self-biting behavior and increases in stereotypic gnawing following treatment with the mixed D1/D2 receptor agonist apomorphine (0.32–3.2 mg/kg) or the D1-like receptor agonist SKF38393 (10 mg/kg). Increases in locomotor activity, rearing, and paw treading were also observed in the lesioned rats after SKF38393 (1–10 mg/kg) treatment. The incidences of the prototypical D1 receptor-mediated behaviors, grooming and abnormal perioral movements (i.e., oral dyskinesias) were not increased in the lesioned rats. However, the low dose (0.32 mg/kg) of apomorphine as well as all doses of the D2-like receptor agonist quinpirole (0.32–3.2 mg/kg) induced grooming in the lesioned rats, which was not observed in nonlesioned control rats. Autoradiographs of [³H]mazindol binding to high affinity DA uptake sites revealed an extensive loss of DA terminals in the striata of the neonatally lesioned rats. These data suggest that near-total (≥95%) DA depletions on Day 0/Day 1 result in long-term alterations in the functional sensitivity of DA receptors, as well as possible changes in the interactions between D1 and D2 receptors. Comparisons of these results with those seen following lesions of the early-developing DA system (“patch-selective” lesions) and lesions made at other time points will be discussed. © 1998 John Wiley & Sons, Inc. Dev Psychobiol 32: 313–326, 1998     

Stimulation of D1 dopamine receptors reveals direct effects of the preferential dopamine autoreceptor agonist B-HT 920 on postsynaptic dopamine receptors

Possible postsynaptic effects of the preferential dopamine autoreceptor agonist B-HT 920 were studied by means of the mouse motor activity. In reserpine-treated mice, B-HT 920 did not cause any motor activity by itself but it markedly potentiated the slight stimulating effect of the D1 dopamine agonist SKF 38 393. The effect was blocked by either the D2-receptor antagonist sulpiride or the D1-receptor antagonist SCH 23 390, indicating that motor activity is dependent on simultaneous activation of both dopamine receptor types. The hyperactivity produced by 0.1 mg kg-1 B-HT 920 in combination with SKF 38 393 in reserpine-treated mice was at least as great as that following a maximal dose of apomorphine, indicating that B-HT 920 is a full agonist at postsynaptic D2 receptors. The effect of 0.1 mg kg-1 B-HT 920 peaked earlier than those of 1 mg kg-1 and particularly, 10 mg kg-1 suggesting additional effects of the later two doses. B-HT 920 stimulates dopamine autoreceptors almost maximally following 0.1 or 1 mg kg-1 but only the latter dose (with or without SKF 38 393) caused hyperactivity of mice not treated with reserpine. This finding indicates that the postsynaptic D2 receptors are less sensitive to B-HT 920 than the D2 dopamine autoreceptors.     

N-methyl-D-aspartate and dopamine receptor involvement in the modulation of locomotor activity and memory processes

In this study we report on the effects of N-methyl-d-aspartate (NMDA)- and dopamine (DA)-receptor manipulation on the modulation of one-trial inhibitory avoidance response and the encoding of spatial information, as assessed with a non-associative task. Further, a comparison with the well-known effects of the manipulation of these two receptor systems on locomotor activity is outlined. It is well assessed that NMDA-receptor blockage induces a stimulatory action on locomotor activity similar to that exerted by DA agonists. There is evidence showing that the nucleus accumbens is involved in the response induced by both NMDA antagonists and DA agonists. We show results indicating a functional interaction between these two neural systems in modulating locomotor activity, with D2 DA-receptor antagonists (sulpiride and haloperidol) being more effective than the D1 antagonist (SCH 23390) in blocking MK-801-induced locomotion. A different profile is shown in the effects of NMDA antagonists and DA agonists in the modulation of memory processes. In one-trial inhibitory avoidance response, NMDA antagonists (MK-801 and CPP) impair the response on test day, while DA agonists exert a facilitatory effect; furthermore, sub-effective doses of both D1 (SKF 23390) and D2 (quinpirole) are able to attenuate the impairing effect in a way similar to that induced by NMDA antagonists. The effects of NMDA- and DA-acting drugs on the response to spatial novelty, as assessed with a task designed to study the ability of animals to react to discrete spatial changes, are in good accord with the effects observed on passive avoidance. The results show that NMDA as well as DA antagonists, at low doses, selectively impair the reactivity of mice to spatial changes. In a last series of experiments, the possible role of NMDA receptors located in the nucleus accumbens was investigated regarding reactivity to spatial novelty. The experiments gave apparently contrasting results: while showing an impairing effect of focal administrations of NMDA antagonists in the nucleus accumbens on reactivity to spatial novelty, no effect of ibotenic acid lesions of the same structure was observed.     

Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats

The aims of the present study were to compare the effect of subchronic administration of MK-801 on performance in the active allothetic place avoidance (AAPA) task and in the working version of Morris water maze (MWM) in Long-Evans and Wistar rats. Animals were trained for four daily sessions either in the AAPA or in the working memory version of the MWM. Wistar rats treated by MK-801 (0.1 mg/kg) showed a cognitive deficit in the AAPA task without a significant hyperlocomotion, whereas they were not impaired in the working memory version of the MWM compared to controls. Long-Evans rats treated by MK-801 (0.1 mg/kg) were not impaired either in the AAPA task or in the MWM task. Higher doses of MK-801 (0.2 and 0.3 mg/kg) produced hyperlocomotion in both strains which corresponded to an inability to solve both spatial tasks. Long-Evans rats were superior in the MWM to the Wistar rats in the groups treated with the low dose of MK-801. In conclusion, intact Wistar rats can efficiently solve both spatial tasks; however, they are more sensitive to MK-801-induced behavioural deficit. This has relevance for modeling of the schizophrenia-related deficits and for screening substances for their therapeutic potential.     

Dopamine D(2) receptor activation modulates perceived odor intensity

Dopaminergic modulation affects odor detection thresholds and olfactory discrimination capabilities in rats. The authors show that dopamine D(2) receptor modulation affects odor discrimination capabilities in a manner similar to the modulation of stimulus intensity. Performance in a simultaneous odor discrimination task was systematically altered by manipulations of both odorant concentration and D(2) receptor activation (agonist quinpirole, 0.025-0.5 mg/kg; antagonist spiperone, 0.5 mg/kg). Rats' discrimination performance systematically improved at higher odor concentrations. Blockade of D(2) receptors improved performance equivalent to increasing odor concentration by 2 log units, whereas activation of D(2) receptors reduced odor discrimination performance in a dose-dependent manner. Bulbar dopamine release may serve a gain control function in the olfactory system, optimizing its sensitivity to changes in the chemosensory environment.     

Involvement of dopamine D(2) receptors in complex maze learning and acetylcholine release in ventral hippocampus of rats

In the current study we focus on the involvement of dopamine D(2) receptors in the ventral hippocampus in memory performance and acetylcholine release. Using the aversively motivated 14-unit T-maze (Stone maze) the injection of raclopride, a D(2) receptor antagonist, into the ventral hippocampus (8 microg/kg) was found to impair memory performance. Co-injection of quinpirole, a D(2) receptor agonist (8 microg/kg), overcame the impairment in performance. Microdialysis study revealed that quinpirole infusion (10-500 microM) into the ventral hippocampus stimulated acetylcholine release in a dose-dependent manner, and systemic injection of quinpirole (0.5 mg/kg, i.p.) also stimulated acetylcholine release in the ventral hippocampus. Infusion of eticlopride, another D(2) receptor antagonist, into the ventral hippocampus suppressed acetylcholine release in the hippocampus induced by systemic injection of quinpirole. Taken together, we suggest that D(2) receptors in the ventral hippocampus are involved in memory performance, possibly through the regulation of acetylcholine.     

Effects of dopaminergic drugs on innate pheromone-mediated reward in female mice: a new case of dopamine-independent "liking."

Male sexual pheromones are innately rewarding to adult female mice, but the role of dopamine in this natural reward is unknown. The authors have tackled this issue by assessing the effects of intraperitoneal injections of dopamine D1 (SCH 23390, 0.02- 0.05 mg/kg) and D2 (sulpiride, 20.00 mg/kg) antagonists, a dopamine releasing agent (amphetamine, 0.50 -2.00 mg/kg), and D1 (SKF 38393, 10.00 -20.00 mg/kg) and D2 (quinpirole, 0.20 -1.00 mg/kg) agonists on the chemoinvestigation displayed by female mice in male- versus female-soiled bedding 2-choice tests. Dopamine antagonists and quinpirole failed to affect the unconditioned preference displayed by females towards male chemosignals, whereas both amphetamine and SKF 38393 abolished it. Finally, D1 and D2 antagonists did not block the induction of operant place conditioning by male chemosignals. As the female mice were tested in their first encounter with male sexual pheromones, their behavior can only be influenced by the "liking" component of reward. Therefore, the results suggest that dopamine mediates neither the hedonic properties of male sexual pheromones nor the acquisition of conditioned place preference. However, dopamine acting on D1 receptors might inhibit female mice attraction towards male chemosignals.     

Motor depression: a new role for D1 receptors?

The aims of this study were two-fold. Firstly, to characterize the behavioral properties of a potential new dopamine D1 receptor agonist, (-)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3-ab]phenanth ridine (CY 208-243), to determine its suitability as a tool for investigating D1 receptor function in vivo. Secondly, to investigate how the behavioural properties of D1 agonists are modified in the presence of D2 receptor blocking drugs. For this purpose, using mice, we employed CY 208-243 and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393) as reference D1 agonists, and the substituted benzamides metoclopramide and sulpiride as selective D2 antagonists. CY 208-243 (0.25-10 mg/kg) caused only a modest increase in grooming in non-habituated mice, but stimulated locomotion, rearing, grooming and orofacial activities in habituated animals. These responses were inhibited by a D1 antagonist, but not by D2 antagonists, suggesting CY 208-243 behaves as a selective agonist of D1 receptors in vivo. In non-habituated mice, doses of metoclopramide and sulpiride which had little or no effect on motor behaviour by themselves, interacted synergistically with CY 208-243 (4 mg/kg) and SKF 38393 (30 mg/kg) to cause extended periods of immobility. Other species-typical behaviours were not affected in this way. For example, grooming was decreased by metoclopramide and increased by sulpiride, indicating that an increase in behavioural competition from this parameter was not the cause of the hypokinesia. To explain the apparent ability of D1 receptor stimulation to increase exploratory activity in earlier experiments and to decrease it here, it is proposed that this behaviour is regulated by D1 receptors coupled to two functionally opposite postsynaptic D2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Basal local cerebral glucose utilization is not altered after behavioral sensitization to quinpirole

Sensitization to psychostimulants results in a behavioral response of a greater magnitude than that produced by a given single dose. Previously, we have shown that sensitization to the D(2)/D(3) dopamine receptor agonist quinpirole produces alterations in quinpirole-stimulated local cerebral glucose utilization (LCGU) in ventral striatal and limbic cortical regions. To determine whether basal neuronal activity is altered in the sensitized animal, this study examined the effects of a sensitizing course of quinpirole on basal neuronal activity using the [(14)C]-2-deoxyglucose (2-DG) method in rats with verified sensitization. Adult, male Long-Evans rats (n = 7 or 10/group) were subjected to 10 injections of quinpirole (0.5 mg/kg, s.c.) or saline administered every 3rd day. Sensitization was verified on the basis of locomotor activity. The 2-DG procedure was performed in freely moving rats 3 days after the last quinpirole injection. LCGU was determined by quantitative autoradiography. No alterations in basal LCGU were detected in quinpirole-sensitized rats compared to those treated with saline. The present finding suggests that either the basal activity of very discrete populations of neurons is affected by sensitization to quinpirole that are not likely to be detected by the 2-DG method, or that the neurobiological changes that result in the sensitized behavioral response affect only stimulated, but not basal, neuronal activity.     

Dual effects of L-3,4-dihydroxyphenylalanine on aromatic L-amino acid decarboxylase, dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent

The comparative effects of L-3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25-200 mg/kg) dose-dependently inhibited the activity of aromatic L-amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25-50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100-200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 microM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25-100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride. These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D2 and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D1 > D2 receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.