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.     

Bromocriptine-induced locomotor stimulation in mice is modulated by dopamine D-1 receptors

Summary Mice were pretreated with reserpine plus-methyl-p-tyrosine (10 mg/ kg plus 200 mg/kg). One hour later they were administered the selective dopamine D-2 agonist bromocriptine or vehicle. Three hours after the bromocriptine, mice were challenged with the selective D-1 agonist SKF 38393, and locomotor activity was measured each 5 min for three hours. Neither bromocriptine nor SKF 38393 produced significant stimulation. The combination, however, produced a dose-dependent and coordinated increase in activity. If the bromocriptine was given only one hour before the SKF 38393 challenge (i.e., three hours after the reserpine plus-methyl-p-tyrosine), no interaction was seen. In naive mice, when SKF 38393 and bromocriptine were administered together, the locomotor response to bromocriptine was quantitatively and qualitatively altered. The initial depressant response to bromocriptine was shortened, producing a more rapid onset of the stimulant response. In one experiment, the maximal activity induced by bromocriptine was increased by SKF 38393. The ability of SKF 38393 to alter the locomotor stimulant effect of bromocriptine in naive mice was blocked by their pretreatment with the selective D-1 antagonist, SCH 23390. The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors.     

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.     

Electrophysiological verification of the presence of D1 and D2 dopamine receptors within the ventral pallidum

The ventral pallidum is a basal forebrain region recently shown to receive dopaminergic projections from the midbrain. Binding sites for the D1 and D2 dopamine receptor families have been identified within the ventral pallidum, yet the consequences of activating these receptors have not been studied. Thus, to characterize the physiological pharmacology of D1 and D2 receptor subtypes for the ventral pallidum, extracellular single-neuron recording and microiontophoretic techniques were used in chloral hydrate-anesthetized rats. Half of the 93 ventral pallidal neurons tested were sensitive to iontophoresis of dopamine (DA), and both rate increases and decreases were observed. Co-iontophoresis of either the D1 antagonist SCH23390, or the D2 antagonist sulpiride, generally attenuated the DA-induced rate changes. Like DA, about half of the ventral pallidal neurons tested were sensitive to the D1 agonist, SKF38393. Yet in contrast to DA, rate suppression was observed almost exclusively, and the magnitude of this decrease was greater than that produced by DA. SKF38393-induced suppressions were antagonized by SCH23390, but not by sulpiride, demonstrating the specificity of the D1 agonist. Most of the neurons tested were not affected by quinpirole, but when responsive to the D2 agonist, rate increases were observed most often. The increases were antagonized by the D2 antagonist sulpiride, but not SCH23390, demonstrating that this response resulted from an activation of D2 receptors. These results support binding studies demonstrating that both D1 and D2 receptors are present in the ventral pallidum, and reveal that the independent activation of each of these is sufficient to alter neuronal activity. © 1994 Wiley-Liss. Inc.     

Attenuation of the locomotor-sensitizing effects of the D2 dopamine agonist bromocriptine by either the D1 antagonist SCH 23390 or the D2 antagonist raclopride

Injections of the selective D₂ dopamine agonist bromocriptine (5.0 mg/kg, IP) produced progressively stronger locomotion over 10 days of repeated testing. Concurrent treatment with either the D₁ antagonist SCH 23390 (0.01 or 0.1 mg/kg, IP) or the D₂ antagonist raclopride (0.1 or 1.0 mg/kg, IP) suppressed bromocriptine-induced locomotion on treatment days and attenuated or blocked the progressive increases in locomotion that accompanied repeated injections of bromocriptine alone. The fact that D₁ and D₂ antagonists each block the acute actions of bromocriptine and attenuate the development of bromocriptine sensitization is suggested to imply a striatal rather than a ventral tegmental mechanism for the sensitization produced by repeated treatments with direct dopamine agonists. © 1994 Wiley-Liss, Inc.     

Blockade of globus pallidus adenosine A(2A) receptors displays antiparkinsonian activity in 6-hydroxydopamine-lesioned rats treated with D(1) or D(2) dopamine receptor agonists

We have recently demonstrated how antagonism of adenosine A(2A) receptors within the globus pallidus (GP) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor L-DOPA in 6-hydroxydopamine-lesioned hemiparkinsonian rats. To further characterize the influence of pallidal A(2A) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation, hemiparkinsonian rats were infused with the water-soluble A(2A) antagonist SCH BT2 in the GP, alone or in combination with systemic administration of either SKF 38393 or quinpirole, to stimulate dopamine D(1) or D(2) receptors, respectively. SCH BT2 alone (5 mug/1 mul) neither altered motor behavior nor produced postural asymmetry. In contrast, the contralateral rotations elicited by SKF 38393 (1.5 mg/kg) as well as quinpirole (0.05 mg/kg) were potentiated by the concomitant intrapallidal infusion of SCH BT2. The results of this study demonstrate that blockade of pallidal A(2A) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D(1) or D(2) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A(2A) receptor antagonists.     

Synergistic effects of D1 and D2 dopamine agonists on turning behaviour in rats

In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, a specific D1 dopamine receptor agonist, SKF 38393A, at a dose that does not itself produce turning, significantly increased the contralateral rotation observed following a low dose of the specific D2 agonist LY 171555. Doses of SKF 38393A or the D2 agonist bromocriptine, which would themselves not induce turning, in combination produced a high rate of turning. These results suggest a synergistic interaction between D1 and D2 dopamine receptors in this system.     

SKF 38393 alters the rate-dependent D2-mediated inhibition of nigrostriatal but not mesoaccumbens dopamine neurons

Previous electrophysiological studies have failed to identify significant effects of the D1 dopamine (DA) agonist SKF 38393, either alone or in combination with the D2 agonist quinpirole (LY 171555), on the spontaneous firing rate of midbrain DA neurons. We have utilized extracellular single-unit recording techniques to examine whether SKF 38393 can alter D2-mediated inhibition of DA cell activity. Quinpirole-induced inhibition of the spontaneous activity of midbrain DA neurons was observed to be positively correlated with the basal firing rate of the neuron being examined (i.e., faster cells required higher doses to achieve 50% and maximal inhibition). Pretreatment with SKF 38393 (1.0 mg/kg, i.v.; 4 minutes) eliminated the rate dependency of quinpirole-induced inhibition of nigrostriatal but not mesoaccumbens DA neurons. This effect of SKF 38393 was blocked both by the D1 antagonist SCH 23390 and by hemitransections of the forebrain. In summary, SKF 38393 appears to exert Dl-specific, feedback pathway-dependent effects on the profile of responsiveness of nigrostriatal DA neurons to D2-mediated inhibition of cell firing rate.     

Locomotor behavior of dopamine D1 receptor transgenic/D2 receptor deficient hybrid mice

Mice that incorporate the dopamine D1 receptor transgene controlled by the D1 receptor promoter exhibit a marked increase of D1 binding in several extra-striatal brain regions and show a paradoxical hypokinetic response to D1 agonist [Exp. Neurol. 157 (1999) 169]. The agonist-induced locomotor behavior of D1 receptor transgenic mice is similar to baseline locomotor activity manifested by D2 receptor deficient mice [J. Neurosci. 18 (1998) 3470]. The similarity between these two behavioral phenotypes raised the possibility that stimulation of the over-expressed D1 receptors in the transgenic mice could cause a suppression of D2 receptor responses that manifest in hypokinesia. Alternatively, the similar phenotypes could result from altered D1/D2 receptor balance in both animal models. Two different approaches were undertaken to test these alternative hypotheses. (1) The effects of pharmacological blockade of D2 receptors on D1 agonist-stimulated hypokinesia of the D1 over-expressing animals were investigated. (2) The behavioral phenotype of hybrid D1 receptor over-expressing/D2 receptor deficient mice generated by crossbreeding the D2 knockout mice and the D1 transgenic animals was studied. The results of these studies suggested that the hypomotor response of the D1 transgenic mice was not a result of an interaction of the over-expressed D1 receptors with the native D2 receptors and that over-expressed D1 receptors likely mediate hypokinesia in the D1 transgenic animals. Considering the significance of the D1 dopamine receptor as a therapeutic target for Parkinson's disease, this D1 receptor over-expressing model provides an important experimental system to probe the basis for altered behavioral responses following stimulation of transgenetically up-regulated receptors.     

Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum

Summary. The aim of this study was to compare dopamine receptor binding affinities of all currently approved dopamine receptor agonist treatments for Parkinsons disease (PD) in human brain tissue. -Dihydroergocryptine and lisuride displayed higher comparative affinities (K_i=35.4 and 56.7nM, respectively) for D₁ receptors, than the D₁/D₂ dopamine agonist pergolide (K_i=447nM). The second generation non-ergot dopamine receptors agonists pramipexole and ropinirole demonstrated no affinity for D₁ receptors at concentrations up to 10^–4M. The ergoline dopamine agonists cabergoline and lisuride displayed the highest affinities for the D₂ receptor (K_i=0.61 and 0.95nM, respectively). Surprisingly, the second generation non-ergot dopamine receptors agonists pramipexole and ropinirole only weakly inhibited binding to D₂ receptors (K_i=79.5 and 98.7µM, respectively using [³H]spiperone). Interestingly we also found that the affinities of cabergoline (K_i=1.27nM), lisuride (K_i=1.08nM) and pergolide (K_i=0.86nM) for the D₃ receptor subtype were comparable to that of pramipexole (K_i=0.97nM). The present results thus support the hypothesis that the antiparkinsonian effect of dopamine receptor agonists is mediated by a more complex interactions with dopamine receptor subtypes than currently believed.Received January 7, 2003; accepted May 20, 2003 Published online August 13, 2003     

D1 receptor activation enhances sciatic nerve stimulation-induced inhibition of nigrostriatal dopamine neurons

Nigrostriatal dopamine (NSDA) neurons have been hypothesized to play an important regulatory role in neostriatal sensorimotor integration. In order to provide further information on the nature of sensory modulation of NSDA cells, we have examined the pharmacology of the responsiveness of these neurons to peripheral nerve stimulation. The selective D1 dopamine receptor agonist SKF 38393 enhanced the normal inhibition of NSDA neurons produced by electrical stimulation of the sciatic nerve. The SKF 38393-induced enhancement, but not the basal stimulation-induced inhibition itself, was blocked by prior hemitransection of the forebrain and was reversed by the selective D1 antagonist SCH 23390 but not by the selective D2 antagonist 1-sulpiride. SCH 23390 alone, however, exerted no effect on this inhibition. The selective D1 receptor agonist fenoldopam, which does not cross the blood-brain barrier, also failed to alter the response to sciatic nerve stimulation (i.v. administration). Thus, central D1 receptors (rostral to the midbrain) appear to be involved in a system which mediates phasic control over sensory modulation of NSDA neuronal activity.     

Dopamine D2(High) receptors moderately elevated by bifeprunox and aripiprazole

Because long-term antipsychotics elicit behavioral dopamine supersensitivity, the present study examined whether 7-9 days administration of partial dopamine D2 agonists with antipsychotic activity, bifeprunox and aripiprazole, could induce biochemical changes that suggest dopamine supersensitivity. In rats, behavioral dopamine supersensitivity is associated with increased dopamine D2(High) receptors in homogenized striata. In control rat striata, bifeprunox and aripiprazole had similar K(i) values at D2 receptors. In human cloned D2Long receptors, however, aripiprazole had a K(i) of 9.6 nM and recognized 41% of the D2 receptors to be in the D2(High) state, while the values for bifeprunox were 1.3 nM and 69%, indicating that bifeprunox had higher potency and efficacy at D2. Nine days of subcutaneously injected bifeprunox (0.25 mg/kg/day) and 7 days of aripiprazole (1.5 mg/kg) increased D2(High) receptors by 102-129% and 108-188%, respectively, although the total population of D2 receptors revealed no significant changes. The increase in D2(high) receptors induced by dopamine D2 partial agonists appear to be of smaller magnitude than those seen previously with D2 antagonist antipsychotics. Future research needs to test directly whether long-term treatment with dopamine partial agonists leads to any behavioral dopamine supersensitivity.     

Dopamine D2(High) receptors moderately elevated by sertindole

Because long-term administration of antipsychotics can cause behavioral dopamine supersensitivity, this study examined whether the antipsychotic sertindole could elicit biochemical changes indicative of dopamine supersensitivity. In rats, behavioral dopamine supersensitivity is consistently associated with an increased proportion of dopamine receptors that have high affinity for dopamine, namely D2(High), in homogenized striata. Nine days of subcutaneously injected sertindole (1.25 mg/kg/day) increased the proportion of D2(High) receptors between 186% and 215%, although the total population of D2 receptors did not change. Although the findings suggest that rats or patients treated with sertindole might exhibit behavioral dopamine supersensitivity, the drug-induced increase in D2(High) receptors was less than that previously found with haloperidol.     

Increased affinity of dopamine for D(2) -like versus D(1) -like receptors. Relevance for volume transmission in interpreting PET findings

Evidence indicates that dopamine (DA) mainly acts as a volume transmission (VT) transmitter through its release into the extracellular fluid where the D(1) -like and D(2) -like receptors are predominantly extrasynaptic. It was therefore of interest to compare the affinities of the two major families of DA receptors. [(3)H] raclopride /DA and [(3)H] SCH23390/DA competition assays compared the affinity of DA at D(2) -like and D(1) -like receptors in rat dorsal striatal membrane preparations as well as in membrane preparations from CHO cell lines stably transfected with human D(2L) and D(1) receptors. The IC(50) values of DA at D(2) -like receptors in dorsal striatal membranes and CHO cell membranes were markedly and significantly reduced compared with the IC(50) values of DA at D(1) -like receptors. These IC(50) values reflect differences in both the high and low affinity states. The K(iH) value for DA at [(3)H] raclopride-labeled D(2) -like receptors in dorsal striatum was 12 nM, and this can help explain PET findings that amphetamine-induced increases in DA release can produce an up to 50% decrease of [(11)C] raclopride binding in the dorsal striatum in vivo. These combined results give indications for the existence of striatal D(2) -like receptor-mediated DA VT at the local circuit level in vivo. The demonstration of a K(iH) value of 183 nM for DA at D(1) antagonist-labeled D(1) -like receptors instead gives a likely explanation for the failure of a reduction of D(1) -like receptor binding after amphetamine-induced DA release in PET studies using the D(1) -like antagonist radioligands [(11)C] SCH23390 and [(11)C] NNC. It seems difficult to evaluate the role of the extrasynaptic D(1) receptors in VT in vivo with the PET radioligands available for this receptor.     

Differential distributions and trafficking properties of dopamine D1 and D5 receptors in nerve cells

Objective

To explore the possible differential trafficking properties of the dopamine D1-like receptor subtypes, D1 receptor and D5 receptor.

Methods

To visualize distributions of dopamine D1-like receptor subtypes at subcellular level, the yellow and cyan variants of green fluorescent protein (GFP) were used to tag D1 and D5 receptors. After transfection with the tagged dopamine receptors, the neuroblastoma cells NG108-15 were treated with D1 agonist SKF38393 or acetylcholine (ACh). Then we observed the subcellular distributions of the tagged receptors under the confocal microscopy and tried to determine trafficking properties by comparing their distribution patterns before and after the drug treatment.

Results

In resting conditions, D1 receptors located in the plasma membrane of NG108-15 cells, while D5 receptors located in both plasma membrane and cytosol. With the pre-treatment of SKF38393, the subcellular distribution of D1 receptors was changed. The yellow particle-like fluorescence of tagged D1 receptors appeared in the cytosol, indicating that D1 receptors were internalized into cytosol from the cell surface. Same situation also occurred in ACh pre-treatment. In contrast, the subcellular distribution of D5 receptors was not changed after SKF38393 or ACh treatment, indicating that D5R was not translocated to cell surface. Interestingly, when D1 and D5 receptors were co-expressed in the same cell, both kept their distinct subcellular distribution patterns and the trafficking properties.

Conclusion

Our present study reveals that in NG108-15 nerve cells, dopamine D1 and D5 receptors exhibit differential subcellular distribution patterns, and only D1 receptor has a marked trafficking response to the drug stimulation. We further discuss the potential role of the differential trafficking properties of D1-like receptors in complex modulation of DA signaling.     

Dopamine D1 receptor activity modulates object recognition memory consolidation in the perirhinal cortex but not in the hippocampus

It has been proposed that distributed neuronal networks in the medial temporal lobe process different characteristics of a recognition event; the hippocampus has been associated with contextual recollection while the perirhinal cortex has been linked with familiarity. Here we show that D1 dopamine receptor activity in these two structures participates differentially in object recognition memory consolidation. The D1 receptor antagonist SCH23390 was infused bilaterally 15 min before a 5 min sample phase in either rats' perirhinal cortex or dorsal hippocampus, and they were tested 90 min for short‐term memory or 24 h later for long‐term memory. SCH23390 impaired long‐term memory when infused in the perirhinal cortex but not when infused in the hippocampus. Conversely, when the D1 receptor agonist SKF38393 was infused 10 min before a 3 min sample phase in the perirhinal cortex, long‐term memory was enhanced, however, this was not observed when the D1 agonist was infused in the hippocampus. Short‐term memory was spared when SCH23390 or SKF38393 were infused in the perirhinal cortex or the dorsal hippocampus suggesting that acquisition was unaffected. These results suggest that dopaminergic transmission in these medial temporal lobe structures have a differential involvement in object recognition memory consolidation. © 2013 Wiley Periodicals, Inc.     

Nigrostriatal lesion alters neurophysiological responses to selective and nonselective D-1 and D-2 dopamine agonists in rat globus pallidus

The effects of the selective D-1 dopamine agonist SKF 38393, the selective D-2 agonist quinpirole, and the nonselective D-1/D-2 agonist apomorphine on spontaneous activity of globus pallidus neurons were compared in normal control rats and rats with unilateral 6-hydroxydopamine induced lesions of the nigrostriatal pathway. In control, unlesioned rats, SKF 38393 (0.4 and 10 mg/kg, i.v.) caused no significant net change in the activity of globus pallidus neurons, although some individual cells showed significant increases or decreases in discharge rates following 10 mg/kg SKF 38393 administration. In animals with unilateral 6-hydroxydopamine induced lesions, SKF 38393 caused greater increases and decreases in the discharge rates of a larger percentage of pallidal cells recorded on the ipsilateral side than in control, unlesioned animals. These rate changes were effectively reversed by the D-1 antagonist SCH 23390, but not by the D-2 antagonist YM-09151-2. Quinpirole (0.3 mg/kg, i.v.) produced modest rate increases in control, unlesioned animals and significantly larger rate increases in nigrostriatal lesioned animals. YM-09151-2, but not SCH 23390, effectively reversed quinpirole's effects in the lesioned animals. As previously reported, the nonselective D-1/D-2 agonist apomorphine (0.3 mg/kg, i.v.) produced large increases in discharge rates of pallidal cells in control, unlesioned rats. In contrast, in nigrostriatal lesioned rats, the discharge rates of some ipsilateral pallidal neurons were markedly increased, others were decreased, and some were unaffected following apomorphine administration. The dopamine antagonist spiroperidol partially to fully reversed these rate changes. In summary, apomorphine's neurophysiological profile appears to be an exaggeration of the D-1 agonist profile in the globus pallidus of these lesioned animals. The degree of change observed after apomorphine administration is consistent with results from other studies that have indicated that a synergistic interaction between effects triggered by stimulation of the two receptor subtypes can occur in these animals, as in control, unlesioned animals. However, these results further show that in rats with unilateral nigrostriatal lesions, the denervated dopamine receptors or the processes they mediate are altered so that they no longer have the requirement seen in controls for concurrent stimulation of the complementary dopamine receptor subtype for expression of the selective agonist effects.     

Loss of D1/D2 dopamine receptor synergisms following repeated administration of D1 or D2 receptor selective antagonists: Electrophysiological and behavioral studies

Many effects resulting from D₂ dopamine (DA) receptor stimulation are manifest only when D₁ DA receptors are stimulated by endogenous DA. When D₁ receptor stimulation is enhanced by administration of selective D₁ receptor agonists, the functional effects of selective D₂ agonists are markedly increased. These qualitative and quantitative forms of D₁/D₂ DA receptor synergism are abolished by chronic DA depletion when both D₁ and D₂ DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D₁ and D₂ renaptnr supersensitivity, induced by repeated administration of selective D₁ or D₂ receptor antagonists, on the synergistic relationships between D₁ and D₂ receptors. Daily administration of the selective D₂ antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate-putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D₂ agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D₁ agonist SKF 38393 to potentiate quinpirole-induced inhibition, and relieved D₂ receptors from the necessity of D₁ receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (sterotypy) effects of quinpirole in eticlopride-pretreated, but not saline-pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D₁ receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole-induced inhibition and the necessity of D₁ receptor stimulation for such inhibition. However, both quinpirole-induced inhibition of striatal cells and stereotyped responses were also somewhat enhanced in SCH 23390-pretreated rats. When such Dl-sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline-pretreated rats with acute DA depletion and SCH 23390-pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D₁-sensitized rats are due to a heterologous sensitization of D₂ receptors rather than to enhanced enabling resulting from supersensitive D₁ receptors. It is suggested that supersensitivity of either D₁ or D₂ receptors can lead to an uncoupling of normal qualitative and quantitative D₁/D₂ synergisms and that the heterologous regulation of D₂ receptor sensitivity by D₁ receptors may be related to uncoupling of functional D₁/D₂ synergisms.     

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.     

烟碱上调大鼠脑纹状体多巴胺D1受体mRNA表达诱导其行为改变

目的　 通过观察烟碱对大鼠脑纹状体D1,D2 受体mRNA表达的影响 ,研究烟碱诱导大鼠行为改变的可能机制 ,以进一步探讨烟碱对帕金森病具有保护效应的作用机理。 方法 SD大鼠 2 4只 ,随机分为生理盐水组(12只 )、烟碱组 (12只 )。分别给予生理盐水、烟碱 4mg/kg·d,2次 /d ,共 14d。每次注射药物后 0 .5h观察大鼠行为活动 ,并于末次注射药物后 0 .5h处死动物 ,快速分离纹状体 ,采用RT PCR方法检测大鼠纹状体D1,D2 受体mRNA的表达。结果 烟碱组大鼠于用药后第 3天 ,出现走动增多 ,易激惹 ,定型活动明显 ,并于第 714天达到高峰。在大鼠纹状体内 ,烟碱组D1受体mRNA表达比对照组上升 2 3% (分别为 98.6 3± 1.13,6 5 .2 9± 1.4 5 ,P <0 .0 1) ,两组D2 受体mRNA的表达无显著性差异 (P >0 .0 1)。 结论 烟碱可能通过上调大鼠纹状体D1受体mRNA的表达而诱导大鼠理毛、张口等行为改变 ;烟碱可能有部分D1受体激动样作用。