Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.     

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.     

Interactions of dopamine D1 and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions

The effects of the dopamine D1 receptor antagonist R(+)-SCH-23390 and D2 receptor antagonist S(-)-eticlopride on d-methamphetamine-induced striatal monoamine reductions 72 h after treatment were investigated in relation to changes in body temperature. Rats were administered four 10-mg/kg doses of d-methamphetamine or saline with a 2-h interval between treatments; 0.5 mg/kg eticlopride or SCH-23390 was administered 15 min before each methamphetamine or saline injection. Two ambient temperature conditions were investigated: 24 and 33 degrees C. Methamphetamine administered at 24 degrees C induced hyperthermia and reduced striatal dopamine content by 73%; 0.5 mg/kg eticlopride or SCH-23390 administered in combination with methamphetamine at 24 degrees C attenuated methamphetamine-induced hyperthermia and prevented significant reductions in dopamine content. At 33 degrees C, eticlopride and SCH-23390 were ineffective in blocking methamphetamine-induced hyperthermia and dopamine content was reduced by 65% in the SCH-23390-methamphetamine group. By contrast, dopamine content was reduced by only 31% in the 33 degrees C eticlopride-methamphetamine group. Thus, although the eticlopride-methamphetamine treatment combination at 33 degrees C exhibited a hyperthermic response comparable to that seen with methamphetamine alone at 24 degrees C, reductions in dopamine content were attenuated in the combination group compared with methamphetamine alone at 24 degrees C. Serotonin changes showed similar attenuated reductions after SCH-23390 or eticlopride pretreatment at 24 degrees C in combination with methamphetamine, but this attenuation was absent at 33 degrees C. The dissociation of methamphetamine-induced striatal dopamine reduction and hyperthermia seen after eticlopride pretreatment suggests a dopamine D2 receptor mechanism in mediating methamphetamine-induced dopamine depletion. However this D2 mechanism does not apply to methamphetamine-induced striatal serotonin reductions.     

D1 dopamine receptor--the search for a function: a critical evaluation of the D1/D2 dopamine receptor classification and its functional implications

The present review focuses on the hypothesized D1/D2 dopamine (DA) receptor classification, originally based on the form of receptor coupling to adenylate cyclase activity. The pharmacological effects of compounds exhibiting putative selective agonist or antagonist profiles at those DA receptors positively coupled to adenylate cyclase activity (D1 DA receptors) are extensively reviewed. Comparisons are made with the effects of putative selective D2 DA receptor agonists and antagonists, and on the basis of this work, the DA receptor classification is critically evaluated. A variety of biochemical, behavioral, and electrophysiological evidence is presented which supports the view that D1 and D2 DA receptors can interact in both an opposing and synergistic fashion. Particular attention is focused on the possibility that D1 receptor stimulation is required to enable the expression of certain D2 receptor-mediated effects, and the functional consequences of this form of interaction are considered. A hypothetical model is presented which considers how both the opposing and enabling forms of interaction between D1 and D2 DA receptors can control behavioral expression. Finally, the clinical relevance of this work is discussed and the potential use of selective D1 receptor agonists and antagonists in the treatment of psychotic states and Parkinson's disease is considered.     

Relationship between D 1 dopamine receptors,adenylate cyclase,and the electrophysiological responses of rat nucleus accumbens neurons

Summary The electrophysiological effects of three selective D 1 dopamine (DA) receptor agonists, which exhibit different potencies and efficacies for stimulation of adenylate cyclase, were compared in the rat nucleus accumbens (NAc) using single unit recording and microiontophoretic techniques. The partial agonists SKF 75670 and SKF 38393, and the full agonist SKF 81297 produced nearly identical current-response curves for the inhibition of firing of NAc neurons. In rats acutely depleted of DA by-methyl-p-tyrosine (AMPT) pretreatment, all three D 1 agonists enabled the inhibition of firing produced by the selective D 2 receptor agonist quinpirole, with SKF 38393 exerting the greatest efficacy, followed by SKF 81297 and SKF 75670. Thus, no apparent relationship was found between the previously reported ability of these compounds to stimulate cyclic adenosine monophosphate (cAMP) production and their ability either to inhibit the firing of NAc neurons or to enable quinpirole-mediated inhibition of firing in DA-depleted rats. In addition, the membrane-permeable cAMP analog 8-bromo-cAMP also caused a current-dependent inhibition of the firing of NAc neurons, but failed to enable quinpirole-mediated inhibition in AMPT-pretreated animals. These results suggest either that only a small percentage of D 1 receptors need to be stimulated to produce these electrophysiological effects, or that D 1 receptors exist within the rat NAc which are linked to transduction mechanisms other than, or in addition to, adenylate cyclase.     

Differential expression of D1 and D2 dopamine and m4 muscarinic acetylcholine receptor proteins in identified striatonigral neurons

Large families of genetically distinct G-protein coupled receptor subtypes mediate dopamine's (D1–D5) and acetylcholine's effects (m1–m5). A functional balance of dopamine and acetylcholine may be based in part on the differential expression of receptor subtypes by distinct neuron subpopulations. The localization of the D1 and D2 receptors, the predominant dopamine receptors in neostriatum, to distinct subpopulations of striatal projection neurons has been controversial. In addition, m4 receptor localization to specific striatal projection neuron subpopulations is also at question. To determine whether rat striatonigral neurons differentially express D1, D2, and m4 receptor proteins, we combined immunocytochemistry by using receptor subtype specific antibodies and retrograde tracing with cholera toxin-colloidal gold. D1 and m4 receptor immunoreactivity was visualized in 95% and 92% of identified striatonigral neurons, respectively. By contrast, D2 receptor immunoreactivity was visualized in only 1% of these neurons. These findings support models of basal ganglia in which D1 and D2 receptors are segregated, as well as indicate that D1 and m4 are colocalized. These cellular distributions may be important substrates for the putative DA/ACh balance that is implicated in certain movement disorders. Synapse 27:357–366, 1997. © 1997 Wiley-Liss, Inc.     

Dopamine displays an identical apparent affinity towards functional dopamine D1 and D2 receptors in rat striatal slices: Possible implications for the regulatory role of D2 receptors

In this study we examined the selectivity of dopamine (DA) for rat striatal DA D₁ and D₂ receptors. In a Krebs-HEPES buffer, the K_i values of DA for D₁ binding sites (labelled with [³H]SCH23390) and D₂ binding sites (labelled with [³H]spiroperidol) in striatal membranes amounted to about 30 and.0.3 μM, respectively. However, the EC50s of DA (3 μM) and the DA releasing drug amphetamine (1 μM) were identical considering D₁ receptor-stimulated and D₂ receptor-inhibited adenylate cyclase activity in superfused striatal slices. Moreover, these EC₅₀ values were also obtained studying DA- and amphetamine-induced D₂ receptor activation, resulting in inhibition of the electrically evoked release of [¹⁴C]acetylcholine from the slices. Therefore, with regard to the apparent affinity of exogenous and endogenous DA for D₁ and D₂ receptors in rat striatal slices, the ligand-receptor binding data appeared to be misleading. Thus, our data show that in rat striatal slices DA has an identical apparent affinity towards functional D₁ and D₂ receptors, which is particularly intriguing in view of the very high receptor selectivity of synthetic D₁ and D₂ receptor agonists for these functional receptors in superfused brain slices as predicted on the basis of binding assays. This may have important implications for our understanding of central DA neurotransmission. For instance, since the inhibitory effect of opioid and muscarinic receptor activation on adenylate cyclase activity has been shown to be inversely related to the degree of DA D₂ receptor activation, the degree of activation of D₁ and D₂ receptors by released DA is suggested to act as a functional gate allowing distinct neurotransmitters to play a role in striatal neurotransmission. © 1994 Wiley-Liss, Inc.     

Selective induction of Fos and FRA immunoreactivity within the mesolimbic and mesostriatal dopamine terminal fields

The influence of the mesencephalic dopaminergic projections on the neurons within the basal forebrain and prefrontal cortex is not well understood although it has been intensely investigated. The purpose of this study was to evaluate the expression of Fos-like and FRA-like (Fos Related Antigens) immunoreactivity (IR) as a qualitative and quantitative marker of neuronal activity within the mesolimbic and mesostriatal dopamine terminal fields. Following the administration of apomorphine (5.0 mg/kg S.C.), a rapid increase in FRA-IR, accompanied by Fos-IR, was observed within the striatum in a patchy distribution. Apomorphine also induced the expression of FRA-IR within the nucleus accumbens, cortex, septum, and the islands of Calleja complex. This broad pattern of activation contrasts with the limited expression of Fos-IR and FRA-IR within the dorsolateral striatum, dorsomedial shell of the nucleus accumbens, and cingulate cortex following haloperidol administration (2.0 mg/kg, S.C.). Finally, it was observed that nuclei expressed Fos-IR rapidly and transiently within the striatum following haloperidol, whereas the number of FRA-IR nuclei remained elevated but changed in distribution and intensity over time. In conclusion, different regions within the dopamine terminal fields express varying concentrations of Fos-IR and FRA-IR after stimulation or blockade of dopamine receptors. These data indicate that Fos, as well as selective FRAs, can be used to delineate populations of neurons with altered metabolic activity resulting from the administration of dopaminergic agents. Furthermore, the data support the concept of segregated mesostriatal and mesolimbic projections, in particular the divison of the nucleus accumbens into the shell and core compartments. © 1993 Wiley-Liss, Inc.     

Chronic administration of morphine is associated with a decrease in surface AMPA GluR1 receptor subunit in dopamine D1 receptor expressing neurons in the shell and non-D1 receptor expressing neurons in the core of the rat nucleus accumbens

The nucleus accumbens (Acb) is an extensively studied neuroanatomical substrate of opiate reward and the neural plasticity associated with chronic opioid use. The cellular mechanisms mediating opioid-dependent plasticity are uncertain, however AMPA-type glutamate receptor trafficking in dopamine D1 dopamine receptor (D1R) expressing neurons may be a potential cellular pathway for these adaptations, although there is no evidence for this possibility. Immunogold electron microscopy was used to quantify the surface expression of the AMPA GluR1 subunit in dendritic profiles of neurons in the Acb in response to intermittent 14-day non-contingent injections of escalating doses of morphine, a model that parallels opioid self-administration. To determine if changes in GluR1 trafficking occurred in neurons potentially sensitive to dopamine-induced D1R activation, immunoperoxidase labeling of D1R was combined with immunogold labeling of GluR1. Immunogold quantification was performed in two distinct Acb subregions, the shell, an area involved in processing incentive salience related to rewarding stimuli, and the core, an area involved in reward-seeking behaviors. We provide the first report that chronic morphine administration is associated with a receptor-phenotypic decrease in surface trafficking of GluR1 in Acb subregions. When compared to saline injected animals, morphine produced a decrease in plasma membrane GluR1 labeling in medium- and large-sized D1R expressing dendritic profiles in the Acb shell. In contrast, in the Acb core, surface GluR1 was decreased in small-sized dendrites that did not express the dopamine receptor. These results indicate that chronic intermittent injection of escalating doses of morphine is accompanied by ultrastructural plasticity of GluR1 in neurons that are responsive to glutamate and dopamine-induced D1R activation in the Acb shell, and neurons capable of responding to glutamate but not D1R receptor stimulation in the Acb core. Thus, AMPA receptor trafficking associated with chronic opiate exposure in functionally distinct areas of the Acb may be distinguished by D1R receptor activation, suggesting the potential for differing neural substrates of reward and motor aspects of addictive processes involving glutamate and dopamine signaling.     

Changes in dopamine and DOPAC following systemic administration of apomorphine and 3,4-dihydroxyphenylamino-2-imidazoline (DPI) in rats

Rats were injected systemically with either saline, apomorphine, or one of four doses of DPI (3,4-dihydroxyphenylamino-2-imidazoline) and the levels of dopamine and DOPAC determined in the nucleus accumbens and the caudate regions. DPI reduced dopamine and DOPAC levels in the nucleus accumbens, while apomorphine did not. On the other hand, apomorphine reduced the levels of dopamine and DOPAC in the caudate but not the nucleus accumbens. DPI largely was without effect in the caudate. The results are discussed in terms of possible specificity of the two dopamine agonists in the two forebrain regions.     

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.     

Glycine site antagonists abolish dopamine D 2 but not D 1 receptor mediated catalepsy in rats

Summary Catalepsy—a state of postural immobility (akinesia) with muscular rigidity (rigor)—and reduced locomotion in animals are behavioral deficits showing similarities with symptoms of Parkinson's disease (PD). The effects of the glycine site antagonists 7-chlorokynurenate and (R)-HA-966 on haloperidol-(D2 antagonist) and SCH 23390-(D 1 antagonist) induced catalepsy and reduced locomotion are investigated in rats. Both antagonists dose-dependently counteract dopamine D 2 receptor mediated catalepsy but they have no influence on locomotion. Neither 7-chlorokynurenate nor (R)-HA-966 has any effect on dopamine D 1 receptor mediated catalepsy.This finding is surprising, since NMDA receptor antagonists counteract both, dopamine D 1 and D 2 receptor mediated catalepsy. D 1 and D 2 receptors are located on different populations of neurons. Thus, the present findings suggest that these different neuronal populations have different sensitivity for ligands binding at the glycine binding site of the NMDA receptor.     

Regulation of dopamine release and metabolism in rat striatum in vivo: Effects of dopamine receptor antagonists

1. 1. The acute effects of some of typical and atypical antipsychotic drugs on the dopamine release and metabolism in the dorsal striatum of freely moving rats were studied using transcerebral microdialysis technique.

2. 2. Classical neuroleptic drugs haloperidol (0.05, 0.1 and 0.2 mg/kg), thioproperazine (0.1, 0.2 and 0.4 mg/kg) and spiperone (0.02, 0.04 and 0.07 mg/kg) administered i.p. induced pronounced elevation of extracellular level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) up to 250–300 % to basal level while producing less increase in that of dopamine (DA) (up to 150–170 %).

3. 3. Atypical neuroleptics clozapine and thioridazine (both 2, 5 and 20 mg/kg) increased striatal DA release and DOPAC level approximately at the same degree (maximally up to 200% and 160%, respectively).

4. 4. Dopamine D3 receptor and autoreceptor preferring antagonists (+)-UH232 and (+)-AJ76 (both 4, 7 and 14 mg/kg) more potently increased DA release in comparison with DOPAC dialysate level ( (+)-AJ76 elevated DA level maximally up to 330 %, DOPAC - up to 250 %).

5. 5. The features of typical and atypical neuroleptics in preferential action on DA release or DOPAC output were observed in all doses of the drugs studied .

6. 6. The ability of the drugs to affect preferentially DA release or DOPAC extracellular level in rat striatum correlates to their relative affinities at D3 and D2 DA receptors.

7. 7. It is concluded that typical and atypical antipsychotic drugs might be clearly distinguished on the basis of their ability to affect preferentially DA synthesis/metabolism or release in rat dorsal striatum in vivo.

     

Inputs from the basolateral amygdala to the nucleus accumbens shell control opiate reward magnitude via differential dopamine D1 or D2 receptor transmission

The basolateral amygdala (BLA), ventral tegmental area and nucleus accumbens (NAc) form a functionally connected neural circuit involved in the processing of opiate-related reward and memory. Dopamine (DA) projections from the ventral tegmental area to the BLA modulate associative plasticity mechanisms within the BLA. However, the role of DA receptor signaling in the BLA and its functional outputs to the NAc during opiate reward processing is not currently understood. Using an unbiased place conditioning procedure, we measured the rewarding effects of morphine following intra-BLA microinfusions of specific DA D1 or D2 receptor agonists in either opiate-naive or opiate-dependent/withdrawn rats. Activation of intra-BLA D1 receptors strongly potentiated the behaviorally rewarding effects of opiates, only in the opiate-naive state. However, once opiate dependence and withdrawal occurred, the intra-BLA DA-mediated potentiation of opiate reward salience switched to a D2 receptor-dependent substrate. We next performed single-unit, in-vivo extracellular neuronal recordings in the NAc shell (NA shell), to determine if intra-BLA D1/D2 receptor activation may modulate the NA shell neuronal response patterns to morphine. Consistent with our behavioral results, intra-BLA D1 or D2 receptor activation potentiated NAc 'shell' (NA shell) neuronal responses to sub-reward threshold opiate administration, following the same functional boundary between the opiate-naive and opiate-dependent/withdrawn states. Finally, blockade of N-methyl-d-aspartate transmission within the NA shell blocked intra-BLA DA D1 or D2 receptor-mediated opiate reward potentiation. Our findings demonstrate a novel and functional DA D1/D2 receptor-mediated opiate reward memory switch within the BLA→NA shell circuit that controls opiate reward magnitude as a function of opiate exposure state.