Selective D2 Agonist Research Articles

Dopamine D1/5 and D2/3 agonists differentially attenuate somatic signs of nicotine withdrawal in rats

Abrupt tobacco/nicotine cessation after chronic use causes various withdrawal symptoms/signs. There is evidence that dysfunction of brain dopaminergic system might be responsible for some nicotine withdrawal symptoms. The hypothesis for the present study was that different dopaminergic agonists would relieve different nicotine withdrawal signs. Adult male Sprague–Dawley rats were used. (−)-Nicotine bitartrate (9mg/kg/day, salt content) or equimolar sodium tartrate was infused into each rat via a subcutaneous (s.c.) osmotic minipump for 7days. To assess nicotine withdrawal signs, several somatic abstinence signs including teeth-chattering/chews, stretches/gasps, ptosis, shakes, and yawns were counted one day after removal of pumps. These signs were attenuated by the s.c. injection of 0.4mg/kg nicotine bitartrate. Both a dopamine D1/5 agonist (SKF81297) and a D2/3 agonist (pramipexole) relieved abstinence signs dose-dependently but differentially. SKF81297 (0.32mg/kg, s.c.) reduced teeth-chattering/chews but not shakes. Pramipexole (1mg/kg, s.c.) decreased both teeth-chattering/chews and shakes. A low dose of pramipexole (0.1mg/kg, s.c.) significantly increased yawns, consistent with previous studies that the stimulation of D3 receptors induces yawning. These results indicate that a D2-selective agonist should be considered a candidate to relieve nicotine withdrawal symptoms.

Pergolide elevation of MHPG sulphate concentration in rat hypothalamus blocked by spiperone and mimicked by other dopamine agonists

Pergolide increased the concentration of MHPG sulphate (3-methoxy-4-hydroxy-phenylethylene glycol sulphate) in rat hypothalamus, and the increase was prevented by pretreatment with spiperone, a dopamine antagonist. An increase in hypothalamic MHPG sulphate concentration similar to that caused by pergolide was found after injection of quinpirole, a 'partial ergoline' that is a selective D2 agonist not affecting alpha-adrenoceptors, and by (-)-N-propylnorapomorphine, a dopamine agonist not related to the ergolines. Although the increase in MHPG sulphate concentration produced by pergolide had earlier been assumed to result from blockage of alpha-adrenoceptors, the present data indicate that it is an effect produced by dopamine D2 receptor stimulation.

Non-dopaminergic actions of quinpirole hydrochloride (LY 171555), a selective D2-agonist, in the guinea-pig isolated ileum.

Non-dopaminergic actions of quinpirole hydrochloride (LY 171555), a selective D2-agonist, in the guinea-pig isolated ileum.

Chronic electroconvulsive shock alters hypothermic response of B-HT 920 and SKF 38393 in rats

The hypothermic response of B-HT 920, a D2-dopamine agonist remained unaltered while that of apomorphine, a mixed D1-/D2-agonist was significantly reduced following chronic electro-convulsive shock (ECS) treatment. SKF 38393 (5 mg kg-1), a selective D1-agonist potentiated the hypothermic response of B-HT 920 in non-ECS-treated rats. The response of the combination was, however, attenuated following chronic ECS treatment. These observations suggested a reduction in D1-receptor density following chronic ECS treatment in rats.

Proteomic Analysis of Changes Mediating Tolerance to Dopamine D1 Agonists: Implications for Parkinson's Disease (PD)

Full dopamine D1 agonists have antiparkinson effects that equal or exceed those of L‐DOPA in PD. No full D1 agonists are currently approved for PD, in part because some prior drugs caused rapid tolerance. Previously, we have shown that tolerance requires constant D1 receptor occupation for >22 h regardless of which D1 agonist was administered. For experimental reasons, the present study focused on the long‐acting drug A77636. We used 2‐DIGE and MS/MS to study the striatal synaptoproteome of three groups of male Sprague‐Dawley rats: 1) control: saline (0 h) + saline (24 h); 2) naïve: saline (0 h) + A77636 (1 mg/kg, 24 h); and 3) tolerant: A77636 (0 hr) + A77636 (24 h). Rats were euthanized 2 h after the last injection. Among other changes, we found a switch from Gαolf‐coupling (predominant in naïve rats) to GαS‐coupling after tolerance. These proteomic results are critical to elucidating the functional changes that mediate tolerance to full D1 agonists and could assist in the development of functionally selective D1 agonists that do not cause tolerance. In addition, these data may be critical in predicting the consequences of using D1 agonists constantly to improve function mediated by the prefrontal cortex and/or hippocampus.

In Vivo Chronic Intermittent Ethanol Exposure Reverses the Polarity of Synaptic Plasticity in the Nucleus Accumbens Shell

Glutamatergic synaptic plasticity in the nucleus accumbens (NAc) is implicated in response to sensitization to psychomotor-stimulating agents, yet ethanol effects here are undefined. We studied the acute in vitro and in vivo effects of ethanol in medium spiny neurons from the shell NAc subregion of slices of C57BL/6 mice by using whole-cell voltage-clamp recordings of α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) excitatory postsynaptic current (EPSCs). Synaptic conditioning (low-frequency stimulation with concurrent postsynaptic depolarization) reliably depressed AMPA EPSCs by nearly 30%; this accumbal long-term depression (LTD) was blocked by a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist (DL-2-amino-5-phosphonovaleric acid) and a selective NMDA receptor 2B antagonist [R-(R*,S*)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol]. Acute ethanol exposure inhibited the depression of AMPA EPSCs differentially with increasing concentrations, but this inhibitory action of ethanol was occluded by a D1-selective dopamine receptor agonist. Ethanol dependence was elicited in C57BL/6 mice by two separate 4-day bouts of chronic intermittent ethanol (CIE) vapor exposure. When assessed 24 h after a single bout of in vivo CIE vapor exposure, NAc LTD was absent, and instead NMDA receptor-dependent synaptic potentiation [long-term potentiation (LTP)] was reliably observed. It is noteworthy that both LTP and LTD were completely absent after an extended withdrawal (72 h) after a single 3-day CIE vapor bout. These observations demonstrate that 1) accumbal synaptic depression is mediated by NR2B receptors, 2) accumbal synaptic depression is highly sensitive to both acute and chronic ethanol exposure, and 3) alterations in this synaptic process may constitute a neural adaptation that contributes to the induction and/or expression of ethanol dependence.

ChemInform Abstract: trans-Hexahydroindolo(4,3-ab)phenanthridines (“Benzergolines”), the First Structural Class of Potent and Selective Dopamine D1 Receptor Agonists Lacking a Catechol Group.

In contrast to the many selective dopamine (DA) D2 receptor agonists known, only two prototypes of selective D1 receptor agonists have been described; both show preference for the periphery due to their catechol partial structures. Our search for non-catechol, selective D1 agonists was based on the hypothesis that D1 selectivity could be conferred upon ergolines by annulation with a phenyl ring. The target molecules, trans-4,6,6a,7,8,12b-hexahydroindolo-[4,3-ab]phenanthridi nes (benzergolines), were efficiently synthesized by using the Ninomiya enamide photocyclization reaction. These compounds were found to be as active as the most potent D1 agonists in the adenylate cyclase D1 receptor model, but showed no activity in the ACh release D2 receptor assay. The acquired subtype selectivity of the novel structures was accompanied by an enhanced potency and efficacy as compared to the corresponding ergolines. This points to a D1 affinity enhancing, D2 receptor discriminating role for the additional phenyl group and provides further support for the existence of a D1 receptor specific accessory aryl binding site. Thus the benzergolines represent the first structural class of potent and selective D1 agonists lacking a catechol group which should allow an efficient central nervous system penetration. On the basis of these results, the D1 agonist pharmacophore has to be revised in the sense that potent activity requires neither a catechol function nor an orthogonal conformation of the aromatic rings.

ChemInform Abstract: (.+-.)-3-Allyl-7-halo-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepines as Selective High Affinity D1 Dopamine Receptor Antagonists: Synthesis and Structure-Activity Relationship.

Substituted 1-phenyl-3-benzazepines form a class of compounds possessing potent and selective affinity for the D1 DA receptor. 7,8-Dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 38393) and its 6-halo analogues are potent and selective D1 receptor agonists. Recently, the 3-allyl derivatives of SKF 38393 and its analogues were described as selective D1 agonists with higher D1 efficacy and CNS potency. In order to extend these results to compounds in the 7-halo-8-hydroxy-substituted antagonist series, we have synthesized and pharmacologically characterized 3-allyl analogues of 7-substituted (Cl, Br, H) 8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines. These 3-allyl derivatives were compared with their 3-methyl and 3-unsubstituted analogues in terms of their D1 receptor affinity and selectivity. The results have been used to generate structure-affinity relationships. The D1 receptor affinity, for 3-substitution, is found to be in the order: methyl greater than allyl greater than H. For 7-substitution, the affinity is in the order: Cl = Br greater than H. The 3-allyl compounds show affinity close to that of the parent (3-methyl) compounds while exhibiting a slightly diminished D1 selectivity. However, the greater lipophilicity of the 3-allyl compounds may enable them to cross the blood-brain barrier more readily and thereby exhibit higher in vivo CNS potency. Thus 3-allylbenzazepines have potential as high affinity selective D1 antagonists.

Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists.

Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson's disease; however, little is known about their functional circuitry. We wished to determine if D3R antagonists SB-277011 and PG-01037 and D3R-preferring agonist 7-OH-DPAT are D3R selective in vivo. We further wished to characterize the response to D3R drugs using whole brain imaging to identify novel D3R circuitry. We investigated D3R circuitry in rats using pharmacologic MRI and challenge with selective D3R antagonists and agonist at various doses to examine regional changes in cerebral blood volume (CBV). We compared regional activation patterns with D2R/D3R agonists, as well as with prior studies of mRNA expression and autoradiography. D3R antagonists induced positive CBV changes and D3R agonist negative CBV changes in brain regions including nucleus accumbens, infralimbic cortex, thalamus, interpeduncular region, hypothalamus, and hippocampus (strongest in subiculum). All D3R-preferring drugs showed markedly greater responses in nucleus accumbens than in caudate/putamen consistent with D3R selectivity and contrary to what was observed with D2R agonists. At high doses of D3R agonist, functional changes were differentiated across cortical laminae, with layer V-VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are not inconsistent with differential D1R and D3R innervation in these layers respectively showed previously using post-mortem techniques. MRI provides a new tool for testing the in vivo selectivity of novel D3R dopaminergic ligands where radiolabels may not be available. Further, the functional D3R circuitry strongly involves hypothalamus and subiculum as well as the limbic striatum.

Pharmacologic Neuroimaging of the Ontogeny of Dopamine Receptor Function

Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.

Insights into pathophysiology of punding reveal possible treatment strategies

Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, nongoal oriented, repetitive activity. Men tend to repetitively tinker with technical equipment such as radio sets, clocks, watches and car engines, the parts of which may be analyzed, arranged, sorted and cataloged but rarely put back together. Women, in contrast, incessantly sort through their handbags, tidy continuously, brush their hair or polish their nails. Punders are normally aware of the inapposite and obtuse nature of the behavior; however, despite the consequent self-injury, they do not stop such behavior. The most common causes of punding are dopaminergic replacement therapy in patients affected by Parkinson's disease (PD) and cocaine and amphetamine use in addicts. The vast majority of information about punding comes from PD cases. A critical review of these cases shows that almost all afflicted patients (90%) were on treatment with drugs acting mainly on dopamine receptors D1 and D2, whereas only three cases were reported in association with selective D2 and D3 agonists. Epidemiological considerations and available data from animal models suggest that punding, drug-induced stereotypies, addiction and dyskinesias all share a common pathophysiological process. Punding may be related to plastic changes in the ventral and dorsal striatal structures, including the nucleus accumbens, and linked to psychomotor stimulation and reward mechanisms. Possible management guidelines are proposed.

Receptor signaling and behavioral properties of EFF0311, a longer‐acting selective full D1 agonist as a potential treatment for Parkinson's disease

D1 dopamine full agonists like dihydrexidine (DHX) were previously used to show that D1, but not D2, agonists could match the efficacy of levodopa in the primate MPTP Parkinson's disease (PD) model and in humans with PD. Short duration of action, toxicity, and/or limited bioavailability have prevented a D1 agonist from being approved for clinical use, with only DHX (very short acting) available for limited investigator‐initiated clinical studies. We now report the properties of EFF0311, a DHX analog with greater D1 selectivity and nanomolar affinity for D1 and D5 receptors. EFF0311 had 100% intrinsic activity in stimulating adenylate cyclase via D1 receptors in expressed systems or brain. EFF0311 (relative to quinpirole) was far less potent at D2L‐mediated stimulation of arachidonic acid release than in inhibition of forskolin‐stimulated adenylate cyclase, consistent with functionally selective actions at D2L receptors. In the unilateral 6‐OHDA rat model of PD, EFF0311 effects lasted 3–5 times longer than DHX. These behavioral effects were completely blocked by a D1 antagonist, but not decreased by a D2 antagonist. The properties of EFF0311 (D1 full agonism, longer duration of action, atypical D2 actions) suggest it may be an ideal PD drug candidate.Grant support: MH082441, MH040537, PA Keystone Innovation Grant (RBM), NS042402 and PA Tobacco settlement fund (TS). RBM has a potential CoI.

The effects of the dopamine D2 agonist sumanirole on prepulse inhibition in rats

Dopamine agonists reduce prepulse inhibition (PPI) of startle in rats. While it is used to predict antipsychotic efficacy, the specific receptor subtypes mediating this effect of dopamine agonists remain unclear. We characterized the effects of sumanirole, a highly selective D2 agonist, on PPI in rats. Sumanirole decreased PPI at 60-120 ms prepulse intervals, and increased PPI at 10-20 ms intervals. PPI deficits were antagonized by low doses of the preferential D2 antagonist L741626, supporting a D2 mechanism of action. Sumanirole is a valuable tool for parsing the role of dopamine receptor subtypes in the regulation of PPI.

D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: A PET study in a receptor internalization-deficient mouse model

Dopamine released by amphetamine decreases the in vivo binding of PET radioligands to the dopamine D2 receptor. Although concentrations of extracellular dopamine largely return to baseline within 1 to 2 h after amphetamine treatment, radioligand binding remains decreased for several hours. The purpose of this study was to determine whether the prolonged decrease of radioligand binding after amphetamine administration is caused by receptor internalization. To distinguish dopamine displacement from receptor internalization, we used wild-type and arrestin3 (arr3) knockout mice, which are incapable of internalizing D2 receptors. In addition, we used both the D2 selective agonist [11C]MNPA (which is thought to bind to the high affinity state of the receptor) and the D2 selective antagonist [18F]fallypride (which does not differentiate between high and low affinity state). After an initial baseline scan, animals were divided in three groups for a second scan: either 30 min or 4 h after amphetamine administration (3 mg/kg, i.p.) or as retest. At 30 min, [11C]MNPA showed greater displacement than [18F]fallypride, but each radioligand gave similar displacement in knockout and wild-type mice. At 4 h, the binding of both radioligands returned to baseline in arr3 knockout mice, but remained decreased in wild-type mice. Radioligand binding was unaltered on retest scanning. Our results suggest that the prolonged decrease of radioligand binding after amphetamine is mainly due to internalization of the D2 receptor rather than dopamine displacement. In addition, this study demonstrates the utility of small animal PET to study receptor trafficking in vivo in genetically modified mice.

Specific role of dopamine D1 receptors in spinal network activation and rhythmic movement induction in vertebrates

Dopamine (DA) is well-recognized for its determinant role in the modulation of various brain functions. DA was also found in in vitro isolated invertebrate preparations to activate per se the central pattern generator for locomotion. However, it is less clear whether such a role as an activator of central neural circuitries exists in vertebrate species. Here, we studied in vivo the effects induced by selective DA receptor agonists and antagonists on hindlimb movement generation in mice completely spinal cord-transected (Tx) at the low-thoracic level (Th9/10). Administration of D1/D5 receptor agonists (0.5-2.5 mg kg(-1), i.p.) was found to acutely elicit rhythmic locomotor-like movements (LMs) and non-locomotor movements (NLMs) in untrained and non-sensory stimulated animals. Comparable effects were found in mice lacking the D5 receptor (D5KO) whereas D1/D5 receptor antagonist-pretreated animals (wild-type or D5KO) failed to display D1/D5 agonist-induced LMs. In contrast, administration of broad spectrum or selective D2, D3 or D4 agonists consistently failed to elicit significant hindlimb movements. Overall, the results clearly show in mice the existence of a role for D1 receptors in spinal network activation and corresponding rhythmic movement generation.

A Novel and Efficient Synthesis of Dihydrexidine

An efficient synthesis of the dopamine D1 selective full agonist dihydrexidine has been achieved in high yields and requiring no chromatographic separations via a facilitated intramolecular Henry cyclization of a (nitropropyl)benzophenone and subsequent diastereomerically selective reduction of the resulting tricyclic nitroalkene.

Motor sequence learning in primate: Role of the D2 receptor in movement chunking during consolidation

Motor learning disturbances have been shown in diseases involving dopamine insufficiency such as Parkinson’s disease and schizophrenic patients under antipsychotic drug treatment. In non-human primates, motor learning deficits have also been observed following systemic administration of raclopride, a selective D2-receptor antagonist. These deficits were characterized by persistent fluctuations of performance from trial to trial, and were described as difficulties in consolidating movements following a learning period. Moreover, it has been suggested that these raclopride-induced fluctuations can result from impediments in grouping separate movements into one fluent sequence. In the present study, we explore the hypothesis that such fluctuations during movement consolidation can be prevented through the use of sumanirole – a highly selective D2 agonist – if administered before raclopride. Two monkeys were trained to execute a well known sequence of movements, which was later recalled under three pharmacological conditions: (1) no drug, (2) raclopride, and (3) sumanirole + raclopride. The same three pharmacological conditions were repeated with the two monkeys, trained this time to learn new sequences of movements. Results show that raclopride has no deleterious effect on the well known sequence, nor the sumanirole + raclopride co-administration. However, results on the new sequence to be learned revealed continuous fluctuations of performances in the raclopride condition, but not in the sumanirole + raclopride condition. These fluctuations occurred concurrently with a difficulty in merging separate movement components, known as a “chunking deficit”. D2 receptors seem therefore to be involved in the consolidation of new motor skills, and this might involve the chunking of separate movements into integrated motor sequences.

Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporter

The dopamine transporter (DAT) regulates the temporal and spatial actions of dopamine by reuptaking this neurotransmitter into the presynaptic neurons. We recently generated transgenic mice overexpressing DAT (DAT-tg) that have a 3-fold increase in DAT protein levels which results in a 40% reduction of the extracellular DA concentration in the striatum. The aim of this study was to examine the effect of this reduction in dopaminergic tone on postsynaptic responses mediated by dopamine receptors. We report here that DAT-tg mice have increased levels of striatal D1 (30%) and D2 (~ 60%) dopamine receptors with D1 receptor signaling components not significantly altered, as evidenced by unaffected basal or stimulated levels of phospho-GluR1 (Ser845) and phospho-ERK2. However, the novel D2 mediated Akt signaling is markedly altered in DAT-tg animals. In particular, there is a 300% increase in the basal levels of phospho-Akt in the striatum of DAT-tg, reflecting the reduced extracellular dopamine tone in these animals. This increase in basal pAkt levels can be pharmacologically recapitulated by partial dopamine depletion in WT mice treated with the selective tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (α-MPT). Behaviorally, DAT-tg animals demonstrate an augmented synergistic interaction between up-regulated D1 and D2 receptors, which results in increased climbing behavior in transgenic mice after stimulation with either apomorphine or a co-administration of selective D1 and D2 receptor agonists. In sum, our study reveals that hypodopaminegia caused by up-regulation of DAT results in significant alterations at postsynaptic receptor function with most notable dysregulation at the level of D2 receptor signaling.

Opioidergic and dopaminergic modulation of respiration.

Opioids, dopamine and their receptors are present in many regions of the bulbar respiratory network. The physiological importance of endogenous opioids to respiratory control has not been explicitly demonstrated. Nonetheless, studies of opioidergic respiratory mechanisms are important because synthetic opiate drugs have respiratory side effects that in some situations pose health risks and limit their therapeutic usefulness. They can depress breathing depth and rate, blunt respiratory responsiveness to CO2 and hypoxia, increase upper airway resistance and reduce pulmonary compliance. The opiate respiratory disturbances are mainly due to agonist activation of mu- and delta-subtypes of receptor and involve specific types of respiratory-related neurons in the ventrolateral medulla and the dorsolateral pons. Endogenous dopaminergic modulation in the CNS and carotid bodies enhances CO2-dependent respiratory drive and depresses hypoxic drive. In the CNS, synthetic agonists with selectivity for D1-and D4-types of receptor slow respiratory rhythm, whereas D2-selective agonists modulate acute and chronic responses to hypoxia. D1-receptor agonists also act centrally to increase respiratory responsiveness to CO2, and counteract opiate blunting of CO2-dependent respiratory drive and depression of breathing. Cellular targets and intracellular mechanisms responsible for opioidergic and dopaminergic respiratory effects for the most part remain to be determined.

Neonatal tactile stimulation enhances spatial working memory, prefrontal long-term potentiation, and D1 receptor activation in adult rats

Environmental stimuli during neonatal periods play an important role in the development of cognitive function. In this study, we examined the long-term effects of neonatal tactile stimulation (TS) on spatial working memory (SWM) and related mechanisms. We also investigated whether TS-induced effects could be counteracted by repeated short periods of maternal separation (MS). Wistar rat pups submitted to TS were handled and marked transiently per day during postnatal days 2–9 or 10–17. TS/MS pups were stimulated in the same way as TS pups and then individually separated from their mother for 1 h/day. Their nontactile stimulated (NTS) siblings served as controls. In adulthood, TS and TS/MS rats showed better performance in two versions of the delayed alternation task and superior in vivo long-term potentiation of the hippocampo–prefrontal cortical pathway when compared with controls. Furthermore, there were more doses of A77636 (a selective dopamine D1 agonist) to significantly improve SWM performance in TS and TS/MS rats than in NTS rats, suggesting that activation of prefrontal D1 receptors in TS and TS/MS rats is more optimal for SWM function than in NTS rats. MS did not counteract TS-induced effects because no significant difference was found between TS/MS and TS animals. These data indicate that in early life, external tactile stimulation leads to long-term facilitative effects in SWM-related neural function.