Dopaminergic Receptor Subtypes Research Articles

Design, Synthesis and Pharmacological Evaluation of Novel Conformationally Restricted N-arylpiperazine Derivatives Characterized as D2/D3 Receptor Ligands, Candidates for the Treatment of Neurodegenerative Diseases.

Most neurodegenerative diseases are multifactorial, and the discovery of several molecular mechanisms related to their pathogenesis is constantly advancing. Dopamine and dopaminergic receptor subtypes are involved in the pathophysiology of several neurological disorders, such as schizophrenia, depression and drug addiction. For this reason, the dopaminergic system and dopamine receptor ligands play a key role in the treatment of such disorders. In this context, a novel series of conformationally restricted N-arylpiperazine derivatives (5a–f) with a good affinity for D2/D3 dopamine receptors is reported herein. Compounds were designed as interphenylene analogs of the drugs aripiprazole (2) and cariprazine (3), presenting a 1,3-benzodioxolyl subunit as a ligand of the secondary binding site of these receptors. The six new N-arylpiperazine compounds were synthesized in good yields by using classical methodologies, and binding and guanosine triphosphate (GTP)-shift studies were performed. Affinity values below 1 μM for both target receptors and distinct profiles of intrinsic efficacy were found. Docking studies revealed that Compounds 5a–f present a different binding mode with dopamine D2 and D3 receptors, mainly as a consequence of the conformational restriction imposed on the flexible spacer groups of 2 and 3.

Neurochemical Signalling Associated With Gill Oxygen Sensing and Ventilation: A Receptor Focused Mini-Review

Despite the large body of work describing vertebrate ventilatory responses to hypoxia, remarkably little is known about the receptors and afferent pathways mediating these responses in fishes. In this review, we aim to summarize all receptor types to date implicated in the neurotransmission or neuromodulation associated with O2 sensing in the gills of fish. This includes serotonergic, cholinergic, purinergic, and dopaminergic receptor subtypes. Recent transcriptomic analysis of the gills of zebrafish using single-cell RNA sequencing has begun to elucidate specific receptor targets in the gill; however, the absence of receptor characterization at the cellular level in the gill remains a major limitation in understanding the neurochemical control of hypoxia signalling.

Receptor binding profiles and behavioral effects of psilocybin analogs

4‐phosphorloxy‐N,N‐dimethyltryptamine (psilocybin) is a naturally occurring psychedelic compound that is being investigated in clinical studies in conjunction with psychotherapy for treatment of several psychiatric disorders. It is well established that 4‐hydroxy‐N,N‐dimethyltryptamine (psilocin) is the bioactive metabolite of psilocybin which mediates its in vivo psychedelic activity in humans and rodents (e.g., head twitch response) via agonist actions at 5‐HT2A receptors. Several psilocybin analogs have emerged on recreational drug markets as new psychoactive substances (NPS), some of which are being investigated for their potential clinical utility in psychedelic assisted psychotherapy. For example, 4‐acetoxy‐N,N‐dimethyltrytpamine (psilacetin) is a psychedelic NPS that is hypothesized to be a prodrug which is metabolized to psilocin, similar to psilocybin. Little is known about the pharmacology of psilacetin and related psilocybin analogs, especially with regard to how differences in receptor activity profiles might modulate in vivo behavioral, physiological, and potential clinical effects. The present study investigated the in vitro receptor affinities for a series of psilocybin analogs with differing N‐alkyl substitutions (dimethyl, dipropyl, methylallyl, or methylisopropyl) or 4‐position ring‐substitutions (hydroxy, acetoxy or methoxy). Additionally, in vivo dose‐response (0.03 – 3 mg/kg s.c.) and antagonist reversal experiments were conducted to examine head twitch responses (HTRs) in male C57BL/6J mice after administration of psilocybin, psilacetin, and psilocin. The in vitro receptor screening results revealed that all psilocybin analogs have low to mid nM affinities for 5‐HT1A, 5‐HT2A, 5‐HT2B, and 5‐HT2C subtypes, as well as other 5‐HT receptors. Non‐serotonergic targets included adrenergic, dopaminergic, histaminergic, and sigma receptor subtypes, and monoamine transporters (dopamine & serotonin). However, affinities for the non‐serotonergic sites were less consistent across the various compounds and much weaker when compared to activity at 5‐HT receptors. The in vivo mouse studies revealed that the rank order of potency to induce HTRs was psilocin > psilacetin > psilocybin, suggesting that psilacetin may indeed be converted to psilocin in vivo. Perhaps more importantly, psilacetin may have psychedelic activity on its own based on pharmacological screening data showing nM binding affinity to 5‐HT2A receptors. The HTRs induced by psilocybin, psilocin, and psilacetin (all 0.6 mg/kg s.c.) were blocked by pretreatment with the 5‐HT2A antagonist M100907 (0.01 mg/kg s.c.), indicating the involvement of 5‐HT2Areceptors. Taken together, our data provide key information about structure‐activity relationships for receptor binding profiles of psilocybin analogs and suggest that psilacetin may be an alternative prodrug for psilocin, with possible psychedelic activity of its own. Future studies comparing the pharmacokinetics and metabolism of psilocybin and psilacetin seem warranted to confirm the conversion of these parent compounds to psilocin in vivo.

The Cerebellar Dopaminergic System.

In the central nervous system (CNS), dopamine (DA) is involved in motor and cognitive functions. Although the cerebellum is not been considered an elective dopaminergic region, studies attributed to it a critical role in dopamine deficit-related neurological and psychiatric disorders [e.g., Parkinson's disease (PD) and schizophrenia (SCZ)]. Data on the cerebellar dopaminergic neuronal system are still lacking. Nevertheless, biochemical studies detected in the mammalians cerebellum high dopamine levels, while chemical neuroanatomy studies revealed the presence of midbrain dopaminergic afferents to the cerebellum as well as wide distribution of the dopaminergic receptor subtypes (DRD1-DRD5). The present review summarizes the data on the cerebellar dopaminergic system including its involvement in associative and projective circuits. Furthermore, this study also briefly discusses the role of the cerebellar dopaminergic system in some neurologic and psychiatric disorders and suggests its potential involvement as a target in pharmacologic and non-pharmacologic treatments.

Opposite effects of dopamine on the mechanical activity of circular and longitudinal muscle of human colon.

Because dopamine (DA) has gained increasing evidence as modulator of gut motility, we aimed to characterize dopaminergic response in human colon, evaluating function and distribution of dopamine receptors in circular vs longitudinal muscle strips. Mechanical responses to DA and dopaminergic agonists on slow phasic contractions and on basal tone were examined in vitro as changes in isometric tension. RT-PCR was used to reveal the distribution of dopaminergic receptors. In spontaneous active circular muscle, DA induced an increase in the amplitude of slow phasic contractions and of the basal tone, via activation of D1-like receptors. DA contractile responses were insensitive to neural blockers or to atropine and inhibited by phospholipase C (PLC) pathway inhibitors. In precontracted circular muscle strips, DA, at the higher concentrations tested, caused a relaxant response via activation of D2-like receptors. In the longitudinal muscle, DA caused only muscular relaxation due to activation of D2-like receptors. DA relaxant responses were insensitive to neural blockers or to nitric oxide synthase inhibitor and reduced by a wide-spectrum K+ channel blockers. Transcripts encoding for all the dopaminergic receptor subtypes was observed in both circular and longitudinal preparations. Dopamine is able to modulate contractile activity of the human colon. In the circular muscle layer, DA induces mainly muscular contraction activating non-neural D1-like receptors, coupled to PLC/IP3 pathway. In the longitudinal muscle layer, DA induces muscular relaxation acting on non-neural D2-like receptors leading to the increase in K+ conductance.

The role of dopamine D3 receptors in the mechanism of action of cariprazine.

Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2 and D3 receptors and serotonin 5-HT1A receptors, and as an antagonist at the 5-HT2B receptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3 receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

Long-term effects of iloperidone on cerebral dopamine receptor subtypes.

The atypical antipsychotic drug iloperidone has high affinity for a wide range of neurotransmitter receptors, including dopaminergic (DA), serotonergic, and adrenergic receptors. We examined the long-term effects of multiple doses of iloperidone on DA D1 , D2 , D3 , and D4 receptor subtypes. Sprague-Dawley adult rats (n=8/group) received daily intraperitoneal injections of iloperiodone (0.5, 1, or 5mg/kg) or vehicle for 4 weeks. Receptor autoradiography quantified the levels of DA receptors in medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP). Four weeks of iloperidone treatment at 5mg/kg significantly increased D1 receptors in NAc (36%) and CPu (38%). Iloperidone (1.5 and 5mg/kg) dose-dependently increased D2 receptors in MPC (37 and 47%) and HIP (32 and 40%). Only the high dose of iloperidone (5mg/kg) increased D2 receptors in NAc (39%) and CPu (38%). Repeated treatment with iloperidone (1.5 and 5mg/kg) increased D4 receptors in the NAc (39 and 78%), CPu (42 and 83%) and HIP (54 and 72%). The three doses of iloperidone failed to alter D3 receptors in the brain regions examined in this study. These results suggest that iloperidone exerts region- and dose-specific effects on forebrain DA receptor subtypes, which may contribute to its therapeutic benefits in improving the positive and negative symptoms of schizophrenia with minimal extrapyramidal side effects.

Implication of dorsostriatal D3 receptors in motivational processes: a potential target for neuropsychiatric symptoms in Parkinson\u2019s disease

Beyond classical motor symptoms, motivational and affective deficits are frequently observed in Parkinson’s disease (PD), dramatically impairing the quality of life of patients. Using bilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in rats, we have been able to reproduce these neuropsychiatric/non-motor impairments. The present study describes how bilateral 6-OHDA SNc lesions affect the function of the main striatal dopaminergic (DA) receptor subtypes. Autoradiography was used to measure the levels of striatal DA receptors, and operant sucrose self-administration and neuropharmacological approaches were combined to investigate the causal implication of specific DA receptors subtypes in the motivational deficits induced by a dorsostriatal DA denervation. We found that D3 receptors (D3R) exclusively are down-regulated within the dorsal striatum of lesioned rats. We next showed that infusion of a D3R antagonist (SB-277011A) in non-lesioned animals specifically disrupts preparatory, but not consummatory behaviors. Our findings reveal an unexpected involvement of dorsostriatal D3R in motivational processes. They strongly suggest an implication of dorsostriatal D3R in the neuropsychiatric symptoms observed in PD, highlighting this receptor as a potential target for pharmacological treatment.

Synthesis and evaluation in rats of the dopamine D2/3 receptor agonist 18F-AMC20 as a potential radioligand for PET.

Dopamine D(2/3) receptor (D(2/3)R) agonist PET tracers are better suited for the imaging of synaptic dopaminergic neurotransmission than D(2/3)R antagonists and may also offer the opportunity to study in vivo the high-affinity state of D(2/3)R (D(2/3)RHigh). With the aim to develop (18)F-labeled D2/3R agonists suitable for widespread clinical application, we report here on the synthesis and in vitro and in vivo evaluation of a D(2/3)R agonist ligand from the aminomethyl chromane (AMC) class-(R)-2-[(4-(18)F-fluorobenzylamino)methyl]chroman-7-ol ((18)F- AMC20: ). In vitro affinities of AMC20: toward dopaminergic receptor subtypes were measured in membrane homogenates prepared from HEK293 cells expressing human dopamine receptors. Agonism of AMC20: was assessed in the arrestin recruitment assay in Chinese hamster ovary-K(1) cells expressing the long isoform of D(2)R (D(2)RLong). D(2/3)R-specific binding of (18)F- AMC20: was evaluated in brain slices of Sprague-Dawley rats by in vitro autoradiography and in living rats by in vivo small-animal PET imaging and ex vivo autoradiography. PET data were analyzed with 1- and 2-tissue compartmental models, the simplified reference tissue model, and Logan graphical analysis. Specificity of binding was tested by blocking D(2/3)R with raclopride (coincubation with 10 μM in vitro, administration of 1.0 mg/kg in vivo). In membrane homogenates, AMC20: demonstrated picomolar affinity at D(2)RHigh (mean inhibition constant [K(i)] = 85 pM) and excellent selectivity against the low-affinity state of D(2)R (D(2)RLow) (mean K(i) = 84 nM, 988-fold selectivity) and D(1)-like receptors (mean K(i) = 5,062 nM at D1R). The efficacy of AMC20: was 90% of that of dopamine in the arrestin recruitment assay. Up to 70% of total binding of (18)F- AMC20: in the D2/3R-rich striatum in rat brain slices was D(2/3)R-specific; in living rats, the uptake ratio between the striatum and the D(2/3)R-poor cerebellum reached 2.0-2.5, depending on the measurement method. Radiometabolites of (18)F- AMC20: did not enter the brain. Striatal binding potential of (18)F- AMC20: varied between 0.49 and 0.59 depending on the estimation method. Pretreatment with 1 mg of raclopride per kilogram reduced the apparent specific binding of (18)F- AMC20: in the striatum. (18)F- AMC20: shows specific binding to D(2/3)R in the striatum of living rats. Further optimization of the chemical structure of (18)F- AMC20: can lead to (18)F-labeled D(2/3) agonist PET tracers more suitable for in vivo clinical application.

Implication of dopamine D3 receptor activation in the reversion of Parkinson's disease-related motivational deficits.

In addition to the classical motor symptoms, motivational and affective deficits are core impairments of Parkinson's disease (PD). We recently demonstrated, by lesional approaches in rats, that degeneration of the substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is likely to have a crucial role in the development of these neuropsychiatry symptoms. We have also shown that, as in clinical investigations, chronic treatment with levodopa or the DA D2/D3 receptor (D2/D3R) agonist ropinirole specifically reverses these PD-related motivational deficits. The roles of specific DA receptor subtypes in such reversal effects remain, however, unknown. We therefore investigated here the precise involvement of D1, D2 and D3R in the reversal of the motivational and affective deficits related to SNc DA neuronal loss. Three weeks after bilateral and partial 6-hydroxydopamine (6-OHDA) SNc lesions, rats received 14 daily intraperitoneal administrations of the selective D1R agonist SKF-38393 (2.5 or 3.5 mg kg−1), the selective D2R agonist sumanirole (0.1 or 0.15 mg kg−1), or the preferring D3R gonist PD-128907 (0.1 or 0.15 mg kg−1). Anxiety-, depressive-like and motivated behaviors were assessed in an elevated-plus maze, a forced-swim test, and an operant sucrose self-administration procedure, respectively. All DA agonists attenuated anxiety- and depressive-like behaviors. However, only PD-128907 reversed the motivational deficits induced by 6-OHDA SNc lesions. This effect was blocked by a selective D3R (SB-277011A, 10 mg kg−1), but not D2R (L-741,626, 1.5 mg kg−1), antagonist. These data provide strong evidence for the role of D3R in motivational processes and identify this receptor as a potentially valuable target for the treatment of PD-related neuropsychiatric symptoms.

Genetics of dopamine receptors and drug addiction

Dopamine plays a key role in reward behavior, yet the association of drug dependence as a chronic, relapsing disorder with the genes encoding the various dopaminergic receptor subtypes remains difficult to delineate. In the context of subsequent genome-wide association (GWAS) research and post-GWAS investigations, we summarize the novel data that link genes encoding molecules involved in the dopaminergic system (dopamine receptors, transporter and enzymes in charge of its metabolism) to drug addiction. Recent reports indicate that the heritability of drug addiction should be high enough to allow a significant role for a specific set of genes, and the available genetic studies, which might not be already conclusive because of the heterogeneity of designs, methods and recruited samples, should support the idea of a significant role of at least one gene related to dopaminergic system. Evolutionary changes in primates and non-primate animals of genes coding for molecules involved in dopaminergic system highlight why addictive disorders are mainly limited to humans. Restricting the analyses to more specific intermediate phenotypes (or endophenotypes) such as attention allocation, stress reactivity, novelty seeking, behavioral disinhibition and impulsivity, instead of the broad addictive disorder concept can be instrumental to identify novel genes associated with these traits in the context of genome-wide studies.

The modulatory role of cortisol on prolactin secretion in anestrus Iranian fat-tailed ewes

Release of prolactin, a milk-secreting hormone, is normally inhibited by the neurotransmitter dopamine. Numerous attempts have been made to explain the effects of environmental stress on the level of prolactin, proposing a basic role for cortisol in the modulation of the hormone secretion. The pharmacologic properties of antagonists in the release of prolactin, during the anovulatory early postpartum period, were examined in this research. This study included ten 3-year-old Mehraban ewes that gave birth to their third lambs, at least 2 weeks before the experiment. Each animal was randomly assigned to receive either a corresponding dose of either metoclopramide (0.3 mg/kg BW; im; n = 5) or haloperidol (0.1 mg/kg BW; im; n = 5). During the 2 weeks prior to the start of the study, all ewes were allowed to acclimatize to their environment with free access to food and tap water, in order to avoid stress-induced influences on hormone levels resulting from environmental factors. Blood samples were collected from each ewe through the jugular vein via intravenous catheter immediately at the time of study entry, 2 and 4 h before and after every injection, with a time interval of 30 min. The serum recovered was assayed for prolactin, cortisol, and progesterone. Animals were assumed to be anestrous if the mean serum level of progesterone was lower than 0.4 ng/mL and that of prolactin higher than 80 mIU/L. One-way ANOVA revealed that the mean serum concentrations of prolactin measured at 30 and 90 min after metoclopramide administration were statistically different compared with the control but showed no difference at other time points. The secretion of cortisol prior to the treatment and afterward was statistically similar; however, under haloperidol administration, it increased and the difference was statistically significant (p 0.05). In conclusion, the pharmacologic properties of an antagonist to release prolactin, during the anovulatory early postpartum period, may depend on the presence of dopaminergic D2 receptor subtypes. In addition to its specificity for D2 receptors, the bioactivity of that antagonist may also play a role in the control of the secretion.

From Anti-allergic to Anti-Alzheimer ’ s: Molecular Pharmacology of Dimebon™

Dimebon, originally developed as an anti-histamine drug, is being re-purposed for new indications as an effective treatment for patients suffering from Alzheimer's and Huntington's diseases, albeit with an as-yet unknown mechanism of action. We have performed molecular pharmacology profiling of this drug on a panel of 70 targets to characterize the spectrum of its activity, with the goal to possibly elucidate a potential molecular mechanism for the re-purposing of this drug candidate. We show that in addition to histaminergic receptors, Dimebon exhibits high affinity to a constellation of other receptors; specifically serotonergic, alpha-adrenergic and dopaminergic receptors. Good correlations with published literature were obtained for the affinity of Dimebon to inhibit butyrylcholinesterase, interact with H1and H2 receptors (Ki = 2 nM and 232 nM), and to block histamine-induced calcium fluxes in cells. Within serotonergic receptor subtypes, Dimebon shows highest affinity for 5-HT7 (Ki=8 nM) and 5-HT6 (Ki=34 nM) receptors, with the relative affinity rank-order of 5-HT7 > 5-HT6 > or = 5-HT2A = 5-HT2C > 5-HT1A = 5-HT1B > 5-HT2B=5-HT3. Dimebon also interacts with adrenergic receptor subtypes (rank-order: alpha1A (Ki = 55 nM)= alpha1B > or = alpha2A (Ki = 120 nM) = alpha1D), and dopaminergic receptor subtypes (rank-order: D1=D2S=D2L (Ki approximately 600 nM) >D3> or =D4.2>D4.4> or =D4.7). These results demonstrate a molecular pharmacological basis for re-purposing of this drug to new therapeutic areas. The informed targeting of the combined molecular target activities may provide additional advantages for patients suffering from similar diseases syndromes. Understanding the role that different pathways play in diseases with complex etiologies may allow for the rational design of multi-target drugs.

Mechanisms Underlying Dopamine-Mediated Reward Bias in Compulsive Behaviors

Pathological behaviors such as problem gambling or shopping are characterized by compulsive choice despite alternative options and negative costs. Reinforcement learning algorithms allow a computation of prediction error, a comparison of actual and expected outcomes, which updates our predictions and influences our subsequent choices. Using a reinforcement learning model, we show data consistent with the idea that dopamine agonists in susceptible individuals with Parkinson's disease increase the rate of learning from gain outcomes. Dopamine agonists also increase striatal prediction error activity, thus signifying a "better than expected" outcome. Thus, our findings are consistent with a model whereby a distorted estimation of the gain cue underpins a choice bias toward gains.

Genetics of dopamine receptors and drug addiction: a comprehensive review

Drug dependence is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behaviours persist despite serious negative consequences. Addictive substances, such as opioids, ethanol, psychostimulants and nicotine, induce pleasant states or relieve distress, effects that contribute to their recreational use. Dopamine is critically involved in drug addiction processes. However, the role of the various dopaminergic receptor subtypes has been difficult to delineate. Here, we will review the information collected implicating the receptors of the D1 family (DRD1 and DRD5) and of the D2 family (DRD2, DRD3 and DRD4) in drug addiction. We will summarize the distribution of these receptors in the brain, the preclinical experiments carried out with pharmacological and transgenic approaches and the genetic studies carried out linking genetic variants of these receptors to drug addiction phenotypes. A meta-analysis of the studies carried out evaluating DRD2 and alcohol dependence is also provided, which indicates a significant association. Overall, this review indicates that different aspects of the addiction phenotype are critically influenced by dopaminergic receptors and that variants of those genes seem to influence some addiction phenotypes in humans.

Modulation of AMPA currents by D1-like but not D2-like receptors in spinal motoneurons

Dopamine can modulate and excite spinal locomotor networks, affect afferent transmission and increase motoneuronal excitability. One of the mechanisms whereby dopamine increases motoneuronal excitability is to potentiate AMPA channel-mediated glutamatergic transmission onto motoneurons. However, it is not known which dopaminergic receptor subtypes or the intracellular mechanisms contribute to these effects. In this study, we used whole-cell patch clamp techniques to record chemically evoked AMPA currents in neonatal mouse motoneurons. Bath application of D1-like receptor agonist (SKF 39383) increased the AMPA current amplitude and prolonged the decay time constant. In the presence of D1 receptor antagonist LE300, the effects of DA on AMPA currents were blocked. In contrast, bath-application of the D2-like receptor agonist quinpirole did not modulate AMPA currents. In the presence of D2 receptor antagonist L-741626, dopaminergic modulation of AMPA currents was unaffected. These results suggest that augmentation of AMPA transmission by dopamine is accomplished by D1 receptor-based mechanisms. This short-term modulation does not appear to involve cycling of AMPA receptor into the membrane, since blocking insertion with botulinum toxin C did not affect the augmentation of AMPA currents after activating D1 receptors. On the other hand, blocking protein kinase A (PKA) with H-89 completely abolished the effects of D1 agonists. In addition, we used cell-attached single channel recording to demonstrate that stimulating D1 receptors increased individual AMPA channel open probability and open duration. Our data demonstrate that dopamine increases the efficacy of glutamatergic transmission onto motoneurons by increasing AMPA conductances via a D1 PKA-based signaling system.

Adrenergic, dopaminergic and serotonergic gene expression in low dose, long time insulin and somatotropin treatment to ageing rats: rejuvenation of brain function

Somatotropin (GH) and insulin (INS) low dose, long-term brain rejuvenation effect was studied in the cerebral cortex using NE, EPI, DA and 5-HT receptor subtypes of young (group I-treatment started 4 weeks continued to 16 weeks) and old rats (group II-treatment started 60 weeks continued to 90 weeks). GH and INS treatment showed significant decrease in NE and EPI content in cerebral cortex of both young and old rats. alpha(2A)-adrenergic receptors showed decreased expression whereas beta(2)-adrenergic receptors showed enhanced expression with age. GH and INS treatment significantly increased alpha(2A)-adrenergic receptor protein in group I rats whereas INS treatment could increase beta(2)-adrenergic receptor protein expression in group II rats. DA and 5-HT content decrease with age. GH and INS administration showed increase in DA and 5-HT content in the brain regions-corpus striatum and brainstem of both young and old rats. Also, DA D(2) and 5-HT(2C) receptor gene expression were increased significantly by GH and INS treatment in both young and old rats. In conclusion, low dose, long-term treatment of INS and GH to ageing rats improved the adrenergic, dopaminergic and serotonergic receptor subtypes activity and rejuvenation of brain function.

Lack of improvement in odor identification by levodopa in humans

Several animal studies demonstrated that olfaction is modulated by dopamine (DA). We examined if such results could be replicated in humans. Thus, we tested olfaction in elderly healthy humans before and after external administration of levodopa in a double-blind, placebo-controlled, randomized cross-over study. Main outcome measure was the sum of correctly identified odors in an odor identification paradigm. In contrast to what had been demonstrated in rats, levodopa did not improve olfaction. We even noted a trend for the reverse. Blood pressure, mood ratings, as well as performance in a simple motor task were comparable between conditions, indicating that levodopa did not induce differences in general arousal, mood, attention, or reaction time. Our findings may be explained by differences in the distribution of dopaminergic receptor subtypes in the olfactory system in animals and humans, by relative differences in dosing regimes, or by subtle differences in the respective paradigms. These hypotheses have to be tested in future experiments, but our study demonstrates that results from animal studies cannot be directly transferred to the human situation.

Pharmacological properties of a wide array of ergolines at functional alpha1-adrenoceptor subtypes

Ergot alkaloids act as (partial) agonists or antagonists at serotonergic, dopaminergic and alpha-adrenergic receptors. In contrast to their affinity at serotonergic (5-HT) and dopaminergic receptor subtypes, only limited information is available concerning their interaction with alpha-adrenoceptor subtypes. This especially holds true for native alpha-adrenoceptors. Therefore, we studied the pharmacological profile of 25 ergolines at alpha(1A)-, alpha(1B)- and alpha(1D)-adrenoceptors in vascular rings or strips of rat and guinea pig endowed with these receptors. Contractile responses were studied by measurement of isometric tension changes in rat tail artery (alpha(1A), alpha(1B)), guinea pig spleen (alpha(1B)) and rat thoracic aorta (alpha(1D)). The anti-migraine drugs ergotamine and dihydroergotamine, the anti-parkinsonian drug lisuride and the anti-hyperprolactinemic drug terguride behaved as antagonists or low-efficacy partial agonists at all three alpha(1)-adrenoceptor subtypes with nanomolar receptor affinity. Derivatives of these drugs showed lower affinity at alpha(1)-adrenoceptors than the parent compounds. Each individual ergoline derivative tested showed low discriminatory capability at the subtypes, alpha(1A), alpha(1B), alpha(1D). A low discriminatory power between the subtypes (alpha(1A), alpha(1B), alpha(1D)) seems to be a class effect of the ergolines. The nanomolar affinities of ergotamine, dihydroergotamine and lisuride for alpha(1)-adrenoceptors may affect their effectiveness as anti-migraine and anti-parkinsonian drugs, respectively.

Dopamine D3 receptor agonists for protection and repair in Parkinson's disease

Parkinson's disease is a severe, age-related neurodegenerative disorder in which a loss of substantia nigra-derived dopaminergic pathways to the striatum triggers profound motor perturbation, as well as cognitive, sensory and mood deficits. Although the dopamine precursor, L-dopa, is effective in the short-term in relieving motor dysfunction, it does not stop the progressive disappearance of dopaminergic neurons, encouraging interest in alternative therapeutic strategies. Dopaminergic agonists, such as pramipexole, appear to have neuroprotective and neurorestorative actions based on clinical and, most convincingly, experimental work. The role of specific dopaminergic receptor subtypes is an important issue, especially with respect to new drug development. Of particular interest, dopamine D3 receptors contribute to the beneficial influence of dopaminergic agonists for the protection and restoration of dopaminergic pathways in Parkinson's disease.