Direct Dopaminergic Agonists Research Articles

The 5-alpha reductase inhibitor finasteride reduces dyskinesia in a rat model of Parkinson's disease

Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms. Thus, the present study was designed to verify whether the 5AR inhibitor finasteride (FIN) may counteract the dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. First, we assessed the acute and chronic effect of different doses of FIN (30–60mg/kg) on LID, in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of FIN on LID and its impact on l-DOPA efficacy, we assessed abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30–60mg/kg/24days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the impact of FIN on LID may be ascribed to a modulation of the D1- or D2/D3-receptor function, dyskinesias were assessed in l-DOPA-primed 6-OHDA-lesioned rats that received FIN in combination with selective direct dopaminergic agonists. Finally, we set to investigate whether FIN may produce similar effect in female hemiparkinsonian rats, as seen in males.The results indicated that FIN administrations significantly dampened LID in all tested treatment regimens, without interfering with the ability of l-DOPA to ameliorate forelimb use in the stepping test. The antidyskinetic effect appears to be due to modulation of both D1- and D2/D3-receptor function, as FIN also reduced abnormal involuntary movements induced by the selective D1 receptor agonist SKF-82958 and the D2/D3 receptor agonist ropinirole. Significant dampening of LID was also observed in female rats, although only at the higher tested dose.Clinical investigations are warranted to assess whether similar protection from dyskinesia is seen in PD patients.

Effects of selective dopaminergic compounds on a delay-discounting task

Impulsivity is widely regarded as a multidimensional trait that encompasses two or more distinct patterns of behavior, and dopaminergic systems are implicated in the expression of impulsive behavior in both humans and animal subjects. Impulsive choice, or the tendency to choose rewards associated with relatively little or no delay, has been extensively studied in humans and animal subjects using delay-discounting tasks. Here, delay-discounting procedures were used to assess the effects of receptor-selective dopaminergic agonists, antagonists, and dopamine transporter ligands on choices of immediate versus delayed sucrose pellets. The effects of d-amphetamine, GBR 12909, apomorphine, SKF 81297, sumanirole, pramipexole, ABT-724, SCH 23390, L-741,626, PG01037, and L-745,870 were assessed in 24 Sprague-Dawley rats. The only drugs to affect impulsive choice selectively without altering undelayed choice were the D1-like antagonist, SCH 23390 (0.01 mg/kg), and the D4 partial agonist, ABT-724 (3.2 mg/kg), which both increased impulsive choice. The shared effects of these compounds may be explained by their localization within the prefrontal cortex on different groups of neurons. None of the selective agonists and antagonists tested reduced impulsive choice, so further research is needed to determine if direct dopaminergic agonists or antagonists may be therapeutically useful in the treatment of impulse-control disorders.

Pharmacological Therapy of Parkinsons Disease: Current Options and New Avenues

Parkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discussed.

Fluoxetine does not alter the ability of dopamine D 1- and D 2-like agonists to substitute for cocaine in squirrel monkeys

Fluoxetine has been shown to enhance several behavioral effects of cocaine, including its discriminative-stimulus effects. An interaction between increased serotonergic and dopaminergic actions produced by blockade of serotonin and dopamine reuptake, is one possible mechanism for the enhancement. The present study investigated the effects of fluoxetine on the cocaine-like discriminative-stimulus effects of the D 2-like agonists quinpirole and (−)-NPA, and the D 1-like agonist SKF 82958 in squirrel monkeys trained to discriminate cocaine. The direct dopaminergic agonists, injected 5 min before testing, produced maximal levels of cocaine-appropriate responding of 50% (0.3 mg/kg, SKF 82958), 67% (0.003 mg/kg, (−)-NPA), and 77% (0.1 mg/kg, quinpirole) with ED 50 values of 0.43, 0.003, and 0.06 mg/kg, respectively. Fluoxetine at doses up to 10 mg/kg (also 5 min before testing) did not alter the effectiveness or the potency of any of the dopamine agonists in substituting for cocaine. The present failure of fluoxetine to alter the cocaine-like discriminative effects of the dopamine agonists is consistent with the notion that the mechanism underlying the enhancement of the effects of cocaine by fluoxetine is not simply an interaction between enhanced serotonergic and dopaminergic activation as it is not obtained with direct-acting dopamine receptor agonists.

Sleep disorders in Parkinson’s disease

Sleep disorders in Parkinson's disease (PD) are frequent and have numerous etiologies. Both nighttime sleep disturbances and daytime sleepiness can occur. The key to effective treatment is appropriate diagnosis. A careful interview of the patient and his or her bed partner provides direction for additional evaluations. Referral to a sleep specialist for quantitative studies is necessary to evaluate for rapid eye movement (REM) sleep behavior disorder, sleep apnea, periodic limb movements, and other sleep disorders. Excessive daytime sleepiness may be attributed to interrupted nighttime sleep or daytime medications (particularly the dopamine agonists) or it may be intrinsic to PD. When the diagnosis is established, treatment is directed toward the primary sleep disturbance. Fragmented sleep due to recurrence of PD symptoms may improve with the use of long-acting preparations of carbidopa/levodopa. Sleep apnea is treated using continuous positive airway pressure, and REM sleep behavior disorder may improve using pharmacologic interventions, although controlled trials are lacking. Restless legs syndrome and periodic limb movements during sleep are treated with direct dopaminergic agonists at bedtime. Excessive daytime sleepiness related to the use of direct dopaminergic agonists may improve with dosage reduction or discontinuation. Stimulants such as modafinil may provide modest benefit.

Effects of APGW-AMID on [Ca] in rat pheochromocytoma PC12 cells

Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms. Thus, the present study was designed to verify whether the 5AR inhibitor finasteride (FIN) may counteract the dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. First, we assessed the acute and chronic effect of different doses of FIN (30–60 mg/kg) on LID, in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of FIN on LID and its impact on l-DOPA efficacy, we assessed abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30–60 mg/kg/24 days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the impact of FIN on LID may be ascribed to a modulation of the D1- or D2/D3-receptor function, dyskinesias were assessed in l-DOPA-primed 6-OHDA-lesioned rats that received FIN in combination with selective direct dopaminergic agonists. Finally, we set to investigate whether FIN may produce similar effect in female hemiparkinsonian rats, as seen in males.The results indicated that FIN administrations significantly dampened LID in all tested treatment regimens, without interfering with the ability of l-DOPA to ameliorate forelimb use in the stepping test. The antidyskinetic effect appears to be due to modulation of both D1- and D2/D3-receptor function, as FIN also reduced abnormal involuntary movements induced by the selective D1 receptor agonist SKF-82958 and the D2/D3 receptor agonist ropinirole. Significant dampening of LID was also observed in female rats, although only at the higher tested dose.Clinical investigations are warranted to assess whether similar protection from dyskinesia is seen in PD patients.

512 Effects of erythropoietin on PC12 cells

Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms. Thus, the present study was designed to verify whether the 5AR inhibitor finasteride (FIN) may counteract the dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. First, we assessed the acute and chronic effect of different doses of FIN (30–60 mg/kg) on LID, in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of FIN on LID and its impact on l-DOPA efficacy, we assessed abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30–60 mg/kg/24 days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the impact of FIN on LID may be ascribed to a modulation of the D1- or D2/D3-receptor function, dyskinesias were assessed in l-DOPA-primed 6-OHDA-lesioned rats that received FIN in combination with selective direct dopaminergic agonists. Finally, we set to investigate whether FIN may produce similar effect in female hemiparkinsonian rats, as seen in males.The results indicated that FIN administrations significantly dampened LID in all tested treatment regimens, without interfering with the ability of l-DOPA to ameliorate forelimb use in the stepping test. The antidyskinetic effect appears to be due to modulation of both D1- and D2/D3-receptor function, as FIN also reduced abnormal involuntary movements induced by the selective D1 receptor agonist SKF-82958 and the D2/D3 receptor agonist ropinirole. Significant dampening of LID was also observed in female rats, although only at the higher tested dose.Clinical investigations are warranted to assess whether similar protection from dyskinesia is seen in PD patients.

Low level lead exposure increases sensitivity to the stimulus properties of dopamine D 1 and D 2 agonists

To examine the impact of Pb exposure on dopaminergic (DA) function, weanling rats were chronically exposed to 0, 50 or 250 ppm Pb acetate in drinking water. At 3 months of age, the rats were trained to discriminate the stimulus properties of either the D 1 agonist SKF38393 (3.0 mg/kg i.p.; D 1/sal) or the D 2 agonist quinpirole (0.05 mg/kg i.p., D 2/sal) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. Lead-exposed rats learned the discriminations faster than respective controls. Moreover, they exhibited greater levels of drug lever responding to lower doses of the training drugs (D 1/sal and D 2/sal), and to selected doses of other direct and indirect DA agonists (D 2/sal only), including apomorphine, cocaine and (+)-amphetamine, and less blockade of drug lever responding by haloperidol (D 2/sal). Taken together, these findings are consistent with a generalized DA supersensitivity. There were no differential Pb effects when non-DA compounds including morphine, pentobarbital and MK-801 were substituted for the training drugs, indicating the selectivity of the DA effects in the context of these experiments, and the improbability of a non-specific behavioral causation. Pb-exposed rats in the D 2/sal group also showed a pronounced enhancement of drug lever responding when NMDA was substituted for quinpirole, suggesting the possibility of a Pb-induced NMDA supersensitivity as well.

Catecholamines and the sleep-wake cycle II. REM sleep

The exact role of catecholamines (CA) on REM sleep is still controversial. Lesion studies suggest that norepinephrine plays a neuromodulatory role in REM sleep. Support for this view is provided by pharmacological studies in which noradrenergic neurons are activated or inhibited. Thus, disturbances in the dynamic balance between neurochemical systems may alter the conditions under which optimal REM sleep takes place. Discrete radiofrequency lesions to the pontine giganto-cellular tegmental field (which includes the nuclei reticularis pontis oralis and caudalis and where cholinergic and cholinoceptive neurons have been described), result in the elimination of REM sleep. Circumscribed, electrolytic lesions of the locus coeruleus (IC) area, which only minimally extend beyond it, eliminate atonia and reduce PGO activity in REM sleep. Selective destruction of the LC or ascending noradrenergic axons with 6-hydroxydopamine does not result in significant changes of tonic or phasic components of desynchronized sleep. These results indicate that noradrenergic neurons are not necessary for the initiation and maintenance of REM sleep. Most probably, many of the effects attributed to noradrenergic structures are due to destruction of non-noradrenergic neurons and fibers of passage in the lesioned area. Inhibition of CA synthesis with α-methyl-p-tyrosine has resulted in conflicting effects on REM sleep, which could be related to factors other than NE depletion. Systemic administration of dopamine-β-hydroxylase inhibitors (disulfiram, diethyldithiocarbamate, FLA-63, fusaric acid) produced consistent reductions of REM sleep. However, the simultaneous increase of 5-HT and DA levels complicates the interpretation of these results. Selective pharmacological stimulation of presynaptic α-adrenergic (α2) receptors with clonidine, xylazine or α-methyl-dopa decreases REM sleep. Specific blockade of α 2-receptors with yohimbine, piperoxane or tolazoline also reduces desynchronized sleep, but increases wakefulness. In contrast, drugs with similar affinity for pre and postsynaptic (α1) adrenoceptors (phentolamine) markedly increase REM sleep. Compounds Compounds with agonistic activity at postsynaptic α-adrenergic sites (methoxamine) consistently reduce REM sleep, while derivatives with inhibitory activity restricted to these receptors (thymoxamine, prazosin) produce REM sleep increments. Results from studies where propranolol and isoproterenol were administered to laboratory animals point to an involvement of β-adrenergic mechanisms in REM sleep modulation. Although there is no direct evidence to support a dopaminergic influence upon REM sleep executive mechanisms, indirect pharmacological data suggests a neuromodulatory role for dopaminergic neurons. Direct dopaminergic agonists and antagonists show biphasic effects on REM sleep. Low dosages of apomorphine increase, while large doses decrease, REM sleep. Opposite effects are observed after the dopaminergic antagonist pimozide. These dose-dependent effects seem to be related to the activation or blockade of different receptors.