Indirect Dopamine Receptor Agonist Research Articles

Muscarinic receptor agonists decrease cocaine self-administration rates in drug-naive mice

(5 R,6 R)-6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane (PTAC) is a selective muscarinic receptor ligand. The compound exhibits high affinity for central muscarinic receptors with partial agonist mode of action at muscarinic M 2 and M 4 and antagonist mode of action at muscarinic M 1, M 3 and M 5 receptor subtypes. The compound was earlier reported to exhibit functional dopamine receptor antagonism in rodents despite its lack of affinity for dopamine receptors. In the present study, we report that PTAC, as well as the muscarinic receptor agonists pilocarpine and oxotremorine, dose-dependently decreased rates of intravenous self-administration (fixed ratio 1) of the indirect dopamine receptor agonist cocaine in drug naive mice. Similar decreases in cocaine self-administration rates were obtained with the dopamine receptor antagonists olanzapine, clozapine, risperidone, fluphenazine and haloperidol. These findings suggest that compounds with partial muscarinic receptor agonist mode of action may be used in the medical treatment of cocaine abuse.

Electrophysiological pharmacology of the autoreceptor-mediated responses of dopaminergic cells to antiparkinsonian drugs

It is generally accepted that the dopamine receptor ligands currently used in the treatment of parkinsonian symptoms mainly stimulate dopamine (DA) receptors of the D2 family to produce beneficial effects. Although several animal models can provide useful indications on the activity of the antiparkinsonian drugs in the brain, the specific cellular sites and the mechanism of action of these therapeutic agents are not completely known. In this article, Nicola Mercuri, Antonello Bonci and Giorgio Bernardi suggest that the electrophysiological effects of antiparkinsonian drugs on nigral dopaminergic cells are related to their clinical efficacy. In addition, they report that the stimulation of the D2 ‘autoreceptors’ located on the residual dopamine-containing cells is implicated in the therapeutic response elicited by dopamine receptor agonists in parkinsonism. Thus, an electrophysiological approach, which can give basic information regarding the actions of direct and indirect DA receptor agonists on the dopaminergic neurones, might be relevant for the evolution of the pharmacological strategies in Parkinson's disease.

Electrophysiological pharmacology of the autoreceptor-mediated responses of dopaminergic cells to antiparkinsonian drugs

It is generally accepted that the dopamine receptor ligands currently used in the treatment of parkinsonian symptoms mainly stimulate dopamine (DA) receptors of the D2 family to produce beneficial effects. Although several animal models can provide useful indications on the activity of the antiparkinsonian drugs in the brain, the specific cellular sites and the mechanism of action of these therapeutic agents are not completely known. In this article, Nicola Mercuri, Antonello Bonci and Giorgio Bernardi suggest that the electrophysiological effects of antiparkinsonian drugs on nigral dopaminergic cells are related to their clinical efficacy. In addition, they report that the stimulation of the D2 'autoreceptors' located on the residual dopamine-containing cells is implicated in the therapeutic response elicited by dopamine receptor agonists in parkinsonism. Thus, an electrophysiological approach, which can give basic information regarding the actions of direct and indirect DA receptor agonists on the dopaminergic neurones, might be relevant for the evolution of the pharmacological strategies in Parkinson's disease.

Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa.

In rats with unilateral lesions of the nigrostriatal dopamine pathway with 6-hydroxydopamine, the motor stimulating effects of levodopa, an indirect dopamine receptor agonist, evidenced by contraversive rotations, become enhanced upon repeated intermittent administration. However, the mechanisms of this behavioral sensitization are essentially unknown. We show that development of sensitization is accompanied by a progressive appearance of D3 receptor mRNA and binding sites, visualized by in situ hybridization and 7-[3H] hydroxy-N,N-di-n-propyl-2-aminotetralin autoradiography, respectively, occurring in the denervated caudate putamen, a brain area from which this receptor subtype is normally absent. Development and decay of these two processes occur with closely parallel time courses, whereas there were no marked changes in D1 or D2 receptor mRNAs. D3 receptor induction by levodopa is mediated by repeated D1 receptor stimulation, since it is prevented by the antagonist SCH 33390 and mimicked by the agonist SKF 38393, but not by two D2 receptor agonists. The enhanced behavioral response to levodopa is mediated by the newly synthesized D3 receptor, since it is antagonized by nafadotride, a preferential D3 receptor antagonist, in low dosage, which has no such effect before D3 receptor induction. D3 receptor induction and behavioral sensitization are also accompanied by a sustained enhancement of prodynorphin mRNA level and a progressively decreasing expression of the preprotachykinin gene. We propose that imbalance between dynorphin and substance P release from the same striatonigral motor efferent pathway, related to D3 receptor induction, is responsible for behavioral sensitization.

Intrastriatal injection of a muscarinic receptor agonist and antagonist regulates striatal neuropeptide mRNA expression in normal and amphetamine-treated rats

Systemic administration of the muscarinic receptor antagonist, scopolamine, augments, whereas the muscarinic receptor agonist, oxotremorine, attenuates behaviors (locomotion and stereotypies) and preprodynorphin (PPD) and substance P (SP) gene expression in striatonigral neurons induced by the indirect dopamine receptor agonist, amphetamine (AMPH). In contrast, systemic scopolamine blocks, whereas oxotremorine augments, AMPH-stimulated preproenkephalin (PPE) gene expression in striatopallidal neurons. This study investigated the site of action of these effects by administering scopolamine and oxotremorine directly into the striatum and assessing the expression of neuropeptide mRNAs with quantitative in situ hybridization. Unilateral injection of scopolamine into the dorsal striatum augmented, and oxotremorine attenuated, AMPH (2.5 mg/kg, i.p.)-stimulated behaviors. Intrastriatal scopolamine at a concentration of 62 mM, but not 6.2 mM, increased basal levels of PPD and SP mRNAs in the dorsal striatum. In addition, both 6.2 and 62 mM scopolamine significantly augmented AMPH-stimulated PPD and SP mRNA levels. Intrastriatal infusion of 1.6 or 8.1 mM oxotremorine did not alter basal levels of striatal PPD and SP mRNAs. However, both concentrations of oxotremorine completely blocked AMPH-stimulated SP mRNA and oxotremorine at 8.1 mM blocked AMPH-stimulated PPD mRNA. In contrast, PPE induction by AMPH was blocked by 62, but not 6.2, mM scopolamine. Both concentrations of oxotremorine tended to augment basal and AMPH-stimulated PPE mRNA in the dorsal striatum but the trend was not significant. These data demonstrate an inhibition of striatonigral, and facilitation of striatopallidal, gene expression through activation of local striatal muscarinic receptors, which is consistent with the changes seen after systemic administration of muscarinic agents. Therefore, muscarinic cholinergic regulation of basal and stimulated expression of neuropeptide mRNA is processed within the striatum.

The Molecular Basis of Dopamine and Glutamate Interactions in the Striatum

Publisher Summary Striatal neurons display a high degree of adaptability to changes in dopamine-receptor activation. Drug dependence and withdrawal symptoms after cessation of chronic drug abuse are signs of adaptation to hyperstimulation of dopamine receptors. This chapter summarizes rseveral researches to investigate the cellular components linking dopamine-receptor stimulation with the expression of a particular target gene, c-fos . C-fos is an immediate early gene that is a perfect candidate for studies of neuroplasticity. Psychostimulants, like the indirect dopamine-receptor agonists, cocaine or amphetamine, stimulate c-fos synthesis. In primary striatal cultures, direct activation of D1 receptors with dopamine or D1 agonists also lead to an increase of c-fos levels. D1 dopamine receptor stimulation leads to an increase in cyclic adenosine monophosphate (cAMP) levels, phosphorylation of 133 Ser cAMP-responsive element-binding protein (CREB), and induction of c-fos gene expression. Glutamate-receptor stimulation leads to phosphorylation of 133 Ser cAMP-CERB and induces c-fos gene expression without increasing cAMP levels. The NMDA antagonist MK 801 prevents dopamine-mediated 133 Ser CREB phosphorylation and c-fos gene expression but does not inhibit cAMP induction. Dopamine-receptor-mediated c-fos expression is dependent on functional NMDA receptors and Ca 2+ influx. The route of Ca 2+ influx into the neuron may be crucial for gene expression, because neither L-type Ca 2+ channel blockers nor KCl can reproduce the effects of NMDA antagonists or agonists. The inhibition of dopamine-mediated c-fos gene expression by MK 801 and the activation by glutamate reflect intrastriatal and intraneuronal rather than interneuronal events.

1 S,3 R-ACPD has cataleptogenic effects and reverses MK-801- and less pronounced, d,l-amphetamine-induced locomotion

The purpose of this study was to examine the motor effects of (1 S,3 R)-1-amino-cyclopentane-1,3-dicarboxylic acid (1 S,3 R-ACPD), an agonist at metabotropic glutamate receptors, its interaction with dizocilpine (MK-801), a NMDA receptor antagonist, and with d,l-amphetamine, an indirect dopamine receptor agonist. 1 S,3 R-ACPD (20, 30, 40, 80 μg) evoked prominent locomotor and exploratory deficits in an open-field hole-board test and a moderate akinesia and rigidity in a catalepsy test (30, 40, 80 μg). MK-801 (0.08, 0.16, 0.32 mg/kg i.p.) as well as d,l-amphetamine (1.0, 2.0, 3.0 mg/kg i.p.) potently reversed 1 S,3 R-ACPD-induced (80 μg) catalepsy. MK-801 and d,l-amphetamine, administred alone, induced motor stimulation. 1 S,3 R-ACPD (80 μg) reversed the effects of the two lower doses of MK-801. 1 S,3 R-ACPD reversed d,l-amphetamine-induced motor stimulation to a minor extent than that of MK-801. Thus motor deficits induced by 1 S,3 R-ACPD were reversed by both, NMDA receptor blockade and dopamine receptor activation. 1 S,3 R-ACPD reversed motor stimulation, induced by NMDA receptor blockade and, however less pronounced, that by dopamine receptor activation.

Initial increases in extracellular dopamine in the ventral tegmental area provide a mechanism for the development of desipramine-induced sensitization within the midbrain dopamine system.

In an attempt to understand the basis of the changes in the mesolimbic dopamine system that occur in response to chronic treatment with the antidepressant drug, desipramine HCl (DMI), we monitored changes in extracellular dopamine in ventral tegmental area (VTA) and nucleus accumbens septi (NAS) using in vivo microdialysis in freely moving animals. Early in treatment at a time before changes in the responsiveness of the dopamine system are observed, basal levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were found to be increased in the VTA of rats treated with 5.0 mg/kg DMI twice daily for 6 days compared to those of saline-treated animals. After 12 days of treatment, and in a second group of animals after 18 days of treatment, basal levels of dopamine, DOPAC, HVA and 5HIAA, and levels in response to challenge with 1.5 mg/kg d-amphetamine sulphate were measured in the NAS. No differences in these measures taken in NAS were found between DMI- and saline-pretreated animals after 12 days of treatment. In DMI-treated animals tested after 18 days, the dopamine response to amphetamine was elevated compared to that of saline-treated animals. Furthermore, although there were no differences in basal levels of dopamine, basal levels of DOPAC and HVA were increased in DMI-treated animals. These findings lend support to the view that the time-dependent sensitization of dopaminergic function brought about by the tricyclic antidepressants may share processes in common with the development of sensitization to the indirect dopamine receptor agonist, amphetamine.

Alteration of cataleptic responses induced by dopamine receptor antagonists after chronic cocaine administration in mice

The influence of chronic treatment of mice with cocaine, an indirect dopamine receptor agonist, on the cataleptic effects of R-(+)-chloro-2,3,4,5,-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepin-7ol hydrochloride (SCH23390), a dopamine D 1 receptor antagonist, or haloperidol, mainly a dopamine D 2 receptor antagonist, was investigated. Mice were given cocaine (10 mg/kg s.c.) once every other day for 7 (4 injections), 15 (8 injections) or 21 (11 injections) days. The cataleptic effects of SCH23390 (0.3 mg/kg i.p.) were significantly reduced when it was given 1–7 days after the last dose of a 7- or 15-day pretreatment course of cocaine. When SCH23390 was given 14–21 days after the cocaine the cataleptic effect was increased in the 15-day, but not the 7-day, cocaine-pretreated mice. However, after a 21-day treatment with cocaine, a challenge dose of SCH23390 given 1–3 days thereafter produced a decreased cataleptic response, but an increased response after 7–21 days. The cataleptic effects of haloperidol (0.3 mg/kg i.p.) were reduced when it was given 1–7 days after the last dose of a 7-day pretreatment, but increased 1–3 days after that of a 15-day pretreatment with cocaine (10 mg/kg s.c.). The pretreatment with cocaine for 21 days did not affect the haloperidol catalepsy during a 1- to 3-day withdrawal period. However, haloperidol catalepsy was decreased only 7 days, then reversed 14 days and gradually increased 21 days after the last injection of a 15- or 21-day pretreatment course of cocaine. These results suggest that chronic treatment with the indirect dopamine receptor agonist, cocaine, caused supersensitivity of dopamine D 1 receptors (a decrease in SCH23390 catalepsy) during the early withdrawal period and subsensitivity (an increase in SCH23390 catalepsy) after a longer period of withdrawal. It was apparent that the longer the period and the higher the dose of pretreatment with cocaine, the less were the alterations in initial responses and the greater were the alterations in subsequent responses to the dopamine D 1 receptor antagonists.

Dynorphin opioid inhibition of cocaine-induced, D1 dopamine receptor-mediated immediate-early gene expression in the striatum.

Neurons in the striatum that project to the substantia nigra contain the opioid peptide dynorphin. Stimulation of D1 dopamine receptors results in increased expression of mRNA encoding dynorphin as well as expression of immediate-early genes such as c-fos in these neurons. Levels of dynorphin vary in different regions of the normal rat striatum, being highest in ventral and medial striatum. In a prior study, we have shown that both regional and temporal patterns of c-fos induction following treatment with the indirect dopamine receptor agonist cocaine are inversely related to those of dynorphin expression. These results suggested that dynorphin is involved in regulating the responsiveness of these neurons to dopamine input. In the present experiments, we examined such a potential role for dynorphin by analyzing the influence of the dynorphin (kappa opioid receptor) agonist spiradoline on immediate-early gene induction by cocaine, and we determined that this immediate-early gene response is mediated by D1 dopamine receptors located in the striatum. As a marker of neuron activation, expression of c-fos and zif 268 immediate-early genes was assessed with quantitative in situ hybridization histochemistry. Results showed that 1) intrastriatal infusion of the D1 dopamine receptor antagonist SCH-23390 (2.5-250 pmol) resulted in a dose-dependent blockade of immediate-early gene induction by cocaine (30 mg/kg); 2 systemic administration of the kappa opioid receptor agonist spiradoline (0.5-10.0 mg/kg) decreased cocaine-induced expression of c-fos and zif 268 mRNAs in striatum in a dose-dependent manner; 3) intrastriatal infusion of spiradoline (1-50 nmol) also suppressed immediate-early gene induction by cocaine, demonstrating that kappa opioid receptors located in the striatum mediate such an effect; and 4) systemic and intrastriatal administration of spiradoline also affected immediate-early gene expression in cortex. These results demonstrate that, in striatum, immediate-early gene induction by cocaine is a D1 dopamine receptor-mediated process that is inhibited by activation of kappa opioid receptors. Therefore, these findings suggest that the striatal dynorphin opioid system acts directly and/or indirectly to inhibit dopamine input to striatonigral neurons through kappa opioid receptor-mediated processes in the striatum.

Cocaine-induced c-fos messenger RNA is inversely related to dynorphin expression in striatum

The effects of the indirect dopamine receptor agonist cocaine in the striatum on levels of mRNAs of the immediate-early gene c-fos and the neuropeptides dynorphin, substance P, and enkephalin were analyzed with quantitative in situ hybridization histochemistry. Both single (acute) and repeated (twice a day for 4 d) systemic injections of cocaine (3.75-30 mg/kg) to rats resulted in dose-dependent, regionally specific elevations of mRNA expression in striatal neurons. A single drug treatment elevated c-fos mRNA expression, whereas repeated treatments resulted in little c-fos expression but elevated dynorphin mRNA levels. Both the regional and temporal patterns of gene expression revealed an inverse relationship between dynorphin and c-fos expression. This relationship was examined in a time course experiment in which cocaine (30 mg/kg) was administered for 1, 2, 3 or 4 d. Basal levels of dynorphin expression were relatively high in the ventral striatum, including the nucleus accumbens, a ventrolateral region, and an area along the medial bank of the striatum. A single injection of cocaine induced c-fos mRNA in striatal areas with low basal expression of dynorphin. Thus, c-fos mRNA induction was highest in the dorsal central striatum, where basal dynorphin mRNA levels were lowest. In this region, dynorphin mRNA expression increased on subsequent treatment days parallel to diminished c-fos mRNA induction. Changes in substance P. mRNA levels appeared to match directly both the temporal and regional patterns of c-fos induction. Enkephalin mRNA expression was altered, but only slightly, by these cocaine treatments. Statistical analysis of the regional patterns of basal and altered mRNA levels shows a unique inverse relationship between basal dynorphin expression and c-fos induction by cocaine. Further evidence of this relationship is provided by the dose-dependent blockade of cocaine-induced c-fos expression by spiradoline, a dynorphin agonist. Together, these results suggest that the restricted regional pattern of cocaine-induced c-fos expression is related, in part, to the basal level of dynorphin expression, and that cocaine treatment elevates dynorphin expression in striatal regions with a strong c-fos response, thereby limiting subsequent c-fos induction by cocaine. These findings lead to the hypothesis that dynorphin acts to regulate the responsiveness of striatal neurons to dopamine stimulation.

Different effects of direct and indirect dopamine receptor agonists on immobility time in reserpine-treated mice

1. The effects of dopamine agonists on the immobility time in mice were examined. 2. Apomorphine (APO), bupropion (BUP), bromocriptine (BRC) and quinpirole but not SKF 38393 elicited anti-immobility effect. The effect of the agonists was decreased by the D-2 antagonist sulpiride but not by the D-1 antagonist SCH 23390. 3. In animals pretreated with reserpine, the anti-immobility effects of APO and quinpirole were potentiated, while the response of BPU was decreased and that of BRC was not changed. 4. It is concluded that D-2 dopamine receptors are involved in the anti-immobility effects of dopaminergic agents, D-2 dopamine receptors may become hypersensitive by reserpine and BUP exerts its response through indirect dopaminergic if mechanism.

Memory facilitation produced by dopamine agonists: Role of receptor subtype and mnemonic requirements

The role of dopamine (DA) receptor subtypes in the acquisition of two memory tasks in the 8-arm radial maze was examined. The receptors were manipulated with posttraining, subcutaneous injections of an indirect DA receptor agonist (D-amphetamine), a selective D2 receptor agonist (LY171555), and a selective D1 receptor agonist (SKF-38393). On a win-stay task (sensitive to caudate nucleus lesions) a light cue signalled the location of food in 4 randomly selected arms on each trial. Rats were given one trial per day and injected after training on day 5. D-Amphetamine (2.0 mg/kg) and LY171555 (2.0 mg/kg) improved performance relative to controls; however SKF-38393 (1–4 mg/kg) had no effect on the acquisition of win-stay behavior. On a win-shift task (sensitive to fornix/hippocampal lesions) a delay of 18 hr was imposed between the first 4 and second 4 choices; drugs were injected after the first 4 choices. D-Amphetamine (1.0 mg/kg) and LY171555 (2.0 mg/kg) significantly improved retention relative to controls. SKF-38393 (1–4 mg/kg) had no effect on win-shift retention. These results suggest that the memory-improving properties of DA agonists on tasks sensitive to both hippocampal and caudate lesions are mediated by the D2 receptor.

The effects of haloperidol on amphetamine- and methylphenidate-induced conditioned place preferences and locomotor activity.

Place preferences induced by the indirect dopamine (DA) receptor agonists amphetamine (AMP) and methylphenidate (MPD) were investigated using an unbiased compartment procedure. In this procedure, prior to drug conditioning, rats did not exhibit preferences for either of the two compartments in a shuttle box. Both stimulants produced place preferences. Repeated testing of the MPD conditioned animals revealed an extinction-like decrease in preferences, suggesting that place preferences produced by MPD result from conditioning of MPD's reinforcing properties to environmental cues. During conditioning, the DA receptor antagonist haloperidol was administered prior to drug (S+) treatments, or prior to both drug and vehicle (S-) treatments. Haloperidol pretreatment blocked place preferences induced by AMP but not by MPD. In contrast, haloperidol blocked locomotor activity stimulated by either AMP or MPD. These results suggest that the reinforcing properties of MPD and AMP may be mediated by different mechanisms, while the locomotor stimulant effects of the two drugs have common neural substrates.