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PubMed1992

An assay to measure the simultaneous uptake of [3H]dopamine and [14C]serotonin by the human platelet reveals an imipramine-insensitive [3H]dopamine uptake mechanism.

To determine whether a specific dopamine uptake mechanism is present on the human platelet the simultaneous uptake of [3H]dopamine and [14C]serotonin by platelets was measured. Utilising a dual radiolabel uptake technique, platelets have been shown to take up serotonin more rapidly and to a greater extent than they take up dopamine. Furthermore, at high concentrations serotonin was able to reduce dopamine uptake by platelets by 60% whereas dopamine had no effect on serotonin uptake. Similarly, imipramine and reserpine reduced (97% and 74% respectively) serotonin uptake by platelets in a dose-dependent manner, but did not affect the uptake of dopamine. Our data show that platelets take up dopamine by a mechanism independent of the imipramine-sensitive serotonin uptake mechanism. Furthermore, the increased capacity of platelets to store serotonin is because serotonin, unlike dopamine, is transported into the dense granules of the platelet.

Biological Transport↗
PubMed1994

Nonlinear relationship between impulse flow, dopamine release and dopamine elimination in the rat brain in vivo.

Central dopaminergic neurons exhibit two kinds of discharge activity: single spikes and bursts of two to six action potentials. Since these neurons can switch from one discharge pattern to the other whereas the mean discharge rate remains little affected, bursts may be more potent in triggering the release of their neurotransmitter, dopamine. Electrical stimulations mimicking the bursting pattern were actually twice as potent as regularly spaced stimulations to enhance the dopamine extracellular concentration. This suggested that dopamine release might be facilitated by increasing the impulse flow frequency. The high extracellular overflow evoked by a burst might also be due to accumulation of the released dopamine whereas, at lower frequencies, dopamine might be readily eliminated between every action potential. In the present study the dopamine overflow evoked by electrical stimulation of the dopaminergic pathway was measured in vivo by carbon fibre electrodes combined with continuous amperometry. We observed a small facilitation of the release per pulse during stimulations mimicking a burst but only in mesolimbic areas. The high extra-cellular dopamine level evoked by a burst was mainly due to accumulation of the released dopamine.

Action Potentials↗
PubMed1983

Prolactin increases the activity of tuberoinfundibular and nigroneostriatal dopamine neurons: prolactin antiserum inhibits the haloperidol-induced increases in dopamine synthesis rates in median eminence and striatum of rats.

The role of PRL in mediating the haloperidol-induced increase in tuberoinfundibular dopamine synthesis rate was assessed by studying the effects of administration of PRL antiserum. Antiserum to PRL generated in rabbits and not cross-reacting with other anterior pituitary hormones was administered IV to adult, male rats which received haloperidol 2.5 mg/kg or tartaric acid vehicle SC 22 hr and 12 hr before measurement of dopamine turnover. Comparable groups of haloperidol or vehicle-treated animals received normal rabbit serum as control. Dopamine synthesis or turnover rate was estimated by measurement of accumulation of L-dihydroxyphenylalanine following inhibition of L-aromatic amino acid decarboxylase with m-hydroxybenzylhydrazine. Haloperidol increased median eminence dopamine synthesis rate, and PRL antiserum completely prevented this effect, supporting the thesis that the haloperidol-induced increase in tuberoinfundibular dopamine turnover is mediated by PRL. PRL antiserum did not alter basal median eminence dopamine synthesis rate in male rats. In addition to its effect in median eminence, PRL antiserum blunted the haloperidol-induced increase in striatal dopamine synthesis rate, suggesting that the haloperidol-induced increase in nigroneostriatal dopamine turnover is mediated in part by PRL. Neither haloperidol nor PRL antiserum altered serotonin synthesis rate in mediobasal hypothalamus or striatum. The data provide further support for a mechanism by which PRL can regulate its own secretion. They also suggest that prolactin alters the activity not only of tuberoinfundibular but also of nigroneostriatal neurons.

Animals↗
PubMed1994

Early L-dopa treatment initially retards but later enhances dopamine receptor supersensitivity following unilateral dopamine denervation.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriatal dopamine neurons were administered 25 mg/kg L-DOPA methyl ester/2 mg/kg carbidopa once or twice per day or saline in separate treatment groups for 13 days. Treatment was initiated within 18-20 h postoperative, well-before the onset of denervation supersensitivity. Contralateral rotation emerged as a response to L-DOPA on day 7 postoperative first in the L-DOPA once/day group and then on day 9 for the L-DOPA twice/day group. Thus, early postoperative L-DOPA treatment retarded but did not prevent the development of dopamine receptor supersensitivity. Following a 14-day withdrawal period, these same L-DOPA treated groups exhibited substantially higher rates of contralateral rotation to an L-DOPA challenge as compared to a drug-naive group with comparable 6-OHDA lesions. HPLC-EC measurements of L-DOPA in striatal and cortical tissue samples showed no differences in concentration across the L-DOPA treatment groups. There were several differences, however, in the neurochemical impact of L-DOPA on frontal cortex vs. striatum. In the striatum but not the cortex, L-DOPA concentrations were higher in the 6-OHDA than the intact hemisphere and, L-DOPA increased dopamine concentrations in cortex but not in the striatum. Behaviorally, L-DOPA exerted two diametrically opposite effects linked to the state of dopamine receptors. Prior to the onset of dopamine receptor supersensitivity L-DOPA suppressed locomotor behavior and delayed the emergence of denervation supersensitivity. Once denervation supersensitivity developed, however, the L-DOPA engaged sensitization mechanisms and enhanced locomotor behavior and dopamine receptor supersensitivity. These findings suggest that the initiation of antiparkinsonian treatment prior to the onset of denervated dopamine receptor supersensitivity in the 6-OHDA model is a valuable strategy to determine if a drug treatment retards or facilitates the development of dopamine receptor supersensitivity.

Animals↗
PubMed2001

Activation of 5-HT(1B/1D) receptors in the mesolimbic dopamine system increases dopamine release from the nucleus accumbens: a microdialysis study.

This study was designed to investigate the role of 5-hydroxytryptamine (5-HT)(1B) receptors located in the ventral tegmental area and nucleus accumbens in the modulation of accumbal dopaminergic transmission. The selective 5-HT(1B) receptor agonist CP 93129 [3-(1,2,5,6-tetrahydro-4-pyridyl)pyrrolo[3,2-b]pyrid-5-one] was administered into the ventral tegmental area or nucleus accumbens of freely moving Sprague-Dawley rats via retrograde microdialysis. The effects of intra-accumbal and intra-tegmental CP 93129 on extracellular dopamine levels in the nucleus accumbens were measured using one- and dual-probe microdialysis, respectively. For dual-probe microdialysis, one probe was in the ventral tegmental area for drug administration and the other in the ipsilateral nucleus accumbens for dopamine measurement. The results show that infusion of CP 93129 (2, 5 and 10 microM) into the nucleus accumbens increased local dopamine levels in a concentration-related manner. Infusion of CP 93129 (10 and 20 microM) into the ventral tegmental area also increased dopamine levels in the ipsilateral nucleus accumbens. The increased dopamine release in the nucleus accumbens produced by intra-accumbal or intra-tegmental CP 93129 was antagonized by co-infusion of cyanopindolol (5 microM), a 5-HT(1B/1A) receptor antagonist, but not by WAY-100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-cyclohexanecarboxamide] (5 microM), a highly selective 5-HT(1A) receptor antagonist. In addition, augmentations of dopamine release in the nucleus accumbens induced by intra-accumbal CP 93129 were sensitive to Na(+) channel blockade with tetrodotoxin. These results are not in opposition to the concept that 5-HT(1B) receptors within the ventral tegmental area and nucleus accumbens are all involved in the modulation of dopamine release in the terminal area of the mesolimbic dopamine system.

Animals↗
PubMed2002

Nucleus accumbens dopamine depletion impairs both acquisition and performance of appetitive Pavlovian approach behaviour: implications for mesoaccumbens dopamine function.

The involvement of mesoaccumbens dopamine in adaptive learning and behaviour is unclear. For example, dopamine may act as a teaching signal to enable learning, or more generally modulate the behavioural expression, or selection, of an already-learned response. The present study investigated the involvement of the mesoaccumbens dopamine system in a fundamental form of learning: Pavlovian conditioning. In this case, the temporal association of a previously neutral visual stimulus and a biologically significant unconditioned stimulus (US), subsequently led to the production of the conditioned response (CR) of discriminated approach behaviour directed toward the conditioned stimulus (CS+), relative to a control (CS-) stimulus. 6-hydroxydopamine lesions of the nucleus accumbens (NAcc), leading to approximately 80% reductions in tissue dopamine, were made at varying time points in four experimental groups of rats, either before or subsequent to the acquisition of the CR. NAcc dopamine depletion produced long-term neuroadaptations in dopamine function 2 months after surgery, and profoundly impaired discriminated Pavlovian approach regardless of when the lesion was made. Thus, NAcc dopamine not only plays a role in conditioned behavioural activation, but also in making the appropriate discriminated response i.e. the direction of response. Further, acquisition lesions produced a far greater impact on discriminated approach than performance lesions. This difference in lesion-induced impairment implies that mesoaccumbens dopamine may play differential roles in the learning and performance of preparatory Pavlovian conditioning.

Animals↗
PubMed2006

Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia.

A line of dopamine-deficient (DD) mice was generated to allow selective restoration of normal dopamine signaling to specific brain regions. These DD floxed stop (DDfs) mice have a nonfunctional Tyrosine hydroxylase (Th) gene because of insertion of a NeoR gene flanked by lox P sites targeted to the first intron of the Th gene. DDfs mice have trace brain dopamine content, severe hypoactivity, and aphagia, and they die without intervention. However, they can be maintained by daily treatment with l-3,4-dihydroxyphenylalanine (L-dopa). Injection of a canine adenovirus (CAV-2) engineered to express Cre recombinase into the central caudate putamen restores normal Th gene expression to the midbrain dopamine neurons that project there because CAV-2 efficiently transduces axon terminals and is retrogradely transported to neuronal cell bodies. Bilateral injection of Cre recombinase into the central caudate putamen restores feeding and normalizes locomotion in DDfs mice. Analysis of feeding behavior by using lickometer cages revealed that virally rescued DDfs mice are hyperphagic and have modified meal structures compared with control mice. The virally rescued DDfs mice are also hyperactive at night, have reduced motor coordination, and are thigmotactic compared with controls. These results highlight the critical role for dopamine signaling in the dorsal striatum for most dopamine-dependent behaviors but suggest that dopamine signaling in other brain regions is important to fine-tune these behaviors. This approach offers numerous advantages compared with previous models aimed at examining dopamine signaling in discrete dopaminergic circuits.

Adenoviridae↗
PubMed1985

Complete conversion of brain D2 dopamine receptors from the high- to the low-affinity state for dopamine agonists, using sodium ions and guanine nucleotide.

Since previous work had shown that brain D2 3,4-dihydroxyphenylethylamine (dopamine) receptors were only partly converted from their high-affinity state to their low-affinity state, we here tested whether it was possible to obtain a complete 100% conversion of these receptors into their low-affinity state. It was first essential to resolve the components of [3H]spiperone binding to dopaminergic sites and nondopaminergic sites in rat striatal homogenates. In the presence of 50 microM S-sulpiride (to occlude the dopaminergic sites), therefore, we first determined that the residual binding of [3H]spiperone (approximately 20%) was inhibited by serotonergic agonists much more effectively than dopamine or noradrenaline, thus identifying the serotonergic component of [3H]spiperone binding. Thus, dopamine (or ADTN) inhibited the binding of [3H]spiperone at a high-affinity site (with dissociation constant of 10 nM dopamine), at a low-affinity site (with dissociation constant of 2,000 nM dopamine), and at the serotonergic site (with dissociation constant of 50,000 nM dopamine). In the absence of sodium ions, the high-affinity site was about 50% occupied by [3H]spiperone, and guanine nucleotide had no effect on this proportion. In the presence of 120 mM NaCl, however, the high-affinity site was reduced to 15% and guanine nucleotide completely eliminated this high-affinity site, 100% of the sites having been completely converted to their low-affinity state. Using [3H]N-propyl-norapomorphine to label the high-affinity state of the dopamine receptor, 50% conversion into the low-affinity state occurred at 45 mM LiCl, 69 mM NaCl, and 202 mM KCl. We conclude that it is possible to convert brain D2 dopamine receptors completely into their low-affinity state, in the presence of NaCl and a guanine nucleotide, providing that appropriate allowance is made for the serotonergic component of [3H]spiperone binding.

Animals↗
PubMed1985

Study of dopamine turnover by monitoring the decline of dopamine metabolites in rat CSF after alpha-methyl-p-tyrosine.

CSF was continuously withdrawn from the third ventricle of anesthetized rats. CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid concentrations were determined every 15 min by liquid chromatography coupled with electrochemical detection. Acute tyrosine hydroxylase inhibition [with alpha-methyl-p-tyrosine (alpha-MPT)] induced an exponential decline in levels of DOPAC and HVA in CSF. The decline in DOPAC and HVA concentrations was identical in CSF and forebrain but was much slower in the striatum, suggesting that CSF metabolites of 3,4-dihydroxyphenylethylamine (dopamine) reflect whole forebrain metabolites. The decay in CSF DOPAC and HVA levels after dopamine synthesis inhibition was also used as an in vivo index of forebrain dopamine turnover after various pharmacological treatments. Haloperidol pretreatment accelerated this decay, confirming the increase in brain dopamine turnover induced by neuroleptics. After reserpine pretreatment (15 h before), alpha-MPT produced a very sharp decay in levels of DOPAC and HVA. This result indicates that the residual dopamine that cannot be stored after reserpine treatment is very rapidly renewed and metabolized. Nomifensine strongly diminished the slope of DOPAC and HVA level decreases after alpha-MPT, a result which can be explained either by a slower dopamine turnover or by the involvement of storage dopamine pools. These results exemplify the use of monitoring the decay of dopamine metabolites after alpha-MPT administration in the study of the pharmacological action of drugs on the central nervous system of the rat.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Inhibition of [3H]dopamine uptake by platelets by the dopamine-D2 receptor agonist RU 24926.

We have examined the effect of the dopamine-D2 receptor agonist RU 24926 (N-n-propyl-di-beta(3-hydroxy-phenyl)-ethylamine HCl) on [3H]dopamine uptake by human platelets. RU 24926 reduced the uptake of [3H]dopamine by platelet-rich plasma and this affect was not reversed by the dopamine-D2 receptor antagonist haloperidol, or the dopamine-D1 receptor antagonist SCH 23390 (8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol). These data suggest that RU 24926 reduces [3H]dopamine uptake by platelets by competing for the dopamine uptake mechanism on the platelet and not by activation of the dopamine-D2 receptor.

Benzazepines↗
PubMed1990

Phencyclidine and related compounds evoked [3H]dopamine release from rat mesencephalic cell cultures by a mechanism independent of the phencyclidine receptor, sigma binding site, or dopamine uptake site.

At concentrations greater than or equal to 100 microM, phencyclidine (PCP), N-(1-(2-thienyl)-cyclohexyl)piperidine (TCP), and MK-801 induced [3H]dopamine release from dissociated cell cultures of rat mesencephalon. This release was Ca2+ independent and tetrodotoxin insensitive. Tetrodotoxin (2 microM) itself had no effect on spontaneous release of [3H]dopamine. [3H]Dopamine release was induced by 1,3-di(2-tolyl)guanidine, a sigma ligand, and by 4-aminopyridine (1-3 mM), a K+ channel blocker. No stereoselectivity was observed for [3H]dopamine release evoked by the dioxadrol enantiomers, dexoxadrol, and levoxadrol, or by enantiomers of N-allylnormetazocine (SKF 10,047). The selective dopamine uptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909) did not affect spontaneous or TCP-evoked [3H]dopamine release. Together, these data suggest that the dopamine-releasing effects of PCP-like compounds on the mesencephalic cells were not mediated by actions at the PCP receptor or sigma binding site, Ca2+, or Na+ channels, or at the high affinity dopamine uptake site. It remains conceivable that blocking actions of PCP-like compounds at voltage-regulated K+ channels may at least partly explain the response. These results are discussed in comparison with findings in intact brain.

2-Amino-5-phosphonovalerate↗
PubMed1991

High glutamate concentrations evoke Ca(++)-independent dopamine release from striatal slices: a possible role of reverse dopamine transport.

Glutamate stimulated the efflux of dopamine from slices of rat striatum superfused with a Krebs' bicarbonate buffer containing a physiological concentration of Mg++ (1.2 mM). This effect was observed in the presence of high concentrations of glutamate (3-10 mM), but not at lower concentrations (0.01-1 mM). The response was not accompanied by increased lactate dehydrogenase activity, a measure of glutamate neurotoxicity. At 10 mM, glutamate increased dopamine efflux by more than 9-fold. This was reduced to about 34% of the control response by either the competitive N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovaleric acid (100 microM) or the noncompetitive N-methyl-D-aspartate receptor antagonist MK 801 [(+)-5-methyl-10,11-dihydro-5H-dibenso[a,d]cyclohepten-5,10- imine hydrogen maleate] (1-10 microM), but was unaffected by a kainate/quisqualate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10-100 microM). Glutamate-stimulated dopamine efflux also was unaffected by tetrodotoxin (0.5 microM), withdrawal of extracellular Ca++ [and addition of 1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid] or systemic administration of reserpine (5 mg/kg, 24 hr before the experiment), an inhibitor of the vesicular storage of dopamine. In contrast, nomifensine (10 microM), an inhibitor of high-affinity dopamine transport, reduced glutamate-induced dopamine efflux to 15% of the control response. Moreover, the response to glutamate was blocked by deleting NaCl from the medium. Collectively, these results suggest that, at high concentrations and in the presence of Mg++, glutamate can stimulate the release of dopamine by a mechanism that does not use Ca(++)-dependent exocytosis but instead involves a reversal of the dopamine transport system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Examinations on contribution of bradykinin in the action of dopamine in circulatory system of rats. I. Influence of bradykinin in the action of dopamine on arterial blood pressure of rats.

The influence of different doses of bradykinin (2.5 micrograms, 5 micrograms/kg i.v.) and dopamine (0.5 micrograms - a small dose and 25 micrograms, 250 micrograms/kg i.v. - a big dose) administered into the rat femoral artery on the blood pressure was estimated. Dopamine evoked hypotension (the small dose) or hypertension (the big dose). Bradykinin evoked dose-dependent decrease of the blood pressure. Bradykinin (2.5 micrograms/kg i.v.) administered in the 45th sec of the dopamine action enhanced the hypertensive effect and decreased the hypotensive effect of dopamine. Dopamine administered in the big dose after phentolamine and propranolol evoked hypotension. This effect was stronger after administration of dopamine (25 micrograms/kg i.v.). The hypotensive action of bradykinin persisted in spite of phentolamine and propranolol application but this peptide did not change the hypotensive effect of dopamine under these conditions. The authors discuss hypothetical mechanism of action of the observed influence of bradykinin on the effect of dopamine in the circulatory system.

Animals↗
PubMed1983

Examinations of contribution of bradykinin in the action of dopamine in circulatory system of rats. III. Influence of bradykinin on chosen metabolic effects of dopamine.

The influence of bradykinin on the action of dopamine in the biochemical examinations (the activity of phosphorylase "a" in the heart muscle, the level of free fatty acids and the level of lactic acid in blood) were estimated. It was shown that dopamine (250 micrograms, 500 micrograms, 750 micrograms/kg i.v.) increased and bradykinin (2.5 micrograms, 5 micrograms/kg i.v.) did not change the examined biochemical parameters. Bradykinin applied in the smaller dose simultaneously with dopamine in the smallest dose intensified the amine action. The peptide introduced into the organism in the higher dose increased the stimulatory action of dopamine as estimated by the of phosphorylase "a" activity in the heart muscle and diminished the amine effect as estimated by the free fatty acids and lactic acid in blood. Administration of bradykinin with dopamine in the highest dose - 500 micrograms/kg i.v., did not change the stimulatory action of the catecholamine. But application of bradykinin with dopamine in the highest dose diminished the stimulatory effect of the dopamine. Therefore, bradykinin modified the action of dopamine as it was demonstrated by the estimation of the metabolic effects.

Animals↗
PubMed2006

Behavioral motor recovery in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned squirrel monkey (Saimiri sciureus): changes in striatal dopamine and expression of tyrosine hydroxylase and dopamine transporter proteins.

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provides an excellent opportunity to study repair and response to injury in the basal ganglia. Administration to mammals leads to the destruction of nigrostriatal dopaminergic neurons and depletion of striatal dopamine. In the squirrel monkey (Saimiri sciureus), MPTP-lesioning results in parkinsonian motor symptoms including bradykinesia, postural instability, and rigidity. Over time animals display motor behavioral recovery. To better understand this mechanism we employed a lesioning regimen of two or six subcutaneous injections of MPTP (2.0 mg/kg, free-base) to generate mild or moderate parkinsonism. Brain tissue was harvested at 6 weeks or 9 months after the last injection and analyzed for dopamine and its metabolites by high performance liquid chromatography (HPLC), and by immunohistochemical staining and Western immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine- and cAMP-responsive protein phosphatase of 32 kDa (DARPP-32), an effector molecule enriched in striatal medium spiny neurons. Several months after MPTP-lesioning, when squirrel monkeys displayed full motor behavioral recovery, striatal dopamine levels remained low with a greater return in the ventral striatum. This finding is consistent with other reports using neurotoxicant-lesioning models of the basal ganglia in rodents and other species of nonhuman primates. Elevated dopamine turnover ratio and decreased DAT expression appeared in early behavioral recovery at the 6-week time point in both mild- and moderate-parkinsonian monkeys. Tyrosine hydroxylase and DAT expression was increased in late stage recovery even within dopamine-depleted regions and supports sprouting. Altered DARPP-32 expression suggests a role of medium spiny neurons in recovery.

Animals↗
PubMed1997

The dopamine transporter: a crucial component regulating dopamine transmission.

The dopamine system is implicated in the control of locomotion, cognition, and endocrine function. The relative contribution of the various dopamine-related components is not well established mainly because drugs that target the dopaminergic system often lack selectivity. The in vivo gene inactivation procedure, or knockout, enables the creation of new strains of mice lacking a specific gene. This technique has been applied recently to inactivate the expression of the plasma membrane dopamine transporter. Here we summarize the main findings obtained with these transgenic mice carrying this "genetic defect," leading to a better understanding of the relative contribution of the dopamine transporter regarding locomotor activity, regulation of the expression of peptides under the control of dopaminergic activity, and responses to various drugs targeting the dopamine system. Our results establish not only the central importance of the transporter as the key element controlling dopamine levels in the brain, but also its role as an obligatory target for the behavioral and biochemical action of amphetamine and cocaine. In addition, the genetically altered mice offer a unique model to test the specificity and selectivity of dopamine transporter-acting drugs and may provide important new concepts related to the clinical and social implications of conditions such as Parkinson's disease, schizophrenia, and drug addiction.

Amphetamines↗
PubMed2006

Viral restoration of dopamine signaling to the dorsal striatum restores instrumental conditioning to dopamine-deficient mice.

INTRODUCTION: Instrumental responding was evaluated to determine whether mice lacking dopamine [dopamine-deficient mice (DD mice)] could learn to preferentially press a visually cued, active lever for food reward over an inactive lever. RESULTS: When DD mice were treated with 3,4-L: -dihydroxyphenalanine (L-dopa) to restore dopamine signaling systemically, they were able to learn to press the active lever as well as control mice, whereas mice lacking dopamine would not perform the task. Importantly, DD mice treated with caffeine (to stimulate locomotor and feeding behaviors) also failed to show preference for the active lever and were slower to retrieve rewards after making a reinforced operant response. Selective restoration of dopamine signaling to the nigrostriatal pathway of DD mice via viral-mediated gene transfer completely restored learning and performance of this simple instrumental task. Furthermore, the virally treated DD mice were willing to lever press as much as control mice for reward in progressive-ratio and high fixed-ratio schedules of reinforcement. CONCLUSION: These results suggest that the deficit in goal-directed behavior observed in mice without dopamine signaling is the result of decreased motivation to obtain reward, and that dopamine signaling in the dorsal striatum is sufficient to restore normal goal-directed behavior on a variety of operant responding tasks.

Adenoviruses, Canine↗
PubMed1985

Inhibition of dopamine-stimulated cyclic AMP efflux from rat neostriatal slices by activation of mu- and delta-opioid receptors: a permissive role for D-2 dopamine receptors.

The cyclic AMP efflux from rat neostriatal slices induced by simultaneous activation of D-1 (stimulatory) and D-2 (inhibitory) dopamine receptors with 30 microM dopamine was inhibited by morphine (0.3-3 microM), [D-Ala2, D-Leu5]enkephalin (DADLE, 0.03-0.3 microM) but not by [D-Pen2, D-Pen5]enkephalin (DPDPE, 0.03-0.3 microM). The inhibitory effects were abolished by naloxone (0.1 microM). Upon selective D-1 dopamine receptor activation with 30 microM dopamine in the presence of 10 microM of the D-2 dopamine receptor antagonist (-)sulpiride, the enhanced efflux of cyclic AMP was reduced by all three opioid receptor agonists, but only the effect of morphine was antagonized by 0.1 microM naloxone. These data suggest that the cyclic AMP production induced in rat neostriatum by simultaneous D-1 and D-2 dopamine receptor activation may be inhibited through mu-opioid receptors, whereas on blockade of D-2 dopamine receptors both mu- and delta-opioid receptors may be linked to adenylate cyclase in an inhibitory fashion.

1-Methyl-3-isobutylxanthine↗