Action of Dopaminergic Agents on the Impulse Activity of Sensorimotor Cortex Neurons of Cats Performing a Conditioned Motor Task

We demonstrate that dopamine itself, a selective dopamine D1 receptor agonist, SKF 38393, and a selective dopamine D2 receptor agonist, quinpirole, exert both facilitatory and suppressive effects on neuronal activity in the sensorimotor cortex of the cat, which is related to a conditioned movement. These effects are mediated by activation of dopamine receptors. Our data can be used for understanding the mechanisms underlying modulation of the excitability of central neurons during various behavioral events under the influence of dopamine.     

Selective disruption of dopamine D2-receptors/beta-arrestin2 signaling by mood stabilizers

Abstract

Mood stabilizers are a heterogeneous class of drugs having antidepressant and anti-manic effects in bipolar disorders, depression and schizophrenia. Despite wide clinical applications, the mechanisms underlying their shared actions and therapeutic specificity are unknown. Here, we examine the effects of the structurally unrelated mood stabilizers lamotrigine, lithium and valproate on G protein and beta-arrestin-dependent components of dopamine D2 receptor signaling and assess their contribution to the behavioral effects of these drugs. When administered chronically to mice lacking either D2 receptors or beta-arrestin 2, lamotrigine, lithium and valproate failed to affect Akt/GSK3 signaling as they do in normal littermates. This lack of effect on signaling resulted in a loss of responsiveness to mood stabilizers in tests assessing “antimanic” or “antidepressant”-like behavioral drug effects. This shows that mood stabilizers lamotrigine, lithium and valproate can exert behavioral effects in mice by disrupting the beta-arrestin 2-mediated regulation of Akt/GSK3 signaling by D2 dopamine receptors, thereby suggesting a shared mechanism for mood stabilizer selectivity.     

Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila

BACKGROUND: Drugs of abuse have a common property in mammals, which is their ability to facilitate the release of the neurotransmitter and neuromodulator dopamine in specific brain regions involved in reward and motivation. This increase in synaptic dopamine levels is believed to act as a positive reinforcer and to mediate some of the acute responses to drugs. The mechanisms by which dopamine regulates acute drug responses and addiction remain unknown. RESULTS: We present evidence that dopamine plays a role in the responses of Drosophila to cocaine, nicotine or ethanol. We used a startle-induced negative geotaxis assay and a locomotor tracking system to measure the effect of psychostimulants on fly behavior. Using these assays, we show that acute responses to cocaine and nicotine are blunted by pharmacologically induced reductions in dopamine levels. Cocaine and nicotine showed a high degree of synergy in their effects, which is consistent with an action through convergent pathways. In addition, we found that dopamine is involved in the acute locomotor-activating effect, but not the sedating effect, of ethanol. CONCLUSIONS: We show that in Drosophila, as in mammals, dopaminergic pathways play a role in modulating specific behavioral responses to cocaine, nicotine or ethanol. We therefore suggest that Drosophila can be used as a genetically tractable model system in which to study the mechanisms underlying behavioral responses to multiple drugs of abuse.     

"Selective" D-1 and D-2 receptor antagonists fail to differentially alter supersensitive locomotor behavior in the rat

The dopamine receptor antagonists SCH 23390 and spiperone show highly selective in vitro affinity for D-1 and D-2 dopamine receptor subtypes, respectively. We studied the effects of these selective antagonists on the supersensitive locomotor response to apomorphine in rats following 6- hydroxydopamine (6OHDA) lesions of the nucleus accumbens (N. Acc.). Both D-1 and D-2 receptor antagonists produced dose-dependent blockade of the supersensitive locomotor response at doses that did not depress baseline locomotor activity. The behavioral properties of these D-1 and D-2 receptor antagonists were further examined using a simple step-down motor task. Both antagonists produced catalepsy as evidenced by dose-dependent increases in step- down latency. These results indicate that drugs with distinct in vitro dopamine binding affinities cannot be distinguished on the basis of their ability to inhibit supersensitive locomotor activity or simple motor tasks in rats in vivo.     

Effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system

1. A review of the effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system is presented. 2. The effects of antidepressants on adenylate cyclase activity and on receptor binding in brain tissue are discussed. Effects on a variety of receptor types are considered. 3. The utilization of electrophysiological, behavioral, and neurochemical studies to assess receptor function after chronic antidepressant administration is discussed, as is the use of peripheral receptor estimations in clinical studies. 4. Animal studies on the actions of chronic administration of neuroleptics on pre- and postsynaptic dopamine receptors are reviewed. Effects of these drugs on dopamine receptors in humans are considered from the following perspectives: postmortem and in vivo binding studies in schizophrenia, tardive dyskinesia, and central versus peripheral receptor estimation.     

Studies of dopamine pharmacology in molluscs

Dopamine has been established as a putative neurotransmitter in several species of molluscs. Biochemical and neurophysiological studies of the cellular pharmacology of dopamine have revealed several properties of molluscan dopamine receptors. The biochemical synthesis and degredation of dopamine in molluscs follows the same pathways that have been described in mammals. Adenylate cyclase is present, and the receptor mediating CAMP production is blocked by neuroleptics and certain ergot alkaloids. Studies of this enzyme and of radioligand binding indicate that molluscan dopamine receptors and serotonin receptors share certain characteristics. Neurophysiological studies have shown that dopamine induces several forms of ionic conductance changes in molluscan neurons. The receptors mediating these conductance changes may be differentiated pharmacologically. Neuroleptics are antagonists at certain receptors and ergot alkaloids have been shown to be either partial agonists or antagonists. Present evidence indicates that molluscan and mammalian CNS dopamine receptors have some similarities. However, further biochemical and neurophysiological investigations will be necessary to fully characterize molluscan dopamine receptors.     

Effects of SCH23390 and raclopride on a run-climb-run behavioral task in rats

The present study was designed to compare the putative differential behavioral consequences of treatment with SCH23390 (a selective dopamine D1 receptor blocker) and raclopride (a selective dopamine D2 receptor blocker) by employing a run-climb-run (RCR) behavioral task of different lengths. Rats were trained to traverse an uncovered floor alleyway (150 cm), climb a vertical rope (70 or 130 cm), and run across an upper board (100 cm) to access water for the reinforcement. At doses of 0.05, 0.10 and 0.15 mg/kg administered intraperitoneally 60 min before the behavioral session, both SCH23390 and raclopride significantly increased the total time to complete the tasks in a dose-related fashion. Microstructural analysis on the RCR behavioral performance revealed that the most apparent impairment induced by either drug was observed as the subject shifted motion from the end of the floor alleyway to the rope when hopping or to initiate climbing. However, the motion shift from climbing to running on the upper board was significantly impaired by raclopride, but not by SCH23390. Surprisingly, neither SCH23390 nor raclopride affected the climbing response itself. Running responses on the floor alleyway board were significantly disrupted by raclopride, whereas those on the upper board were significantly disrupted by SCH23390. Deficits induced by both drugs were more profound for the longer compared to the shorter rope, and were most notably shown at the transition area from running to climbing. These data indicate that both dopamine D1 and D2 receptors are involved in the RCR behavior performance. The results also suggest that the cost of motoric demand for behavioral performance is important for evaluating of the effects of drugs blocking dopamine receptors.     

Biotechnology and genetics of ergot alkaloids

Ergot alkaloids, i.e. ergoline-derived toxic metabolites, are produced by a wide range of fungi, predominantly by members of the grass-parasitizing family of the Clavicipitaceae. Naturally occurring alkaloids like the D-lysergic acid amides, produced by the "ergot fungus" Claviceps purpurea, have been used as medicinal agents for a long time. The pharmacological effects of the various ergot alkaloids and their derivatives are due to the structural similarity of the tetracyclic ring system to neurotransmitters such as noradrenaline, dopamine or serotonin. In addition to "classical" indications, e.g. migraine or blood pressure regulation, there is a wide spectrum of potential new applications of this interesting group of compounds. The biotechnology of ergot alkaloids has a long tradition, and efficient parasitic and submerse production processes have been developed; the biochemistry of the pathway and the physiology of production have been worked out in detail. The recent identification of a cluster of genes involved in ergot alkaloid biosynthesis in C. purpurea and the availability of molecular genetic techniques allow the development of strategies for rational drug design of ergoline-related drugs by enzyme engineering and by biocombinatorial approaches.     

Effect of ergot alkaloids on 3H-flunitrazepam binding to mouse brain GABAA receptors

In vitro effects of dihydroergotoxine, dihydroergosine, dihydroergotamine, alpha-dihydroergocriptine (ergot alkaloids), diazepam, methyl-beta-Carboline-3-carboxilate (beta-CCM), flumazenil (benzodiazepines), gamma-amino butyric acid (GABA) and thiopental (barbiturate) were studied on mouse brain (cerebrum minus cerebral cortex) benzodiazepine binding sites labeled with 3H-flunitrazepam. Specific, high affinity (affinity constant, Kd = 57.7 8.6 nM) binding sites for 3H-flunitrazepam on mouse brain membranes were identified. All benzodiazepine drugs inhibited 3H-flunitrazepam binding with nanomolar potencies. In contrast to benzodiazepines, all ergot drugs, GABA and thiopental produced an enhancement of 3H-flunitrazepam binding to its binding site at the GABAA receptor of the mouse brain. The rank order of potency was: neurotransmitter (GABA) > dihydroergotoxine > thiopental > alpha-dihydroergocriptine > dihydroergosine > dihydroergotamine. The results suggest that dihydrogenated ergot derivatives do not bind to the brain benzodiazepine binding sites labeled with 3H-flunitrazepam. However, an enhancement of 3H-flunitrazepam binding by all ergot drugs tested, clearly identifies an allosteric interaction with the benzodiazepine binding sites of GABAA receptors.     

How addictive drugs disrupt presynaptic dopamine neurotransmission

The fundamental principle that unites addictive drugs appears to be that each enhances synaptic dopamine by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. This occurs via the modulation of synaptic mechanisms that can be involved in learning, including enhanced excitation or disinhibition of dopamine neuron activity, blockade of dopamine reuptake, and altering the state of the presynaptic terminal to enhance evoked over basal transmission. Amphetamines offer an exception to such modulation in that they combine multiple effects to produce nonexocytic stimulation-independent release of neurotransmitter via reverse transport independent from normal presynaptic function. Questions about the molecular actions of?addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, but their ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has been challenging.     

Effect of dihydroergocryptine and dihydroergocristine on cyclic AMP accumulation and prolactin release in vitro: evidence for a dopaminomimetic action

Dihydroergocryptine and dihydroergocristine, two C-9, 10-hydrogenated ergot alkaloids, inhibited in a concentration-dependent manner prolactin release and cyclic AMP accumulation in cultured anterior pituitary cells. The inhibitory effect of dihydroergocryptine was more potent and started at lower concentrations than that of dihydroergocristine. Haloperidol and pimozide, two dopamine receptor antagonists, completely abolished the inhibitory activity of the ergot alkaloids. The involvement of the adenylate cyclase-cyclic AMP system in the inhibitory action of the two compounds was demonstrated by the antagonism by pertussis toxin of the reduction of both prolactin release and cyclic AMP accumulation produced by dihydroergocryptine and dihydroergocristine.     

DIFFERENTIAL EFFECTS OF THREE DOPAMINE AGONISTS: APOMORPHINE, BROMOCRIPTINE AND LERGOTRILE

Abstract— The ergolines are a new class of proposed dopamine receptor agonists, whose efficacy in treatment of Parkinsonism is under investigation. In order to explore the mechanisms of their action. two ergolines (bromocriptine and lergotrile) were compared to apomorphine for in vivo effects on behavior and in vitro effects on uptake and release of [³H]dopamine by brain minces. Inhibition of dopamine synthesis in vivo significantly interfered with both bromocriptine- and lergotrile-induced stereotypy, while apomorphine-induced stereotypy was not affected. Significant differences among the compounds were also seen neurochemically: bromocriptine inhibited the release of [³H]dopamine. while lergotrile increased release. Apomorphine did not affect uptake or release of [³H]dopamine. The results, of both behavioral and neurochemical experiments, suggest that two ergolines enhance dopaminergic function by action on presynaptic dopaminergic sites in addition to receptor agonism.     

Effect of experimenter-delivered and self-administered cocaine on extracellular beta-endorphin levels in the nucleus accumbens

Beta-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of beta-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular beta-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on beta-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 microm) and was blocked by coadministration of SCH-23390 (10 microm). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular beta-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in beta-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the beta-endorphin neurons within the arcuate nucleus-nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.     

Behavioral and radioligand binding evidence for irreversible dopamine receptor blockade by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible alpha adrenergic antagonist, also acts as a potent and longlasting in vivo antagonist of D-2 dopamine receptors. Rats given EEDQ 3-10 mg/kg i.p. exhibit catalepsy and greatly reduced apomorphine-induced stereotypy, behavioral effects associated with D-2 dopamine receptor blockade. These effects are apparent up to 4 days after drug administration, with scores returning to control level by day 7. In vitro receptor binding assays of striatal membrane preparations from these animals using the radioligand 3H-spiroperidol directly demonstrate that EEDQ is a potent D-2 dopamine receptor antagonist, revealing the apparent basis of the behavioral effects of EEDQ. This antagonism proceeds via a reduction in D-2 receptor Bmax, with no change in the observed KD for 3H-spiroperidol, and is resistant to extensive washing of the membrane preparation after in vivo EEDQ exposure. These observations suggest that EEDQ inhibition of D-2 receptors is irreversible. Administration of behaviorally active doses of EEDQ effect a reduction of 50-85% in D-2 receptor number. Recovery of this loss roughly parallels recovery of normal catalepsy and apomorphine stereotypy scores. These doses of EEDQ also reduce binding of 3H-flupentixol to D-1 and 3H-dopamine to D-3 type dopaminergic binding sites, putative dopamine receptors with no known behavioral correlates. Recovery of D-1 and D-3 binding also occurs with a similar timecourse. Because of the apparent covalent nature of its interaction with dopamine receptors and because of its activity after peripheral administration, EEDQ may prove useful in the study of the function and turnover of dopamine receptors.     

Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons

Drug seeking and drug self-administration in both animals and humans can be triggered by drugs of abuse themselves or by stressful events. Here, we demonstrate that in vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress both increase strength at excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal abuse potential do not cause this change. The synaptic effects of stress, but not of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These results suggest that plasticity at excitatory synapses on dopamine neurons may be a key neural adaptation contributing to addiction and its interactions with stress and thus may be an attractive therapeutic target for reducing the risk of addiction.     

Effects of N-acetylaspartylglutamate (NAAG) peptidase inhibition on release of glutamate and dopamine in prefrontal cortex and nucleus accumbens in phencyclidine model of schizophrenia

The "glutamate" theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3.     

Exposure to Far Infrared Ray Protects Methamphetamine-Induced Behavioral Sensitization in Glutathione Peroxidase-1 Knockout Mice via Attenuating Mitochondrial Burdens and Dopamine D1 Receptor Activation

Evidence indicates that stress conditions might lead to drug dependence. Recently, we have demonstrated that exposure to far infrared ray (FIR) attenuates acute restraint stress via induction of glutathione peroxidase-1 (GPx-1) gene. We investigated whether FIR affects methamphetamine (MA)-induced behavioral sensitization and whether FIR-mediated pharmacological activity requires interaction between dopamine receptor and GPx-1 gene. We observed that MA treatment significantly increased GPx-1 expression in the striatum of wild-type (WT) mice. Interestingly, exposure to FIR potentiated MA-induced increase in GPx-1 expression. This phenomenon was also observed in animals receiving MA with dopamine D1 receptor antagonist SCH23390. However, dopamine D2 receptor antagonist sulpiride did not affect MA-induced GPx-1 expression. FIR exposure or SCH23390, but not sulpiride, significantly attenuated MA-induced behavioral sensitization. Exposure to FIR significantly attenuated MA-induced dopamine D1 receptor expression, c-Fos induction and oxidative burdens. FIR-mediated antioxidant effects were also more pronounced in mitochondrial- than cytosolic-fraction. In addition, FIR significantly attenuated against MA-induced changes in mitochondrial superoxide dismutase and mitochondrial GPx activities, mitochondrial transmembrane potential, intramitochondrial Ca²⁺ level, mitochondrial complex-I activity, and mitochondrial oxidative burdens. The attenuation by FIR was paralleled that by SCH23390. Effects of FIR or SCH23390 were more sensitive to GPx-1 KO than WT mice, while SCH23390 treatment did not exhibit any additive effects on the protective activity mediated by FIR, indicating that dopamine D1 receptor constitutes a molecular target of FIR. Our result suggests that exposure to FIR ameliorates MA-induced behavioral sensitization via possible interaction between dopamine D1 receptor and GPx-1 gene.     

A mutation in CLOCK leads to altered dopamine receptor function

Mice with a mutation in the Clock gene (ClockΔ19) have a number of behavioral phenotypes that suggest alterations in dopaminergic transmission. These include hyperactivity, increased exploratory behavior, and increased reward value for drugs of abuse. However, the complex changes in dopaminergic transmission that underlie the behavioral abnormalities in these mice remain unclear. Here we find that a loss of CLOCK function increases dopamine release and turnover in striatum as indicated by increased levels of metabolites HVA and DOPAC, and enhances sensitivity to dopamine receptor antagonists. Interestingly, this enlarged dopaminergic tone results in downstream changes in dopamine receptor (DR) levels with a surprising augmentation of both D1‐ and D2‐type DR protein, but a significant shift in the ratio of D1 : D2 receptors in favor of D2 receptor signaling. These effects have functional consequences for both behavior and intracellular signaling, with alterations in locomotor responses to both D1‐type and D2‐type specific agonists and a blunted response to cAMP activation in the ClockΔ19 mutants. Taken together, these studies further elucidate the abnormalities in dopaminergic transmission that underlie mood, activity, and addictive behaviors.     

Minireview: Cholinergic and monoaminergic substrates of startle habituation

Research is reviewed arising from the proposition that behavioral habituation is mediated by brain mechanisms operated by the neurotransmitter, acetylcholine. Effects of cholinergic drugs on habituation of the startle response in rats fail to support involvement of acetylcholine. Likewise, serotonergic drug effects do not favor the more recent view that startle habituation depends on brain serotonin, nor is there sufficient evidence for an essential role of either dopamine or noradrenalin. Because of persistence of habituation following challenge with a variety of pharmacological agents, the phenomenon probably depends upon a complex interplay between a number of transmitters and behavioral processes. Contrary to earlier belief, no single transmitter should be seen as crucially responsible for startle habituation.