dizocilpine-maleate and eticlopride

Single nucleus accumbens (NAcc) neurons receive excitatory synaptic input from cortical and limbic structures, and the integration of converging goal- and motivation-related signals in these neurons influences reward-directed actions. While limbic/cortical synaptic input summation has been characterized at subthreshold intensities, the manner in which multiple inputs govern NAcc neuron spike discharge has not been measured and is poorly understood. Single NAcc neurons were recorded in urethane-anesthetized rats, and spiking was evoked by coincident stimulation of two major NAcc afferent regions: the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). BLA input increased NAcc spiking elicited by mPFC stimulation depending on the timing of the stimulation pulses, consistent with the summation of monosynaptically evoked excitatory activity. When mPFC input intensity was below threshold for evoked spiking, the addition of BLA input produced the largest facilitation of evoked spiking, and the latency of the evoked spikes reflected the latency of the individual inputs. When mPFC inputs were stimulated at higher intensities, BLA-mediated facilitation was weaker, and the spike latency reflected only the mPFC input. Thus NAcc neurons integrate both the magnitude and timing of afferent synaptic activity, suggesting that NAcc neuron output is strongly dependent on the comparative magnitude of synaptic activity in its afferent structures. These interactions may be crucial integrative mechanisms that allow motivational and cognitive information to produce appropriate reward-directed actions.

Topics: Action Potentials; Animals; Benzazepines; Biophysics; Brain Mapping; Dizocilpine Maleate; Dopamine Antagonists; Electric Stimulation; Excitatory Amino Acid Antagonists; Limbic System; Male; Neural Pathways; Neurons; Nucleus Accumbens; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Reaction Time; Salicylamides

Cocaine is an addictive psychostimulant that induces fos and opioid gene expression by activating the dopamine receptors and the PKA pathways in dopamine D1 and a glutamate NMDA-dependent mechanisms in the striatum. In this study, we show that a single cocaine administration induces ERK phosphorylation in the caudate/putamen of Fischer rats. This increase in Phospho-ERK is diminished by pre-administration of SCH23390, or MK801 but not with pre-administration of eticlopride. Furthermore, this single cocaine administration does not alter the levels of phospho-CREB protein or CREB-DNA bindings in the caudate/putamen protein extracts but does increase phospho-Elk-1 protein levels in the same extracts.

Topics: Animals; Benzazepines; Blotting, Western; Cocaine; Corpus Striatum; Cyclic AMP Response Element-Binding Protein; Dizocilpine Maleate; Dopamine Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Electrophoretic Mobility Shift Assay; Enzyme Induction; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Male; Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Inbred F344; Salicylamides

The N-methyl-D-aspartate (NMDA) glutamate receptor possesses an obligatory co-agonist site for D-serine and glycine, named the glycineB site. Several clinical trials indicate that glycineB agonists can improve negative and cognitive symptoms of schizophrenia when co-administered with antipsychotics. In the present study we have investigated the effects of glycineB agonists on the endogenous release of dopamine from preparations of rat striatal tissue prisms in static conditions. The glycineB agonists glycine (1 mM) and D-serine (10 microM), but not D-cycloserine (10 microM), substantially increased the spontaneous release of dopamine, but significantly reduced the release of dopamine evoked by NMDA. The effect of glycine on spontaneous release was abolished by the non-competitive NMDA antagonists 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801, 10 microM) and ifenprodil (5 microM), but was only partially suppressed by the competitive antagonist 4-(3-phosphonopropyl)-piperazine-2-carboxylic acid (CPP, 10 microM). The selective inhibitor of the glial glycine transporter GlyT1 N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS, 10 microM) significantly increased the release of dopamine in an MK-801-sensitive manner. Interestingly, haloperidol (1 microM), but not clozapine (10 microM), prevented the effects of glycine. This study shows that glycineB modulators can control dopamine release by interacting with a distinctive NMDA receptor subtype with which some typical antipsychotics can interfere.

Topics: Animals; Antipsychotic Agents; Clozapine; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Glycine; Haloperidol; Magnesium; Male; N-Methylaspartate; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Salicylamides

The noncompetitive NMDA receptor antagonist MK801 (dizocilpine) produces behavioral stimulation mediated, in part, through indirect activation of the dopamine (DA) system. Previous reports indicate that D2/3 agonists inhibit MK801-induced stereotypies; however, it is unclear if these agonists also attenuate MK801-induced locomotion. As such, the ability of the D2/3 agonists, quinelorane and quinpirole, and the partial D3 agonist, BP897, to attenuate the locomotor activating effects of MK801 was examined in mice. MK801 (0.1-1.0 mg/kg) produced a biphasic effect on total distance traveled with the intermediate dose of 0.3 mg/kg producing the greatest stimulation. The increase in MK801-induced total distance traveled was attenuated by the coadministration of quinelorane and quinpirole at doses that alone had no effect on activity. Similarly, the partial D3 agonist, BP897, blocked the effects of MK801. The D3-preferring antagonist, nafadotride, reversed the attenuation of quinelorane and partially reversed the attenuation of quinpirole. The D2-preferring antagonist, eticlopride, reversed the attenuating effects of quinelorane, but was not effective against quinpirole. Nafadotride and eticlopride were ineffective against the attenuating effects of BP897 on MK801-induced locomotion. Because BP897 is a partial agonist it was tested against quinelorane/MK801 and quinpirole/MK801 combinations. BP897 reversed the attenuating effects of quinelorane, but not those of quinpirole on MK801's effects. These results demonstrate that the DA system, through D2/3 receptor activation, modulates the locomotor activating effects produced by noncompetitive NMDA receptor blockade.

Topics: Animals; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Mice; Motor Activity; Naphthalenes; Piperazines; Pyrrolidines; Quinolines; Quinpirole; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, N-Methyl-D-Aspartate; Salicylamides; Stereotyped Behavior

Phencyclidine (PCP) rapidly (within 1 h) increased vesicular dopamine uptake and binding of the vesicular monoamine transporter-2 (VMAT-2) ligand, dihydrotetrabenazine. Uptake returned to basal values 3 h in the striatum after a high-dose administration of this drug (15 mg/kg i.p.). In contrast, a similar pretreatment with another non-competitive NMDA receptor antagonist, dizocilpine;([5R,10S]-[+]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine; MK-801; 1 mg/kg, i.p.), was without effect on vesicular dopamine uptake. Pretreatment with the dopamine D2 receptor antagonist, eticlopride, blocked the increase in vesicular dopamine uptake caused by PCP administration. These data demonstrate a heretofore unreported mechanism that may contribute to the ability of PCP to influence dopamine neuronal function and exert its pharmacological effects.

Topics: Animals; Binding, Competitive; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Phencyclidine; Rats; Rats, Sprague-Dawley; Salicylamides; Synaptic Vesicles; Tetrabenazine; Tritium

Cortical afferents excite striatal efferent neurons through activation of N-methyl-D-aspartate (NMDA) receptors, which can be modulated by D2 dopamine receptors. It is suggested that activation of PKA by D2 receptor blockade leads to NMDA receptor phosphorylation in the dendrites or phosphorylation of transcription factors in the nucleus. Thus, the levels and cellular localization of activated PKA may determine if D2 antagonist-mediated gene expression is dependent on NMDA receptor activation. We have previously demonstrated that NMDA receptor antagonists block gene expression induced by a high dose of eticlopride in medial and central but not lateral striatum. Here, we examined the effects of NMDA receptor antagonists on striatal gene expression after administration of a low dose of eticlopride. The results showed that NMDA receptor antagonists blocked gene induction by eticlopride throughout striatum. Less PKA activation by the low dose of eticlopride might explain why the expression was more sensitive in the lateral striatum to NMDA receptor blockade than in our previous study. To increase levels of PKA activation to the extent that NMDA receptor blockade would have less effect on eticlopride-mediated gene induction in all regions of striatum, we administered the phosphodiesterase inhibitor IBMX to animals treated with eticlopride. The combined administration of IBMX and eticlopride induced gene expression that was only partially attenuated (c-fos) or unaffected (zif268) by NMDA receptor blockade. These data support the suggestion that the degree of second messenger activation by D2 receptor blockade determines whether D2 dopamine receptor antagonist-mediated gene expression is dependent on NMDA receptor activation.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Gene Expression; Genes, Immediate-Early; Male; Phosphodiesterase Inhibitors; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Salicylamides

The function of striatopallidal neurons is regulated by N-methyl-D-aspartate (NMDA) and dopamine D2 receptors. Previous studies show that immediate early gene induction by D2 receptor blockade is suppressed by NMDA receptor antagonists. Because the pharmacology of NMDA receptors depends on the incorporation of different NR2 subunits and NR2 subunits show regional and cellular differences in their expression in striatum, our study examined whether different NMDA receptor antagonists would have differential effects on eticlopride-induced immediate early gene expression in striatum. Male Sprague-Dawley rats were pretreated with vehicle, CGS 19755, MK-801 or ifenprodil. Rats then received injections of eticlopride and were killed 40 min later. In situ hybridization histochemistry was used to determine the expression of c-fos and zif268 in the striatum. Eticlopride increased immediate early gene expression in striatum, with the increase generally being greater in lateral than in medial striatum. Pretreatment with each of the NMDA receptor antagonists dose-dependently decreased the expression of the immediate early genes. This suppression of eticlopride-induced gene expression was significant only in the medial-central aspect of striatum. Although there was a trend toward suppression of the gene induction in lateral striatum, it did not reach statistical significance and was not typically dose dependent. The data suggest that different types of NMDA receptor antagonists do not exert differential effects on D2 dopamine receptor-mediated function in the striatum. In addition, the data indicate that eticlopride-induced gene expression in the striatum is not uniformly dependent on NMDA receptor activation.

Topics: Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Gene Expression; Genes, Immediate-Early; Male; Pipecolic Acids; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Salicylamides

The bilateral administration of 10 micrograms of (+)MK-801, but not (-)MK-801, into either the VTA or the N.Ac. stimulated locomotor activity. The stimulation induced by (+)MK-801 at both sites was inhibited by reserpine (5 mg/kg, SC) and the D1 antagonist, SCH 23390 (0.1 mg/kg, SC). Eticlopride (0.03 mg/kg, SC), a D2 antagonist, inhibited the stimulation produced by MK-801 in the VTA but not in the N.Ac. Baclofen (32 ng), a GABAB receptor agonist, injected into the VTA inhibited the stimulatory response to MK-801 injected systemically, into the VTA, or into the N.Ac., but did not significantly inhibit spontaneous locomotion or the stimulatory response to apomorphine (5 mg/kg, SC). These observations suggest that the stimulatory effects of MK-801 in the VTA and the N.Ac. are dependent on endogenous dopamine. In addition, the effects produced by MK-801 injected into the VTA closely resemble those produced by the systemic administration of low doses of MK-801, suggesting that this is the primary site of action of MK-801.

Topics: Adrenergic Uptake Inhibitors; Animals; Apomorphine; Baclofen; Benzazepines; Dizocilpine Maleate; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Excitatory Amino Acid Antagonists; GABA Agonists; Histocytochemistry; Injections; Male; Motor Activity; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Reserpine; Salicylamides; Stimulation, Chemical; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevents the development of sensitization to the locomotor-activating effects of amphetamine. In the present study, the possibility that the NMDA receptor might also play a role in the rewarding effects of amphetamine (as measured in the conditioned place preference paradigm) was investigated. Male Sprague-Dawley rats received amphetamine (2.0 mg/kg IP) paired with one side of a two-compartment box and saline paired with the other side. During these pairings locomotor activity was measured. On the test day, the amount of time drug-free rats spent in each compartment was determined. Rats trained with amphetamine alone showed a significant increase in time spent on the drug-paired side from pre- to postconditioning, indicating a place preference. When rats were injected with MK-801 (0.03, 0.1, or 0.3 mg/kg SC) prior to amphetamine, no significant effects on amphetamine place conditioning were observed. Rats treated with MK-801 alone showed significant place conditioning, but only at the intermediate dose. On conditioning days, MK-801 produced a dose-dependent enhancement of amphetamine-induced locomotor activity; however, MK-801 alone caused a similar increase in activity. The preferential D2 dopamine receptor antagonist eticlopride (0.01, 0.05, or 0.1 mg/kg SC) significantly reduced amphetamine locomotor activity, and the highest dose blocked place conditioning. These data suggest that the NMDA receptor is not involved in either the rewarding or locomotor-activating effects of amphetamine.

Topics: Animals; Conditioning, Psychological; Dextroamphetamine; Dizocilpine Maleate; Dopamine D2 Receptor Antagonists; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reward; Salicylamides

Repeated administration of methamphetamine (m-AMPH) to rats induces dopamine (DA) terminal damage, and coadministration of antagonists of the N-methyl-D-aspartate (NMDA) or dopamine D1 or D2 receptors are protective. Striatal microdialysis of rats given a neurotoxic regimen of 4 x m-AMPH (4 mg/kg, s.c.) treatments revealed a dramatic and prolonged elevation of extracellular DA after the final m-AMPH administration. Neuroprotective regimens of MK-801, SCH 23390, or eticlopride greatly attenuated the overflow of DA resulting from the fourth m-AMPH treatment. By itself, MK-801 had no significant influence on striatal DA overflow, whereas either DA antagonist given alone elevated dialysate DA concentrations. A significant correlation was found between the magnitude of the m-AMPH-induced DA overflow of individual microdialyzed rats and their striatal DA content at sacrifice one week later. We conclude that the ability of non-competitive NMDA antagonists and of the D1 or D2 antagonists to protect against m-AMPH-induced striatal DA terminal injury can be accounted for by their attenuation of m-AMPH-evoked DA overflow. These findings underscore the important role played by elevated extracellular DA concentrations to the injurious effects of this stimulant drug.

Topics: Animals; Benzazepines; Chromatography, High Pressure Liquid; Corpus Striatum; Dialysis; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Glutamates; Glutamic Acid; Male; Methamphetamine; Microchemistry; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Salicylamides

The effects of typical and atypical neuroleptics on MK-801-induced locomotor activity and stereotyped sniffing were tested. Pretreatment with the typical neuroleptic haloperidol (0.01, 0.05, 0.1, 0.5 mg/kg SC) and the dopamine D2 receptor selective antagonist eticlopride (0.005, 0.01, 0.05 mg/kg SC) each resulted in significant and dose-dependent reductions of locomotor activity and sniffing. The atypical neuroleptic clozapine (1.0, 5.0, 10.0 mg/kg SC) was somewhat unique in that all doses reduced locomotor activity, but only the highest dose (10.0 mg/kg) significantly reduced sniffing. The data support a functional interaction between glutamate and dopamine systems, and suggest that the behavioral activation associated with MK-801 may represent a valid model for detecting potential therapeutic agents in the treatment of schizophrenia. The data should be viewed as preliminary, however, until neuroleptics are characterized in other glutamate-based models that minimized or exclude the possible influence of nonspecific motor effects.

Topics: Animals; Antipsychotic Agents; Clozapine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Haloperidol; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Salicylamides; Stereotyped Behavior