The effect of heliox treatment in a rat model of focal transient cerebral ischemia

At nerve terminals G protein coupled receptors modulate neurotransmitter release probability. We recently showed that prolonged activation of metabotropic glutamate receptor 7, mGlu7 receptor, potentiates glutamate release. This signalling involves phospholipase C activation via a pertussis toxin insensitive G protein, the hydrolysis of phosphatidylinositol (4,5)-bisphosphate, and the subsequent activation of the non-kinase diacylglycerol binding protein Munc13-1 which primes synaptic vesicle for exocytosis at the active zone. Here we found that inhibitors of diacylglycerol metabolism (diacylglycerol kinase inhibitor II and diacylglycerol lipase inhibitor RHC80267) remarkably reduce the time of mGlu7 receptor stimulation required for glutamate release potentiation in mice cerebrocortical nerve terminals. We conclude that changes in diacylglycerol levels at nerve terminals control the efficiency of the exocytotic release machinery.     

Dopamine-regulated phosphorylation of synaptic vesicle-associated proteins in rat neostriatum and substantia nigra

Dopamine, acting through dopamine D1 receptors and cyclic AMP-dependent protein kinase, has been found to increase the state of phosphorylation of the synaptic vesicle-associated phosphoproteins synapsin I and protein III in slices of rat neostriatum and substantia nigra. In the neostriatum, the effect of dopamine was mimicked by SKF 38393, a D2 receptor agonist, and was abolished by preincubation of the slices with fluphenazine or SCH 23390, antipsychotic drugs which are potent D1 receptor antagonists, but not by the D2 receptor antagonists l-sulpiride or spiroperidol. The maximal effect of dopamine in the neostriatum represented approximately 30-35% of the maximal effect induced by 8-bromo cyclic AMP, suggesting that a similar fraction of nerve terminals in the neostriatum may express the dopamine D1 receptor. Evidence for a small population of beta-adrenergic receptors regulating nerve terminal protein phosphorylation in the neostriatum, distinct from the D1 dopamine receptors, was also obtained. In the substantia nigra, the effect of dopamine also appeared to be mediated through a D1 dopamine receptor, since it was abolished by fluphenazine and SCH 23390. The maximal effect of dopamine in the substantia nigra represented approximately two-thirds of the effect induced by 8-bromo cyclic AMP, suggesting that a similar fraction of nerve terminals in the substantia nigra may express the dopamine D1 receptor. The ability of dopamine D1 receptor activation to stimulate both synapsin I and protein III phosphorylation and GABA release in both the neostriatum and substantia nigra may be causally linked.     

Dopamine D1-like receptor activation depolarizes medium spiny neurons of the mouse nucleus accumbens by inhibiting inwardly rectifying K currents through a cAMP-dependent protein kinase A-independent mechanism

Dopamine/cAMP signaling has been reported to mediate behavioral responses related to drug addiction. It also modulates the plasticity and firing properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), although the effects of cAMP signaling on the resting membrane potential (RMP) of MSNs has not been specifically defined. In this study, activation of dopamine D1-like receptors (D1Rs) by SKF-38393 elicited membrane depolarization and inward currents in MSNs from the NAc core of 14–17 day-old mice. Similar results were obtained following stimulation of adenylyl cyclase (AC) activity with forskolin or application of exogenous cAMP. Forskolin occluded SKF-38393's effects, thus indicating that D1R action is mediated by AC/cAMP signaling. Accordingly, AC blockade by SQ22536 significantly inhibited the responses to SKF-38393. Effects elicited by D1R stimulation or increased cAMP levels were unaffected by protein kinase A (PKA) or protein kinase C (PKC) blockade and were not mimicked by the Epac agonist, 8CPT-2Me-cAMP. Responses to forskolin were also not significantly modified by cyclic nucleotide-gated (CNG) channel blockade. Forskolin-induced membrane depolarization was associated with increased membrane input resistance. Voltage-clamp experiments revealed that forskolin and SKF-38393 effects were due to inhibition of resting K⁺ currents exhibiting inward rectification at hyperpolarized potentials and a reversal potential (around −90 mV) that shifted with the extracellular K⁺ concentration. Forskolin and D1R agonist effects were abolished by the inward rectifier K⁺ (Kir)-channel blocker, BaCl₂. Collectively, these data suggest that stimulation of postsynaptic D1Rs in MSNs of the NAc core causes membrane depolarization by inhibiting Kir currents. This effect is mediated by AC/cAMP signaling but it is independent on PKA, PKC, Epac and CNG channel activation, suggesting that it may stem from cAMP's direct interaction with Kir channels. D1R/cAMP-mediated excitatory effects may influence the generation of output signals from MSNs by facilitating their transition from the quiescent down-state to the functionally active up-state.     

Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation

The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic N-methyl-d-aspartic acid (NMDA) receptors are required to support hallucinogen-induced cortical network activity. Since microdialysis studies suggest that psychedelic hallucinogens and dopamine D1/D5 receptor agonists have opposite effects on extracellular glutamate in prefrontal cortex, we hypothesized that these two families of psychoactive drugs would have opposite effects on cortical network activity. We found that network activity can be enhanced by 2,5-dimethoxy-4-iodoamphetamine (DOI) (a psychedelic hallucinogen that is a partial agonist of 5-HT(2A/2C) receptors) and suppressed by the selective D1/D5 agonist SKF 38393. This suppression could be mimicked by direct activation of adenylyl cyclase with forskolin or by addition of a cAMP analog. These findings are consistent with previous work showing that activation of adenylyl cyclase can upregulate neuronal glutamate transporters, thereby decreasing synaptic spillover of glutamate. Consistent with this hypothesis, a low concentration of the glutamate transporter inhibitor threo-beta-benzoylaspartic acid (TBOA) restored electrically-evoked recurrent activity in the presence of a selective D1/D5 agonist, whereas recurrent activity in the presence of a low level of the GABA(A) antagonist bicuculline was not resistant to suppression by the D1/D5 agonist. The tempering of network UP states by D1/D5 receptor activation may have implications for the proposed use of D1/D5 agonists in the treatment of schizophrenia.     

Synergistic interactions of dopamine D1 and glutamate NMDA receptors in rat hippocampus and prefrontal cortex: Involvement of ERK1/2 signaling

Interactions between dopamine and glutamate receptors are essential for the prefrontal cortical (PFC) and hippocampal cognitive functions. In order to understand the molecular basis of dopamine/glutamate interactions in rat PFC and hippocampus, we investigated (a) the effect of in vitro dopamine D1 receptor stimulation on glutamate N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits' phosphorylation and (b) the signal transduction pathway underlying these interactions, by examining the involvement of D1–extracellular regulated kinase 1/2 (ERK1/2) and D1/protein kinase A (PKA)/dopamine- and cyclic AMP-regulated phosphoprotein-32 (DARPP-32) signaling pathways. Furthermore, we compared the D1/NMDA/AMPA receptor interactions seen in PFC and hippocampus with those appearing in striatum, in which the D1 receptors' density is the highest within the mammalian brain. Our results showed that stimulation of D1 receptor by the specific agonist SKF38393 (10 μM) in PFC and hippocampal slices significantly increased the phosphorylation state of NR1ser897 and NR2Bser1303 subunits of NMDA receptor and of the GLUR1 (ser831 and ser845) subunit of AMPA receptor, as well as of ERK1/2, but not of DARPP-32. Interestingly, co-stimulation of D1 and NMDA receptors with an ineffective dose of SKF38393 (2 μM) and NMDA (5 μM) respectively, elevated further the phosphorylation level of NMDA and AMPA receptor subunits, as well as of ERK1/2, but not of DARPP-32. The D1- and D1/NMDA-induced phosphorylations were totally inhibited by SL327 (specific ERK1/2 inhibitor). Conversely, in striatal slices our data confirm that the D1-mediated phosphorylation of NMDA and AMPA receptor subunits relies on D1/PKA/DARPP-32 signaling. In conclusion, in PFC and hippocampus: (a) a strong synergistic interaction of D1 and NMDA receptors exists, which results in a significant ERK1/2 pathway activation, (b) the D1 and the D1/NMDA receptor-induced phosphorylation of NMDA and AMPA receptor subunits seems to rely on ERK1/2 signaling and could to some extent underlie the enhancement of NMDA and AMPA receptor currents mediated by D1 receptor activation.     

Glutamate exocytosis from astrocytes controls synaptic strength

The release of transmitters from glia influences synaptic functions. The modalities and physiological functions of glial release are poorly understood. Here we show that glutamate exocytosis from astrocytes of the rat hippocampal dentate molecular layer enhances synaptic strength at excitatory synapses between perforant path afferents and granule cells. The effect is mediated by ifenprodil-sensitive NMDA ionotropic glutamate receptors and involves an increase of transmitter release at the synapse. Correspondingly, we identify NMDA receptor 2B subunits on the extrasynaptic portion of excitatory nerve terminals. The receptor distribution is spatially related to glutamate-containing synaptic-like microvesicles in the apposed astrocytic processes. This glial regulatory pathway is endogenously activated by neuronal activity-dependent stimulation of purinergic P2Y1 receptors on the astrocytes. Thus, we provide the first combined functional and ultrastructural evidence for a physiological control of synaptic activity via exocytosis of glutamate from astrocytes.     

Dopamine D1 receptor-dependent regulation of extracellular citrulline level in the rat nucleus accumbens during conditioned fear response

Nucleus accumbens (N.Acc) contains a subclass of nitric oxide (NO)-generating interneurons that are presumably regulated by the dopamine input. Receptor mechanisms underlying dopamine-NO interaction in the N.Acc are poorly understood. In the current study, we used in vivo microdialysis combined with high-performance liquid chromatography to examine participation of dopamine D1 receptors in regulation of extracellular levels of citrulline (an NO co-product) in the medial N.Acc of Sprague-Dawley rats during both pharmacological challenge and a conditioned fear response. The intraaccumbal infusion of the D1 receptor agonist SKF-38393 (100-500 microM) increased dose-dependently the local dialysate citrulline levels. The SKF-38393-induced increase in extracellular citrulline was prevented by intraaccumbal infusions of 500 microM 7-nitroindazole, a neuronal NO synthase inhibitor. In behavioral microdialysis experiment, the accumbal levels of extracellular citrulline markedly increased in rats given a mild footshock paired with tone. The presentation of the tone previously paired with footshock (the conditioned fear response) produced a "conditioned" rise of extracellular citrulline levels in the N.Acc which was attenuated by intraaccumbal infusion of 100 microM SCH-23390, a dopamine D1 receptor antagonist, and prevented by intraaccumbal infusion of 500 microM 7-nitroindazole. The results suggest that in the N.Acc, the dopamine D1 receptors might regulate the neuronal NO synthase activity; this dopamine-dependent mechanism seems to participate in activation of the neuronal NO synthase and probably NO formation in this brain area during the conditioned fear response.     

Vesicular release mode shapes the postsynaptic response at hippocampal synapses

Release of neurotransmitters from synaptic vesicles is a central event in synaptic transmission. Recent evidence suggests that synaptic vesicles fuse with the plasma membrane by multiple routes during exocytosis, but the regulation and physiological implications of this choice are unclear. At hippocampal synapses, two modes of synaptic vesicle exocytosis can be distinguished by virtue of the rate and extent of loss of a fluorescent lipid marker (FM1-43). Here these two modes of exocytosis were investigated with a combination of electrophysiological recording and fluorescence imaging. It is shown that these exocytic modes result in distinct postsynaptic consequences, such that so-called 'kiss-and-run' exocytosis results in negligible activation of AMPA receptors, compared to the robust postsynaptic responses elicited by apparent full fusion. In contrast NMDA receptors are robustly activated by this form of glutamate delivery. Addition of cyclothiazide, which blocks AMPA receptor desensitization, reveals that the relatively slow rate of release of glutamate during kiss-and-run exocytosis shifts the population of AMPA receptors into a desensitized state, rather than simply being insufficient for receptor activation. These findings provide further support for the existence of a fusion pore mediated mode of exocytosis, and demonstrate that these two exocytic modes directly affect the throughput of synaptic transmission.     

Pressure reversed extracellular striatal dopamine decrease produced by D1 receptor agonist SKF 38393, and D2 receptor agonist LY 171555, but failed to change the effect of the activation of both D1 and D2 receptors.

When human divers or experimental animals are exposed to high pressure, they develop the high-pressure neurological syndrome which is characterized by electroencephalographic changes, and behavioral disturbances. Recently, neurochemical disorders such as a pressure-induced increase in dopamine release have been demonstrated. In the present study, pharmacological experiments, using dopamine receptor agonists such as D1 receptor agonist SKF 38393, D2 receptor agonist LY 171555, and D1/D2 receptor agonist apomorphine, were performed to investigate dopamine receptor function at the neurochemical level. Only apomorphine and mixed SKF 38393 + LY 171555 prevented the pressure-induced increase in dopamine release while SKF 38393 or LY 171555 administered alone failed to do so. The results suggest that the D1-D2 link would be reduced under high pressure because of an abnormal function of D1 receptors which would allow high-affinity D2 states for dopamine. If so, such a preponderance of high-affinity states in D2 postsynaptic receptors could be associated with hyperbaric hyperlocomotor activity. Elsewhere, results also suggested that the pressure-induced disorders in dopamine receptor function could be involved in the pressure-induced elevation in dopamine release.     

Neurochemical evidence of dopamine release by lateral olivocochlear efferents and its presynaptic modulation in guinea-pig cochlea

In this study, using an in vitro superfusion technique for the first time, we provide direct neurochemical evidence of the transmitter role of dopamine at the level of lateral olivocochlear efferent fibres of the guinea-pig cochlea. Our results revealed that nerve terminals are able to take up and release dopamine upon axonal stimulation. Since dopamine is thought to protect the afferent nerve fibres from damage due to acoustic trauma or ischaemia, enhancement of the release of dopamine, a potential therapeutic site of these injuries, was investigated. Positive modulation of dopamine release has been shown by a D1 dopamine receptor agonist, an antagonist and piribedil. Furthermore, negative feedback on the stimulation-evoked release of dopamine via D2 dopamine receptors has been excluded. Electrical stimulation of the cochlear tissue produced a significant and reproducible release of [3H]dopamine, which could be blocked by tetrodotoxin (1 microM) and cadmium (100 microM), proving that axonal activity releases dopamine and its dependence on Ca2+ influx verifies its neuronal origin. Nomifensine, a high-affinity dopamine uptake blocker, prevented the tissue from taking up [3H]dopamine from the bathing solution, also indicating the neural origin of dopamine released in response to stimulation. SKF-38393 (a selective D1 agonist) increased both the resting and electrically evoked release of dopamine. Piribedil (a D3/D2/D1 agonist), a drug under investigation, known to prevent acoustic trauma or ischaemia-induced hearing loss, had a similar and concentration-dependent increasing effect on both resting and evoked release of dopamine. The effect of both drugs on stimulation-evoked release could be prevented by SKF-83566 (a selective D1 antagonist). However, SKF-83566 alone enhanced the resting and axonal conduction-associated release of dopamine. D2 agonists and antagonists failed to modulate the release of dopamine, indicating the lack of negative feedback modulation of dopamine release. Our results suggest that the release of dopamine was subjected to modulation by a D1 receptor agonist and an antagonist. In addition, it is concluded that D2 receptors are not involved in the modulation of dopamine release. This observation may have clinical relevance in the prevention or therapy of particular types of hearing loss, because enhanced dopaminergic input into the primary auditory neuron may inhibit the (over)excitation of this neuron by glutamatergic input from inner hair cells.     

Reversal of quinpirole inhibition of ventral tegmental area neurons is linked to the phosphatidylinositol system and is induced by agonists linked to G(q)

Putative dopaminergic (pDAergic) ventral tegmental area neurons play an important role in brain pathways related to addiction. Extended exposure of pDAergic neurons to moderate concentrations of dopamine (DA) results in a time-dependent decrease in sensitivity of pDAergic neurons to DA inhibition, a process called dopamine inhibition reversal (DIR). We have shown that DIR is mediated by phospholipase C and conventional protein kinase C through concurrent stimulation of D2 and D1-like receptors. In the present study, we further characterized this phenomenon by using extracellular recordings in brain slices to examine whether DIR is linked to phosphatidylinositol (PI) or adenylate cyclase (AC) second-messenger pathways. A D1-like dopaminergic agonist associated with PI turnover (SKF83959), but not one linked to AC (SKF83822), promoted reversal of inhibition produced by quinpirole, a dopamine D2-selective agonist. Other neurotransmitter receptors linked to PI turnover include serotonin 5-HT(2), α(1)-adrenergic, neurotensin, and group I metabotropic glutamate (mGlu) receptors. Both serotonin and neurotensin produced significant reversal of quinpirole inhibition, but agonists of α(1)-adrenergic and group I mGlu receptors failed to significantly reverse quinpirole inhibition. These results indicate that some agonists that stimulate PI turnover can facilitate desensitization of D2 receptors but that there may be other factors in addition to PI that control that interaction.     

Neonatal dopamine depletion reveals a synergistic mechanism of mRNA regulation that is mediated by dopamine(D1) and serotonin(2) receptors and is targeted to tachykinin neurons of the dorsomedial striatum

It has been hypothesized that dopamine(D1) and serotonin(2) receptors become sensitized to agonist-mediated regulation of gene expression following loss of dopaminergic innervation to the striatum. We have previously demonstrated that the combined administration of dopamine(D1) and serotonin(2) receptor agonists to dopamine-depleted adult rats induced preprotachykinin mRNA expression within the periventricular rostral striatum to levels which were significantly different than what could be elicited by either agonist alone. In the present study, we have determined that this phenomenon is revealed only after dopamine depletion. In addition, it is targeted primarily to tachykinin producing neurons of the dorsomedial striatum and is dependent on both dopamine(D1) and serotonin(2) receptor activation. Preprotachykinin mRNA levels in the intact striatum were unaltered 4 h following an i.p. injection of either SKF-38393 (1 mg/kg, dopamine(D1) partial agonist) or (+/-)-1-(4-Iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI 1 mg/kg, serotonin(2) agonist). However, the combined application of both agonists increased (+44%) preprotachykinin message levels, but these changes were restricted to the dorsomedial striatum. In adult animals depleted of dopamine as neonates, striatal preprotachykinin mRNA expression was reduced by approximately 50%. From this lowered level of basal expression, DOI or SKF-38393 raised preprotachykinin mRNA levels within the dorsomedial, but not the dorsolateral striatum. Furthermore, co-stimulation of dopamine(D1) and serotonin(2) receptors produced a nearly four-fold induction of preprotachykinin message levels in the dorsomedial striatum that was significantly greater than either agonist alone. Application of both agonists also elevated preprotachykinin mRNA expression within the dorsolateral striatum, but to a lesser extent. All increases in preprotachykinin mRNA resulting from co-application of SKF-38393 and DOI were prevented by pretreatment with either SCH-23390 (1 mg/kg, dopamine(D1) antagonist) or ritanserin (1 mg/kg, serotonin(2) antagonist). Alternately, preproenkephalin mRNA expression was unaffected by dopamine(D1) receptor stimulation, but was slightly elevated by DOI or both agonists together (42-58%) in intact animals. However, neither agonist treatment in this experiment significantly altered preproenkephalin mRNA expression in the dopamine-depleted striatum which was elevated in response to dopamine lesion alone.Dopamine depletion appears to promote a synergistic interaction between dopamine(D1) and serotonin(2) receptors that leads to enhanced expression of striatal preprotachykinin mRNA levels. The localization of this phenomenon to tachykinin neurons of the direct striatonigral pathway specifically within the dorsomedial regions of the rostral striatum may be relevant to the problem of dyskinetic behaviors which arise during the pharmacological treatment of movement disorders.     

Protein kinase A mediates adenosine A2a receptor modulation of neurotransmitter release via synapsin I phosphorylation in cultured cells from medulla oblongata

Synaptic transmission is an essential process for neuron physiology. Such process is enabled in part due to modulation of neurotransmitter release. Adenosine is a synaptic modulator of neurotransmitter release in the Central Nervous System, including neurons of medulla oblongata, where several nuclei are involved with neurovegetative reflexes. Adenosine modulates different neurotransmitter systems in medulla oblongata, specially glutamate and noradrenaline in the nucleus tractussolitarii, which are involved in hypotensive responses. However, the intracellular mechanisms involved in this modulation remain unknown. The adenosine A2a receptor modulates neurotransmitter release by activating two cAMP protein effectors, the protein kinase A and the exchange protein activated by cAMP. Therefore, an in vitro approach (cultured cells) was carried out to evaluate modulation of neurotransmission by adenosine A2a receptor and the signaling intracellular pathway involved. Results show that the adenosine A2a receptor agonist, CGS 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase A activation, which in turn increased synapsin I phosphorylation. This suggests a mechanism of A2aR modulation of neurotransmitter release in cultured cells from medulla oblongata of Wistar rats and suggest that protein kinase A mediates this modulation of neurotransmitter release via synapsin I phosphorylation.     

Dopamine receptor activation can reduce voltage-gated Na+ current by modulating both entry into and recovery from inactivation

We tested whether dopamine receptor activation modulates the voltage-gated Na+ current of goldfish retinal ganglion cells, using a fast voltage-clamp amplifier, perforated-patch whole cell mode, and a physiological extracellular Na+ concentration. As found in other cells, activators of D1-type dopamine receptors and of protein kinase A reduced the amplitude of current activated by depolarizations from resting potential without altering the current kinetics or activation range. However, D1-type dopamine receptor activation also accelerated the rate of entry into inactivation during subthreshold depolarizations and slowed the rate of recovery from inactivation after single, brief depolarizations. Our results provide the first evidence in any preparation that D1-type receptor activation can produce both of these latter effects.     

Activation of calcium/calmodulin-dependent protein kinase IIα in the striatum by the heteromeric D1-D2 dopamine receptor complex

Synaptic plasticity in the striatum is a key mechanism that underlies processes such as reward related incentive learning and behavioral habit formation resulting from drugs of abuse. Key aspects of these functions are dependent on dopamine transmission as well as activation of calcium/calmodulin-dependent protein kinase IIα (CaMKIIα). In this study, we examined the ability of a recently identified heteromeric complex composed of D1 and D2 dopamine receptors coupled to Gq/11 to activate striatal CaMKIIα. Using the dopaminergic agonist SKF83959, which selectively activates the D1-D2 complex, we demonstrated phosphorylation of CaMKIIα at threonine 286, both in heterologous cells and in the murine striatum in vivo. Phosphorylation of CaMKIIα by activation of the receptor complex required concurrent agonism of both D1 and D2 receptors and was independent of receptor pathways that modulated adenylyl cyclase. The identification of this novel mechanism by which dopamine may modulate synaptic plasticity has implications for our understanding of striatal-mediated reward and motor function, as well as neuronal disorders in which striatal dopaminergic neurotransmission is involved.     

The signal transduction pathway for the dopamine D1 receptor in the guinea-pig cochlea

Dopamine released from lateral efferent fibers modulates the activity of the auditory nerve, but the signaling mechanism by which this is mediated is not known. The present study investigated the signal transduction pathway for the dopamine D1 receptor in the guinea-pig cochlea. D1 receptor immunolabeling was localized to the spiral ganglia neurons and at the base of the inner hair cells. Western immunoblotting on whole cochlear preparations revealed positive bands for the D1 receptor and for dopamine and the cyclic AMP-regulated phosphoprotein. The amplitude of the compound action potential was enhanced in the presence of the D1 receptor agonist, SKF 38393, an effect that was abolished by H89, a protein kinase A inhibitor. Conversely, SKF 83566, a D1 receptor antagonist decreased the amplitude of compound action potential, while forskolin, a protein kinase A activator prevented this effect. Furthermore, it was found that the level of glutamate receptor 1 phosphorylation at the protein kinase A site (Ser845) was increased by the D1 agonist, but decreased by D1 antagonist. Our results provide evidence that the D1 receptor is localized in the spiral ganglion neurons as well as the nerve endings under the inner hair cells and they can modulate auditory nerve function. One signal transduction pathway of D1 receptor in the auditory nerve is via protein kinase A-mediated glutamate receptor 1 phosphorylation.     

Stimulation of the Immune Response During Activation of the Dopaminergic System in Mice with Opposite Types of Behavior

Studies reported here demonstrated that activation of the dopaminergic system induces increases in the immune response regardless of the type of behavior in mice (line CBA), i.e., in aggressive mice, submissive mice, and mice lacking experience of victory or defeat (controls). Changes in the activity of the dopaminergic system were induced with SKF-38393, a selective agonist of dopamine D1 receptors, and with p-chlorophenylalanine (PCPA), which we have previously shown to activate D2 receptors. In the aggressive form of behavior, which was characterized by strong (compared with controls) immune responses, SKF-38393 and PCPA led to further increases in the immune response. In submissive mice, activation of the dopaminergic system altered the nature of the immune response, with immunostimulation, as in aggression. It is suggested that activation of the dopaminergic system in conditions of defined psychoemotional status fixed by acquisition of opposite types of behavior, induces the formation of a new neurochemical pattern--the dopaminergic set--which led to changes in the nature and intensity of the immune response.     

Regulation of kainate receptors by protein kinase C and metabotropic glutamate receptors

Kainate receptors have recently been shown to be involved in synaptic transmission, to regulate transmitter release and to mediate synaptic plasticity in different regions of the CNS. However, very little is known about endogenous mechanisms that can control native kainate receptor signalling. In this study we have found that GluR5-containing kainate receptor-mediated actions can be modulated by activation of protein kinase C (PKC) but not protein kinase A (PKA). However, both PKA and PKC directly phosphorylate the GluR5 subunit of kainate receptors. Metabotropic glutamate (mGlu) receptors are well known to be involved in synaptic transmission, regulation of transmitter release and synaptic plasticity in a variety of brain regions. We now demonstrate that kainate receptor signalling is enhanced by activation of group I mGlu receptors, in a PKC-dependent manner. These data demonstrate for the first time that kainate receptor function can be modulated by activation of metabotropic glutamate receptors and have implications for understanding mechanisms of synaptic transmission, plasticity and disorders such as epilepsy.     

D-1 and D-2 dopaminergic receptors regulate protein phosphorylation in the rat neurohypophysis

Dopamine stimulates the phosphorylation of the neuron-specific synaptic vesicle proteins Synapsin I, Protein IIIa and Protein IIIb in the posterior pituitary gland of the rat [Tsou and Greengard (1982) Proc. natn. Acad. Sci. U.S.A. 79, 6075-6079]. This effect has been characterized in the present investigation. The stimulatory effect of dopamine was mimicked by the selective D-1 receptor agonist SKF 38393 and was competitively and potently inhibited by the selective D-1 receptor antagonist SKF 83509 as well as by the mixed D-1/D-2 antagonist fluphenazine. Conversely, the effect of dopamine was attenuated by a D-2 receptor agonist (LY 141865) and potentiated by a D-2 receptor antagonist (sulpiride). Norepinephrine also stimulated phosphorylation of the synaptic vesicle proteins, apparently through activation of the D-1 receptor. D-1 and D-2 dopaminergic receptors may play a role in the regulation of hormone secretion from the neurohypophysis. Evidence exists that in the isolated neurophypophysis activation of D-1 receptors facilitates, while activation of D-2 receptors inhibits, release of vasopressin. Further work will be required to determine whether the regulation by D-1 and D-2 receptors of the protein phosphorylation in the neurohypophysial peptidergic terminals is related to the regulation by those receptors of the neurohypophysial hormone secretion.