Involvement of dopamine D1 and D2 receptors in the rat nucleus accumbens in immunostimulation.

Analysis of the nature of changes in the immune response in operated Wistar rats showed that electrolytic lesioning of the nucleus accumbens, the site of the greatest density of dopamine D1 and D2 receptors, led to suppression of the immune response in animals immunized with sheep erythrocytes. Administration of SKF 38393 (20 mg/kg) and quinpirol (1 mg/kg), selective agonists of dopamine D1 and D2 receptors respectively, to sham-operated rats induced significant increases in immune responses. However, no immunostimulation was seen on administration of the selective dopamine D2 agonist quinpirol to animals with lesions to the nucleus accumbens as compared with controls. At the same time, treatment of animals with nucleus accumbens lesions using the dopamine D1 receptor agonist SKF 38393 had no effect on the immune response as compared with that in sham-operated animals given the D1 receptor agonist. These data provide evidence that dopamine D2 receptors in the nucleus accumbens have a role in the mechanisms of immunostimulation, though D2 receptors in other brain structures may also make some contribution to this process; D1 receptors in the nucleus accumbens make no significant contribution to controlling the immune response.

Interaction between dopamine D1 and D2 receptors in modulation of the immune response.

The interaction between dopamine D1 and D2 receptors plays a role in immunomodulation. The results of thus interaction depends on the degree of receptor activation with selective agonists in different doses. Combined treatment with agonists of D1 and D2 receptors in high doses had a synergistic effect in the mechanisms of immunomodulation. Receptor agonists in low doses suppressed the immune response. Our results suggest that weak activation of one of these receptors is accompanied by inactivation of the other receptor type.

Significance of initial emotional state for neuroimmunomodulation in conditions of activation and blockade of 5-HT(1A) receptors.

Experiments performed on male CBA mice immunized with sheep erythrocytes at a dose of 5 x 10(8) cells showed that the selective agonist of serotonin 5-HT(1A) receptors 8-OH-DPAT (1 mg/kg) suppresses the immune response in aggressive animals. In mice demonstrating the submissive type of behavior, formed during 10 days of experience of defeats, activation of 5-HT(1A) receptors with 8-OH-DPAT had no effect on the immune response. However, treatment with the selective 5-HT(1A) receptor blocker WAY-100635 stimulated the immune response, but only in submissive mice. These data lead to the conclusion that activation and blockade of 5-HT(1A) receptors have different effects on the immune response in CBA mice depending on the initial emotional state of the animals, due to different activities of neurotransmitter systems, particularly the serotoninergic, in aggressive and submissive mice.

[Significance of initial emotional state for neuroimmunomodulation under conditions of activation or blockade of 5-HT1A receptors].

Selective agonist of 5-HT1A receptors--8-OH-DPAT (1 mg/kg) induced a suppression of the immune reaction in aggressive male CBA mice immunized with SRBC (5 x 10(8)). In submissive mice with 10-day defeat experience in confrontation tests, the activation of 5-HT1A receptors with 8-OH-DPAT did not alter the immune response, whereas the application of selective antagonist of 5-HT1A receptors WAY-100635 increased the immune reaction only in submissive mice. It is concluded that activation or blockade of 5-HT1A receptors produced different effects on the immune function of CBA mice depending on the initial emotional state which is known to be provided in aggressive and submissive animals by different activities of the brain neurotransmitter systems including the 5-HTergic system.

[The role of D1 and D2 dopamine receptors of the rat nucleus accumbens in immunostimulation].

The analysis of the immune response changes in Wistar rats has shown that bilateral electrolytic lesions of the nucleus accumbens characterized by a high density of D1 an D2 dopamine (DA) receptors resulted in a decrease of the immune response to SRBC. Administration of selective agonists of D1 and D2 DA receptors to sham-operated animal: 20 mg/kg of SKF 38393 or 1.0 mg/kg of quinpirol, respectively, produced significant enhancement of plaque- and rosette-formation. However, the immune response level in the damaged rats did not increase following quinpirol administration, but was maintained at control values, rather. At the same time, activation of D1 DA receptors in rats with destructed nucleus accumbens did not affect the immune response level as compared to that of sham-operated animals receiving SKF 38393. The data obtained give evidence of involvement of D2 DA receptors of the nucleus accumbens in immunomodulation, although D2 DA receptors of other brain structures may also contribute to this process. D1 DA receptors of this localization seem not to play any important role in the immune response control.

[Changes in the immune reaction of animals under conditions of drug-induced activation and blockade of D1 dopamine receptors]. / Izmenenie immunnoi reaktsii u zhivotnykh v usloviiakh aktivatsii i blokady D1 dofaminovykh retseptorov.

A highly selective dopamine D1 receptor agonist (compound SKF 38393) administered in a dose of 20 mg/kg produced a significant increase in the number of rosette-forming cells (RFCs) in the spleen of Wistar rats on the 5th day upon their immunization with goat erythrocytes (5 x 10(8)). At the same time, a specific blocker of these receptors (compound SCH 23390) in a dose of 0.5 or 1 mg/kg inhibited the immune response of rats. In C57BL/6J mice, SCH 23390 (0.25, 0.5, or 1 mg/kg) also significantly reduced the number of RFCs. Preliminary blockade of the D1 dopamine receptors with SCH 23390 (1 mg/kg) prevented the immunostimulating effect of SKF 38393. These data indicate that D1 dopamine receptors are involved in immunomodulation.

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.

[Contribution of D2 dopamine receptors of the rat dorsolateral caudate nucleus to immunomodulation]. / Vklad v immunomoduliatsiiu dofaminobykh D2-retseptorov dorsolateral'noi zony khvostatogo iadra u krys.

The analysis of the immune response changes in Wistar rats under activation or blockade of D2 DA receptors has shown that electrolytic lesion of the dorsolateral caudate nucleus characterized by a high density of D2 DA receptors resulted in a decrease of the immune response to SRBC. At the same time, in rats with similar lesion stimulation of the immune reactions caused by a selective D2 agonist guinpirol (1.0 mg/kg) did not develop completely. Administration of haloperidol (2.0 mg/kg), the immune-inhibitory effect of which is associated with increasing serotoninergic system activity, to rats with impaired dorso-lateral caudate nucleus did not produce more expressed immunosuppression. However, the level of the immune response in sham-operated rats receiving haloperidol was significantly lower than that of animal with the destructed nucleus caudatus. Considering that qunmpirol-induced immunostimulation is related to the selective activation of the DA-ergic brain system, it is concluded that D2 DA receptors of the nucleus caudatus are involved in the mechanisms of immunostimulation, although D2 DA receptors of other brain structures may also impact this process.

Nature of the distribution of serotonin and a serotonin metabolite in brain structures and the development of immunosuppression in submissive mice.

Studies of C57BL/6J mice with acquired submissive behavior in a sensory contact model demonstrated increases in serotonin (5-HT) levels in the amygdaloid complex, hippocampus, the dopaminergic nuclei A11, A10, and A9, and in the caudate nucleus and hypothalamus, compared with controls, after 10 and 20 days of confrontations. Levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in most structures were significantly higher after 20 days of confrontations than after 10 days. Increases in the 5-HIAA/5-HT ratio in the cervical nuclei of the midbrain, nucleus accumbens, A9, and hypothalamus as compared with controls were seen in mice with 10 and 20 days of confrontations. Immunization of mice on days 10 and 20 of confrontations showed suppression of immune responses as compared with controls, while immune measures reached control values by 40 days of experience of defeat. Thus, experience of 10 days of defeat led to immunosuppression on a background of activation of the 5-HT system in a series of brain structures: the cervical nuclei of the midbrain, the nucleus accumbens, and A9. As confrontations continued, there were decreases in the 5-HIAA/5-HT ratio on these structures, along with a tendency for immune responses to increase.

Involvement of the nucleus accumbens in stimulation of the immune response in rats after activation of opioid mu receptors with DAGO.

The involvement of the nucleus accumbens in neuroimmunostimulation was demonstrated during activation of opioid mu receptors with the selective agonist DAGO (100 microg/kg); single doses of this agent to sham-operated (control) Wistar rats induced significant increases in the numbers of direct IgM antibody-forming and total rosette-forming cells after immunization with sheep erythrocytes. Bilateral electrolytic lesioning of the nucleus accumbens in rats led to sharp decreases in the intensity of immune responses; there was no immunostimulation after administration of DAGO to these animals. These data provide evidence for the involvement of the nucleus accumbens in the process of immunomodulation and for the importance of opioid mu receptors in the nucleus accumbens in the stimulation of immunogenesis.

[Distribution of serotonin and its metabolites in the brain structures and immunosuppression in submissive mice]. / Kharakter raspredeleniia serotonina i ego metabolita v strukturakh mozga i razvitie immunosupressii u submissivnykh myshei.

The development of submissive behaviour in C57BL/6J mice in the sensory contact model was associated with an increase in the content of serotonin (5-HT) in the amygdala, hippocampus, dopaminergic nuclei A11, A10, A9, as well as in the caudate nucleus and hypothalamus after 10 and 20 days of confrontations compared to the controls. The level of 5-HT metabolite 5-hydroxyindolacetic acid (5-HIAA) was significantly higher in the most structures examined after 20 daily encounters as compared to animals with experience of 10 confrontations. The time course of submission over 10 or 20 days resulted in an increase of 5-HIAA/5-HT ratio in the midbrain nucleus raphe, nucleus accumbens, A9 and hypothalamus. In mice immunised on the 10th or 20th day of confrontations, the immune response inhibition was observed while its level remained unchanged after more prolonged confrontations (40 days). Thus, the experience of defeats during 10 days shown to be accompanied with an activation of 5-HT system in a number of the brain structures, produced immunosuppression. With increasing number of confrontations the ratio 5-HIAA/5-HT was decreased in the same structures and a tendency to the immune response elevation appeared.

[Activation of dopaminergic system stimulates an immune response in mice with opposite type of behaviour]. / Stimuliatsiia immunnogo otveta pri aktivatsii dofaminergicheskoi sistemy u myshei s oppozitnymi formami povedeniia.

It was shown that activation of dopaminergic (Daergic) system induced an increase of the immune responsiveness independent of the CBA mice behaviour typeanimals without experience of victories and defeats (control), with aggression and submission. Administration of SKF-38393, a selective agonist of DA D1-receptors, resulted in enhanced immune response as tested by plaque-forming cells and rosette-forming cells number. Similar immunostimulation was observed after injection of p-chlorophenylalanine realizing its influence on the immune response through DA D2-receptors as shown by us elsewhere. It was suggested that activation of Da-ergic system produces a new neurochemical pattern (Daergic neurochemical set) which are responsible for character and intensity changes of the immune response in mice with alternative form of social behaviour.

[Involvement of dopaminergic systems in the functional specialization of brain areas during formation of aggressive and submissive behavior in mice]. / Uchastie dofaminovykh sistem v funktsional'noi spetsializatsii oblastei mozga pri formirovanii agressivnogo i submissivnogo povedeniia myshei.

In addition to its common activating action, the DA system is involved in the functional specialization of the brain areas which participate in the expression of discrete behavioral components. The evidence for different levels of activity of the mesocortical DA system in aggressive and submissive mice were obtained. In C57BL/6J mice, confrontations produced simultaneous increase in the extracellular DA content and its release from the nerve terminals in the nucleus accumbens and frontal cortex, while an elevation of the HVA concentration in these structures was found only in submissive mice. After 20 encounters, the habituation of animals to the repeated stress exposures and conditioning developed. Activation of the DA metabolism (increase in the DOPAC level and DOPAC/DA ratio) in the hippocampus was observed only in aggressive mice after 20 days of confrontation, when the extinction of the information novelty leading to aggression had been already accomplished. Our findings suggest the predominance of the role of the mesolimbic DA system, in particular, of its mesoaccumbens link, in the extinction of the information novelty in aggressors. A role of the mesocortical DA system in realization of the submissive behavior patterns, stress reactions, conditioned defensive behavior, anxiety-related behavior, and in modulation of the anxiety response to social stimuli is considered.

[Involvement of the nucleus accumbens in immune response stimulation following activation of opioid mu-receptors by DAGO]. / Vkliuchenie iadra akkumbens v stimuliatsiiu immunnogo otveta u krys posle aktivatsii opioidnykh mu-retseptorov DAGO]

The data obtained suggest that the agonist of the nucleus accumbens' mu-opioid receptor DAGO significantly increases the number of plaque- and rosette-forming cells following immunisation with sheep red blood cells in sham-operated Wistar rats. Bilateral destruction of the n. accumbens inhibited the immune response.

Involvement of the rat caudate nucleus in the immunostimulatory effect of DAGO.

The involvement of the caudate nucleus, i.e., the terminal zone of the nigrostriatal dopaminergic system, in neuroimmunostimulation during the activation of mu opioid receptors by the highly specific agonist DAGO. Single doses of DAGO (100 microg/kg) in sham-operated control Wistar rats induced significant increases in the numbers of direct IgM-antibody-forming and total rosette-forming cells at the peak of the immune response after immunization with sheet red blood cells. The experiments showed that bilateral electrolytic lesioning of the caudate nucleus in rats suppressed the immune response, demonstrating its involvement in neuroimmunomodulation. Since the effect of immunostimulation induced by DAGO disappeared when given to animals with caudate nucleus lesions, it was concluded that this structure is involved in activatory immunogenesis via mu opioid mechanisms.

Effects of type 1A serotonin receptor agonist 8-OH-DPAT on immune response.

The selective agonist of type 1 A serotonin receptors 8-hydroxy-2-(di-n-propyl-amino)tetra-lin (8-OH-DPAT) suppressed the immune response. Intraperitoneal administration of 1 mg/kg 8-OH-DPAT to Wistar rats over 2 days after immunization decreased the count of plaque- and rosette-forming cells on day 5. Our results indicate that type 1A serotonin receptors are involved in the realization of the immunosuppressive effects of the serotoninergic system.

[Participation of the rat caudate nucleus in the immunostimulating effect of DAGO]. / Uchastie khvostatogo iadra krys v realizatsii immunostimuliruiushchego éffekta DAGO.

The data obtained suggest that administration of the DAGO increased the number of plaque- and rosette-forming cells after immunisation with the sheep red blood cells in the sham-operated Wistar rats. Following destruction of the caudate nucleus, the DAGO administration prevented the immune activation. Bilateral destruction of the caudate nucleus resulted in a considerable inhibition of the immune response as compared with the control rats. Thereupon the caudate nucleus seems to be involved in realisation of the DAGO-induced immune activation.

[Immune responses in C57BL/6J mice with the inverted pattern of behavior during social conflict]. / Kharakter immunnoi reaktsii u myshei linii C57BL/6J pri inversii povedeniia v usloviiakh zoosotsial'nogo konflikta.

Inversion of aggressive behaviour into a submissive one led to immunosuppression in C57BL/6J mice as well as in those mice which did not change their behaviour, whereas inversion of submissive behaviour into aggressive one resulted in immunostimulation. A possibility to influence immune response changing the brain neurochemical pattern by reversing behaviour under conditions of a social conflict, is discussed.

[The neurochemical set of the brain--an extra-immune mechanism of psychoneuroimmunomodulation]. / Neirokhimicheskaia ustanovka mozga--ékstraimmunnyi mekhanizm psikhoneiroimmunomoduliatsii.

The present study provides evidence for involvement of brain neurotransmitters in the control of an immune response. The extra-immune mechanism of immunomodulation is considered by analyzing drug-induced changes in the brain neurotransmitter systems, brain destruction, altered activity of brain regions due to psychoemotional stress, including mental disease. It is suggested that the pattern of neurotransmitter activity with its prevalence in certain brain regions determines the neurochemical set-up of the brain for psychoneuroimmunomodulation, i.e. its extra-immune mechanism.