Neurotrophins in the ventral tegmental area: Role in social stress, mood disorders and drug abuse.

This review discusses the impact of neurotrophins and other trophic factors, including fibroblast growth factor and glial cell line-derived neurotrophic factor, on mood disorders, weight regulation and drug abuse, with an emphasis on stress- and drug-induced changes in the ventral tegmental area (VTA). Neurotrophins, comprising nerve growth factor, brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4/5 play important roles in neuronal plasticity and the development of different psychopathologies. In the VTA, most research has focused on the role of BDNF, because other neurotrophins are not found there in significant quantities. BDNF originating in the VTA provides trophic support to dopamine neurons. The diverse intracellular signaling pathways activated by BDNF may underlie precise physiological functions specific to the VTA. In general, VTA BDNF expression increases after psychostimulant exposures, and enhanced BDNF level in the VTA facilitates psychostimulant effects. The impact of VTA BDNF on the behavioral effects of psychostimulants relies primarily on its action within the mesocorticolimbic circuit. In the case of opiates, VTA BDNF expression and effects seem to be dependent on whether an animal is drug-naïve or has a history of drug use, only the latter of which is related to dopamine mechanisms. Social defeat stress that is continuous in mice or intermittent in rats increases VTA BDNF expression, and is associated with depressive and social avoidance behaviors. Intermittent social defeat stress induces persistent VTA BDNF expression that triggers psychostimulant cross-sensitization. Understanding the cellular and molecular substrates of neurotrophin effects may lead to novel therapeutic approaches for the prevention and treatment of substance use and mood disorders.

Intermittent social defeat stress enhances mesocorticolimbic ΔFosB/BDNF co-expression and persistently activates corticotegmental neurons: implication for vulnerability to psychostimulants.

Intermittent social defeat stress exposure augments behavioral response to psychostimulants in a process termed cross-sensitization. Brain-derived neurotrophic factor (BDNF) mediates synaptic plasticity and cellular responses to stress and drugs of abuse. We previously showed that repeated social defeat stress persistently alters BDNF and activates ΔFosB expression in mesocorticolimbic regions. Here, we hypothesized that social defeat stress would increase ΔFosB expression in BDNF-containing mesocorticolimbic neurons at a time when cross-sensitization is evident. Because the ventral tegmental area (VTA) is critical for cross-sensitization, we similarly hypothesized that repeated social defeat stress would induce ΔFosB in neurons of mesocorticolimbic terminal regions that innervate the VTA. We induced social defeat stress in rats by short confrontations with an aggressive resident rat every third day for 10 days. Control rats were handled according to the same schedule. Defeated rats exhibited sensitized locomotor response to amphetamine (1.0mg/kg, i.p.) 10 days after termination of stress exposure. Separate rats, which underwent stress procedures without amphetamine challenge, were used for histological assessments. Rats received intra-VTA infusion of the retrograde tracer, Fluorogold (FG), and brain tissue was collected 10 days after stress or handling for immunohistochemistry. Stress exposure increased BDNF immunoreactivity in anterior cingulate, prelimbic and infralimbic regions of the prefrontal cortex (PFC), medial amygdala (AMY), nucleus accumbens (NAc) and VTA; ΔFosB labeling in anterior cingulate cortex (ACG) and nucleus accumbens; and ΔFosB/BDNF co-expression in prelimbic cortex (PL), nucleus accumbens and medial amygdala. Infralimbic ΔFosB-labeling was enhanced by stress in neurons innervating the VTA. Increased ΔFosB/BDNF co-expression and persistent functional activation of corticolimbic neurons after stress may contribute to mechanisms underlying cross-sensitization to psychostimulants.

Short- and long-term effects of intermittent social defeat stress on brain-derived neurotrophic factor expression in mesocorticolimbic brain regions.

Social defeat stress is an ethologically salient stressor which activates dopaminergic areas and, when experienced repeatedly, has long-term effects on dopaminergic function and related behavior. The mechanism for these long-lasting consequences remains unclear. A potential candidate for mediating these effects is brain-derived neurotrophic factor (BDNF), a neurotrophin involved in synaptic plasticity and displaying alterations in dopaminergic regions in response to various types of stress. In this study, we sought to determine whether repeated social defeat stress altered BDNF mRNA and protein expression in dopaminergic brain regions either immediately after the last stress exposure or 4 weeks later. Male Sprague-Dawley rats were subjected to social defeat stress consisting of brief confrontation with an aggressive male rat every third day for 10 days; control rats were handled according to the same schedule. Animals were euthanized either 2 h or 28 days after the last stress or handling episode. Our results show that 2 h after stress, BDNF protein and mRNA expression increased in the medial prefrontal cortex. At this time-point, BDNF mRNA increased in the amygdala and protein expression increased in the substantia nigra. Twenty-eight days after stress, BDNF protein and mRNA expression were elevated in the medial amygdala and ventral tegmental area. Given the role of BDNF in neural plasticity, BDNF alterations that are long-lasting may be significant for neural adaptations to social stress. The dynamic nature of BDNF expression in dopaminergic brain regions in response to repeated social stress may therefore have implications for lasting neurochemical and behavioral changes related to dopaminergic function.

Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala.

Repeated exposure to stress induces cross-sensitization to psychostimulants. The present study assessed functional neural activation during social defeat stress-induced sensitization to a subsequent amphetamine challenge. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat once every third day during the course of 10 days. Rats received d-amphetamine injections (1 mg/kg, i.p.) 17 or 70 days after the first social defeat stress exposure. Amphetamine administration induced a significantly higher frequency of locomotor activity in stressed animals than in handled control rats, which was still evident 2 months after the last social stress exposure. Immunohistochemistry for Fos-like proteins was used to detect activated neural profiles in the striatum, nucleus accumbens (NAc), prefrontal cortex, amygdala, and ventral tegmental area (VTA). Repeated social defeat stress significantly increased Fos-like immunoreactive (Fos-LI) labeling 17 days after the start of stress exposure in the prelimbic and infralimbic cortical regions, NAc shell and core, medial, central and basolateral amygdala, and VTA, which probably represented the expression of chronic Fos-related antigens. Amphetamine augmented stress-induced Fos-LI labeling 17 days after the first stress episode in the dorsal striatum, NAc core, and medial amygdala, reflecting a cross-sensitization of Fos response. Amphetamine challenge 70 days after social stress exposures revealed sensitized Fos-LI labeling in the VTA and the amygdala. These data suggest that episodes of repeated social stress induce a long-lasting neural change that leads to an augmented functional activation in the VTA and amygdala, which might represent a neurobiological substrate for long-lasting cross-sensitization of repeated social defeat stress with psychostimulant drugs.

Zolmitriptan--a 5-HT1B/D agonist, alcohol, and aggression in mice.

RATIONALE: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penetrates into the central nervous system and, like other 5-HT1B/D agonists, its pharmacotherapeutic profile may include significant anti-aggressive effects. OBJECTIVES: To examine whether zolmitriptan has potential anti-aggressive effects by studying two kinds of aggressive behavior in mice--species-typical and aggression under the influence of alcohol. A second objective was to study whether pre- or post-synaptic receptors mediate these anti-aggressive effects. METHODS: Initially, the anti-aggressive effects of zolmitriptan were studied in male CFW mice during 5-min resident-intruder confrontations. To confirm the 5-HT1B receptor as a critical site of action for the anti-aggressive effects, the zolmitriptan dose-effect determinations were repeated after pretreatment with GR 127935 (10 mg/kg, i.p.). In further experiments, mice were treated concurrently with alcohol (1.0 g/kg, p.o.) and zolmitriptan (1-30 mg/kg, i.p.) in order to compare the effects of this agonist on species-typical and alcohol-heightened aggression. Finally, mice were infused with the neurotoxin 5,7-DHT (10 microg) into the raphé area to eliminate somatodendritic and presynaptic autoreceptors. The anti-aggressive effects of zolmitriptan (17 mg/kg, i.p.) or CP-94,253 (10 mg/kg, i.p.) were assessed 10 days after the lesion, and levels of 5-HT and 5-HIAA were measured in the hippocampus and prefrontal cortex. RESULTS: Zolmitriptan exerted behaviorally specific anti-aggressive effects. The reduction in aggression was antagonized by GR 127935, indicated by a rightward shift in the dose-effect curves of zolmitriptan, showing the specificity for the 5-HT1B receptors. Zolmitriptan also decreased alcohol-heightened aggression with equal efficacy. The anti-aggressive effects of CP-94,253 and zolmitriptan remained unaltered by 5,7-DHT lesions that depleted cortical and hippocampal 5-HT by 60-80%. CONCLUSIONS: Zolmitriptan proved to be an effective and behaviorally specific anti-aggressive agent in situations that engender moderate and alcohol-heightened levels of aggression. These effects are potentially due to activation of post-synaptic 5-HT1BD receptors.

Social defeat stress increases expression of mu-opioid receptor mRNA in rat ventral tegmental area.

Prompted by previous studies linking social defeat stress to changes in opioid antinociception, we evaluated the expression of mu-opioid receptor (MOR)-encoding mRNA in selected rat brain areas as a function of this type of stress. Because opioids mediate significant regulatory activities of brain dopamine neurons, dopaminergic loci in the ventral tegmental area (VTA) and substantia nigra (SN) were selected for analysis. Within 30 min after social defeat stress, the level of MOR-encoding mRNA, as detected and quantified by in situ hybridization histochemistry, increased in the lateral VTA and this increase was present for at least 6 h. In contrast, defeat stress was without effect on the expression of MOR-encoding mRNA in the SN. These data suggest that stress-induced alteration of MOR-encoding mRNA expression in the VTA may be involved in the consequences of social defeat stress.

Behavioral sensitization to cocaine after a brief social stress is accompanied by changes in fos expression in the murine brainstem.

The objective of the present study was to determine how c-fos gene expression in brainstem structures after a brief episode of social defeat stress is related to behavioral sensitization to cocaine challenge. Social stress was defined as defeat in a brief confrontation with an aggressive resident mouse and subsequent 20-min exposure to the resident's threats behind a protective screen. Mice were treated with cocaine (40 mg/kg, i.p.) immediately or 1 week after social defeat stress. Fos-like immunoreactive (Fos-LI) cell nuclei were analyzed in the ventral tegmental area (VTA), dorsal raphe nucleus (DR), periaqueductal grey area (PAG) and locus coeruleus (LC). One episode of social stress induced behavioral sensitization to cocaine as indicated by an augmented locomotor response to a challenge injection 7 days after a single defeat. In naive mice, social stress markedly increased the number of Fos-LI nuclei in the DR, PAG and LC, but not in the VTA. Similarly, cocaine administration resulted in a significantly increased number of Fos-LI nuclei in the same areas. Administration of cocaine immediately following social defeat significantly reduced the number of Fos-LI nuclei in the DR, PAG and LC. Cocaine-induced Fos expression returned in the PAG and DR, but not in the LC, 1 week after social stress. In conclusion, the present results suggest that the presence of brainstem Fos be related to the ability to express stress-induced behavioral sensitization to cocaine.

[Selection vector and ontogenetic development of behavior under domestication of wild Norway rats]. / Vektor otbora i ontogeneticheskie zakonomernosti formirovaniia povedeniia pri deomestikatsii serykh krys.

Hereditary variation in rates of ontogenetic formation of exploratory behavior, glucocorticoid functions, and neurotransmitter systems in wild Norway rats during selection for absence of defensive response towards humans (domestication) is demonstrated. Interrelated shifts in the development of behavior and neurohormonal systems are shown. A comparison of the data obtained with the results of domestication of another species-silver fox-suggests that equally vectorized selection of animals belonging to different taxa produces equally directed changes of their regulatory systems.

[The participation of the dopaminergic system of the striatum in the regulation of catalepsy in mice and rats of different genotypes]. / Uchastie dofaminergicheskoisistemy striatuma v reguliatsii katalepsii u myshei i krys razlichnykh genotipov.

Dopaminergic striate system was studied in mice of six inbred strains (AKR, BALB/c, DD, CC57BR, C57BL/6, and CBA--the last with hereditary predisposition to catalepsy) and Wistar rats (normal stock and GC stock bred for predisposition to catalepsy in the course of 21-22 generations). No significant differences in the content of dopamine and its main metabolites--3,4-dihydroxyphenylacetic acid and homovanillic acids--were found in the striatum of CBA mice and GC rats in comparison with other groups. In catalepsy-predisposed animals changes were observed only in sensitivity of dopamine receptors. After apomorphine injection the sensitivity of postsynaptic dopamine receptors in CBA mice was decreased (tested by stereotypic climbing). The sensitivity of both pre- and postsynaptic receptors to injected apomorphine and haloperidol was increased in GC rats. Thus, the observed changes in dopaminergic system were not substantial and not of the same direction in rats and mice. It is suggested that the striate dopaminergic system does not play a key role in the mechanisms of genetic predisposition to catalepsy.

[The genotypic correlations of the expression of anxiety and dopamine metabolism in the mouse brain]. / Genotipicheskie korreliatsii ékspressii trevozhnosti i metabolizma dofamina v mozge myshei.

Dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were determined in striatum and nucleus accumbens with olfactory tubercles in four mice strains (C57BL/6, DBA/2, BALB/c, and CBA). The levels of anxiety were estimated in the elevated plus-maze, dark-light test, and by the social activity. Significant correlation was revealed between the content of dopamine (and its main metabolites) and the level of anxiety. All the correlations between the DOPAC level and the percentage of time spent in the open arms, or at the illuminated area, or contacting with a conspecific were positive. The correlations between these anxiety indices and HVA levels were negative. It is suggested that brain dopaminergic system plays an essential role in the regulation of anxiety and that anxiety is associated with increased O-methylation and decreased oxidative deamination of dopamine.

[Effect of a single-locus mutation of the silver-blue color allele in mink on the dopaminergic system of the brain]. / Vliianie odnolokusnoi mutatsii allelia serebristo-goluboi okraski norok (PP) na dofaminovuiu sistemu mozga.

The peculiarities of dopamine metabolism and dopamine receptors in the brain of homozygous silver-blue (pp) minks were examined in comparison with wild-type (PP) minks. A pp mutation was found to affect the dopamine turnover in corpus striatum, which is one of the major dopaminergic brain structures. In silver-blue minks, increased dopamine catabolic enzyme activity monoamine oxidase type B (MAO B), together with the decreased level of dopamine and the tendency for the level of the metabolite 3,4-dihydrophenyl acetic acid to increase, were demonstrated in this brain region. No significant alterations in the level of another dopamine metabolite, homovanillic acid, or in D1 and D2 receptor density were shown. In the midbrain and hippocampus, an elevated level of MAO B activity was detected. We found no modifications in receptor properties, nor in dopamine turnover in a mesolimbic dopamine structure, the nucleus accumbens. We propose that the primary effect of pp mutation is an increase in MAO B activity resulting in dopamine turnover alterations and probably in dopamine-dependent behavior (pleiotropic cascade).

[The action of neuroleptics on different types of catalepsy in rats with a genetic predisposition to catatonic reactions]. / Deistvie neiroleptikov na razlichnye tipy katalepsii u krys s geneticheskim predraspolozheniem k katatonicheskim reaktsiiam.

Rats of GC strain with genetic predisposition to cataleptic reactions bred from Wistar rats are more sensitive to cataleptogenic effect of haloperidol and trifluperidol than Wistar rats. At the same time, chlorpromazine and sulpiride considerably shorten the time of maintenance of imposed vertical cataleptic postures for which GC strain has been selected. This paradoxical situation is interpreted so that the more pronounced neuroleptic-induced catalepsy in GC rats is caused by increased sensitivity of postsynaptic dopamine D receptors in the striatum, while the predisposition to the cataleptic postures attenuated by neuroleptics is associated with dopaminergic hyperactivity of the mesolimbic system.

Dopaminergic brain system in the quaking mutant mouse.

Quaking mice (qk/qk), autosomal recessive mutants with central nervous system dysmyelinization, characterized behaviorally by abnormal locomotion and tremor, are found to have altered brain dopaminergic system parameters, in comparison with phenotypically normal heterozygous littermates. Dopamine metabolism is enhanced in structures of both nigrostriatal and mesolimbic systems, as revealed by increased metabolites content (that of homovanillic acid in striatum and concentration of 3,4-dihydroxy-phenylacetic acid in nucleus accumbens with tuberculum olfactorium) along with unchanged neurotransmitter levels in qk/qk mice. D1 and D2 receptor analysis via radioligand binding using [3H]-SCH 23390 and [3H]-spiperone, correspondingly, showed an increase of D2 receptor density with decreased affinity to D2 ligand in striatum of mutants: both Bmax and Kd were markedly higher. D1 and D2 receptor sensitivity in the quaking mouse was also altered. Stimulation of D1 receptors by a highly specific agonist SKF 38393 (2.5 and 5 mg/kg) decreased locomotor activity only in mutants, but not in controls. In contrast, qk/qk were less sensitive than phenotypically normal qk/+ mice to a selective D2 dopamine receptor agonist, LY 171555 (quinpirole, 1 and 2.5 mg/kg). The alterations found in the brain dopaminergic system of qk/qk mice may be responsible for the behavioral expression of this neurologic mutation.

Dopamine D1 and D2 receptor ligands modulate the behaviour of mice in the elevated plus-maze.

To further our understanding of the potential role of dopamine in mechanisms of anxiety, the effects of four dopamine receptor ligands were examined in an ethological version of the murine elevated plus-maze test. The D1 receptor partial agonist, SKF 38393 (2.5-20.0 mg/kg), had minimal behavioural activity in this test, whereas the selective D1 receptor antagonist, SCH 23390 (0.025-0.2 mg/kg), had dose-dependent but behaviourally nonspecific effects. Quinpirole (0.0625-0.5 mg/kg), a D2 receptor agonist, had no effects at low doses but severely disrupted locomotion and exploration at the highest doses tested. In marked contrast to the lack of effect or nonspecific effects seen with the other ligands tested, the D2 receptor antagonist, sulpiride (2.5-20.0 mg/kg), produced an unambiguous anxiolytic-like profile under present test conditions. Although none of the doses tested adversely affected general activity, clear antianxiety effects were observed on both traditional and novel (i.e., risk assessment) behavioural measures. Data are discussed in relation to the relative importance of D1 and D2 receptor mechanisms in plus-maze anxiety, and the need to further assess D2 involvement through the use of more selective compounds.

[The effect of the pleiotropic action of single-locus (pp) and dual-locus (aapp) mutation of mink fur color genes on serotonin metabolism in the brain]. / Vliianie pleiotropnogo deistviia odnolokusnoi (pp) i dvulokusnoi (aapp) mutatsii genov okraski norok na metabolizm serotonina v mozge.

Specific features of serotonin (5-hydroxytryptamine, 5-HT) metabolism were studied in the brain of mutant sapphire minks, homozygous at genes determining silver-blue and Aleutian fur color (ppaa), and silver-blue minks (pp) in comparison with the standard-colored minks (++/++). In the midbrain of sapphire mutants, the activities of tryptophan hydroxylase (TPH) and monoamine oxidase (MAO), key enzymes of 5-HT biosynthesis and catabolism, were significantly higher; an increase in the 5-HT level was statistically nonsignificant due to considerable variation in this parameter; and the level of 5-hydroxyindole-3-acetic acid remained unchanged. A similar increase in TPH and MAO activities was also found in the midbrain of silver-blue pp minks, suggesting that activation of key enzymes of 5-HT metabolism in sapphire aapp minks is associated with the mutant alleles pp.

[The effect of deprenil on the dopaminergic system of the brain in mice of different genotypes during aging]. / Vliianie deprenila na dofaminergicheskuiu sistemu mozga myshei razlichnykh genotipov pri starenii.

Effects of aging on brain dopaminergic system, e.g., neurotransmitter metabolism and different kinds of dopamine-dependent behaviour, were studied in mice of three inbred strains. Homovanillic acid concentrations in structures of both nigrostriatal (striatum) and mesolimbic (n. accumbens with tuberculum olfactorium) systems were found to be increased in the aged animals. Aged mice of the strains studied were characterized by decreased locomotor activity and stereotypic climbing; CC57Br mice, in contrast to A/He and C3H/He, demonstrated significantly diminished level of investigatory activity. However, genotypic differences in these kinds of behaviour were less pronounced in the aged animals in comparison to the young adults, but interstrain differences in swimming activity (Porsolt's "despair test") which was almost unchanged in aged mice, remained enough pronounced. In the aged mice postsynaptic dopamine receptor sensitivity, assessed after administration of a high dose of the mixed agonist apomorphine, was markedly decreased. Chronic treatment with deprenyl, a specific MAO-B inhibitor, produced a clear-cut genotype-dependent effect on investigatory activity in the aged animals. High level of this activity, characteristic for the young adults, was restored in CC57Br, in A/He it was elevated in comparison both with young and old untreated animals, and the same tendency was observed in C3H/He. This fact seems to reflect an interesting property of deprenyl to increase general adaptation in the aged organism, that might have valuable clinical implications.

Genetic analysis of different kinds of aggressive behavior.

Various kinds of aggressive behavior such as spontaneous intermale aggression, predatory aggression (locust-killing behavior), and irritable (shock-induced) aggression were investigated in inbred strains of mice. Genotype was shown to affect significantly the phenotypic variety of these kinds of aggression. There were, however, no interstrain correlations either between intermale aggression and predatory behavior or between intensity of intermale, shock-induced aggression and locust-killing behavior. Moreover, the intermale aggression level (percentage of fighting mice in each strain) did not correlate with the intensity of fighting. It has been shown by Mendelian analysis on C57BL/6J and BALB/c strains that these indices of intermale aggression are under different genetic control. The selection of Norway rats over 20 generations for reduced fear-induced aggressiveness toward man resulted in a decrease in irritable aggression and loss of an aggressive response to man. No changes in intermale and predatory aggression, however, were found. Hence, different kinds of aggressive behavior--intermale, predatory, and fear-induced aggression--seem to be controlled by different genetic mechanisms.

Strain differences in clonidine-induced aggressiveness in mice and its interaction with the dopamine system.

The influence of a genotype of inbred mice on the aggressive behavior induced by clonidine and the role of dopamine D1 and D2 receptors in that behavior were studied. Clonidine in a dose of 10 mg/kg evoked a strong aggressiveness in BALB/c, DBA/1, and CC57Br mice and an intermediate response in C57BL/6J, Albino Swiss, and CBA mice, whereas DD, A/He, and C3HA/y mice did not show any aggressive behavior. Apomorphine significantly potentiated the clonidine-induced aggressiveness in C57BL/6J mice. In Albino Swiss mice, SK&F38393 as well as quinpirole augmented the aggressive behavior evoked by clonidine. The clonidine-induced aggressiveness was blocked by SCH23390 and cis-flupentixol but not by (-)-sulpiride. In aggressive mice, the binding of [3H]SCH23390 was decreased in the limbic forebrain, whereas the binding of [3H]spiperone was not changed. The obtained results indicate that the potency of the clonidine-induced aggressiveness depends upon genotype of mice; moreover, the presence of a physiological function of D1 receptors is necessary for its occurrence.

[The role of the genotype in the cataleptogenic effect of neuroleptics]. / Rol' genotipa v kataleptogennom éffekte neiroleptikov.

The cataleptogenic effects of three neuroleptics from one chemical group was investigated in 8 mice strains (CBA, A/He, C57B1/6, C3H/He, BALB/c, AKR, DD, and CC57Br. Despite significant interstrain, differences in the action of the drugs, haloperidol (0.5 mg/kg) and trifluperidol (0.5 mg/kg) produced much greater cataleptogenic action than fluspirilene (2 mg/kg). At the same time the intensity of catalepsy in various mice strains after haloperidol was not coincident with that after trifluperidol (r = 0.22): CBA mice displayed the maximum catalepsy, but AKR, DD and CC57Br mice, the minimum when haloperidol was given; with trifluperidol, the maximum catalepsy was observed in AKR mice, but absent in DD mice. Fluspirilene induced catalepsy only in CBA and A/He mice. Thus, the presence of catalepsy, a side effect of most neuroleptics, is largely predetermined by hereditary factors.