Alterations in cognitive function and behavioral response to amphetamine induced by prenatal inflammation are dependent on the stage of pregnancy

Maternal infection during human pregnancy has been associated with the development of schizophrenia in the adult offspring. The stage of development and the maternal inflammatory response to infection, which undergoes quantitative and qualitative changes throughout gestation, are thought to determine critical windows of vulnerability for the developing brain. In order to investigate how these two factors may contribute to the outcome in the offspring, we studied the inflammatory response to turpentine (TURP) injection (100 μl/dam) and its consequences in the adult offspring, in pregnant rats at gestational day (GD) 15 or 18, which correspond to late first and early second trimester of human pregnancy, respectively. Maternal inflammatory response to TURP was different between the two GDs, with fever and circulating levels of the pro-inflammatory interleukin (IL)-6 significantly attenuated at GD 18, compared to GD 15. In the adult offspring, TURP challenge at GD 15 induced a significant decrease in pre-pulse inhibition (PPI) of acoustic startle, increased latency in the cued task of the Morris-water maze, prolonged conditioned fear response and enhanced locomotor effect of amphetamine. In contrast, the same immune challenge at GD 18 induced only a prolonged conditioned fear response. These results suggest a window of vulnerability at GD 15, at which TURP seems to affect several behaviors that are strongly modulated by dopamine. This was supported by increased tyrosine hydroxylase expression in the nucleus accumbens of the adult offspring of mothers treated at GD 15.     

Maternal immune activation in late gestation enhances locomotor response to acute but not chronic amphetamine treatment in male mice offspring: role of the D1 receptor

Exposure to elevated levels of maternal cytokines can lead to functional abnormalities of the dopaminergic system in the adult offspring, including enhanced amphetamine (AMPH)-induced locomotion. Therefore, it seems reasonable to consider that offspring of challenged mothers would behave differently in models of addictive behavior, such as behavioral sensitization. Thus, we sought to evaluate the effects of prenatal exposure to lipopolysaccharide (LPS) on the locomotor response to acute and chronic AMPH treatment in male mice offspring. For this purpose, LPS (Escherichia coli 0127:B8; 120 μg/kg) was administered intraperitoneally to pregnant Swiss mice on gestational day 17. At adulthood, male offspring were studied under one of the following conditions: (1) locomotor response to acute AMPH treatment (2.5 or 5.0 mg/kg) in an open field test; (2) behavioral sensitization paradigm, which consists of a daily injection of AMPH (1.0 mg/kg) for 10 days and observation of locomotion in the open field on days 1, 5, 10 (development phase), 15 and 17 (expression phase). The LPS stimulated offspring showed enhancement of the locomotor-stimulant effect after an acute AMPH challenge in comparison to baseline and saline pre-treated mice. They also showed development of behavioral sensitization earlier than the saline pre-treated group, although no changes between saline and LPS pre-treated groups were observed on development or expression of locomotor behavioral sensitization to AMPH. Furthermore, there was up-regulation of D1 receptor protein level within striatum in the LPS-stimulated offspring which was strongly correlated with increased grooming behavior. Taken together, our results indicate that motor and dopaminergic alterations caused by maternal immune activation are restricted to the acute AMPH challenge, mostly due to up-regulation of the D1 receptor within the mesolimbic and nigrostriatal pathways, but no locomotor differences were observed for behavioral sensitization to AMPH.     

Repeated allergic asthma in early versus late pregnancy differentially impacts offspring brain and behavior development

BackgroundStress during pregnancy and maternal inflammation are two common prenatal factors that impact offspring development. Asthma is the leading chronic condition complicating pregnancy and a common source of prenatal stress and inflammation.ObjectiveThe goal of this study was to characterize the developmental impact of repeated allergic asthma inflammation during pregnancy on offspring behavioral outcomes and brain inflammation.MethodsPregnant female C57BL/6 mice were sensitized with ovalbumin (OVA) or PBS vehicle control and then randomly assigned to receive daily aerosol exposures to the same OVA or PBS treatment during early, gestational days (GD) 2-GD9, or late pregnancy, GD10-GD17. Maternal sera were collected after the first and last aerosol induction regimen and measured for concentrations of corticosterone, anti-OVA IgE, and cytokine profiles. Juvenile male and female offspring were assessed for locomotor and social behaviors and later as adults assessed for anxiety-like, and marble burying behaviors using a series of behavioral tasks. Offspring brains were evaluated for region-specific differences in cytokine concentrations.ResultsIn early gestation, both PBS and OVA-exposed dams had similar serum corticosterone concentration at the start (GD2) and end (GD9) of daily aerosol inductions. Only OVA-exposed dams showed elevations in cytokines that imply a diverse and robust T helper cell-mediated immune response. Male offspring of early OVA-exposed dams showed decreases in open-arm exploration in the elevated plus maze and increased marble burying without concomitant changes in locomotor activity or social interactions. These behavioral deficits in early OVA-exposed male offspring were associated with lower concentrations of G-CSF, IL-4, IL-7, IFNγ, and TNFα in the hypothalamus. In late gestation, both PBS and OVA-exposed dams had increased corticosterone levels at the end of daily aerosol inductions (GD17) compared to at the start of inductions (GD10). Male offspring from both PBS and OVA-exposed dams in late gestation showed similar decreases in open arm exploration on the elevated plus maze compared to OVA male offspring exposed in early gestation. No behavioral differences were present in female offspring across all treatment groups. However, females of dams exposed to OVA during early gestation displayed similar reductions as males in hypothalamic G-CSF, IL-7, IL-4, and IFNγ.DiscussionThe inflammatory responses from maternal allergic asthma in early gestation and resulting increases in anxiety-like behavior in males support a link between the timing of prenatal insults and sex-specific developmental outcomes. Moreover, the heightened stress responses in late gestation and concomitant dampened inflammatory response to allergic asthma suggest that interactions between the maternal immune and stress-response systems shape early life fetal programming.     

Cholecystokinin modulation of locomotor behavior in rats is sensitized by chronic amphetamine and chronic restraint stress exposure

DA release in the nucleus accumbens (NAcc) is a critical substrate mediating locomotor behavior. Cholecystokinin (CCK) is co-localized with dopamine (DA) in up to 90% of mesolimbic DA neurons. We have previously shown that while CCKA receptor antagonists generally do not affect locomotor behaviors, systemic administration of a CCKA receptor antagonist attenuates amphetamine (AMPH)-induced locomotion in animals previously treated chronically with AMPH, suggesting that chronic stimulant pretreatment may sensitize CCK systems. The present studies examined this issue by testing the effects of CCKA antagonists on AMPH- and novel environment-induced locomotor activity following two manipulations which are known to alter mesolimbic system function: Chronic AMPH administration and chronic restraint stress (RS). Additionally, CCK immunoreactivity in the mesolimbic system following these manipulations was examined using immunohistochemistry. Results indicated that intra-NAcc microinjections of the selective CCKA receptor antagonist PD-140548 attenuated AMPH-induced and novel environment-induced locomotion only in animals which had previously been exposed to chronic AMPH or chronic RS pretreatment. However, chronic AMPH and chronic RS did not produce detectable changes in the number of CCK-immunostained neurons in the ventral tegmental area (VTA) or substantia nigra (SN), or in CCK levels in any of the subregions of the NAcc. Together, these results suggest that the role of endogenous CCK in the modulation of locomotor behaviors is sensitized following chronic psychostimulant or chronic RS exposure. However, this sensitization does not appear to be accompanied by changes in the overall basal levels of CCK or in the number of CCK-positive cells within the mesoaccumbens system.     

Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring

OBJECTIVE: Many studies have implicated prenatal infection in the etiology of schizophrenia. Cytokines, a family of soluble polypeptides, are critically important in the immune response to infection and in other inflammatory processes. The goal of this study was to determine whether second-trimester levels of four cytokines-interleukin-8 (IL-8), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)-are higher in the mothers of offspring who later developed schizophrenia spectrum disorders than in matched comparison subjects. METHOD: The authors conducted a nested case-control study of maternal serum cytokine levels in a large birth cohort, born 1959-1967. Cases (N=59) were subjects diagnosed with schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder) who had available second-trimester maternal serum samples. Comparison subjects (N=105) were members of the birth cohort, had not been diagnosed with a schizophrenia spectrum disorder or major affective disorder, and were matched to subjects with schizophrenia for date of birth, gender, length of time in the cohort, and availability of maternal sera. Maternal second-trimester serum levels of IL-8, IL-1beta, IL-6, and TNF-alpha were determined by sandwich enzyme-linked immunosorbent assay. RESULTS: The second-trimester IL-8 levels in mothers of offspring with schizophrenia spectrum disorders were significantly higher than those of the mothers of comparison subjects. There were no differences between subjects with schizophrenia and comparison subjects with respect to maternal levels of IL-1beta, IL-6, or TNF-alpha. CONCLUSIONS: Using prospectively collected prenatal sera in a large and well-characterized birth cohort, the authors have documented a significant association between maternal IL-8 level during the second trimester and risk of schizophrenia spectrum disorders in the offspring. These findings provide further support for a substantive role of in utero infection or inflammation in the etiology of schizophrenia. Moreover, these results may have important implications for elucidating the mechanisms by which disrupted fetal development raises the risk of this disorder.     

Maternal immune stimulation during pregnancy affects adaptive immunity in offspring to promote development of TH17 cells

Behavioral abnormalities in offspring of murine dams that receive immune stimulation with (poly)I:C during pregnancy are well-documented. In this prenatal model, (poly)I:C-induced maternal cytokines, particularly IL-6, appear involved in the etiology of the behavioral abnormalities. While much has been published on the abnormal behaviors of offspring in this model, much less is known about how maternal immune stimulation affects the adaptive immune system of the offspring, and its possible role in the observed pathophysiology. In the present study, pregnant dams were stimulated with (poly)I:C at E12, and 24 h later cytokine levels were measured in maternal sera and amniotic fluids. Lymphocytes from offspring were also analyzed for T Helper (TH) cell subsets. The results demonstrate that lymphocytes from offspring of pregnant dams stimulated with (poly)I:C develop into TH17 cells upon in vitro activation. This preferential TH17 cell differentiation occurs in offspring of pregnant dams with an immunological “memory” phenotype, but not in offspring of immunologically “naive” dams. Comparable levels of IL-6 were found in the sera of immune and naïve pregnant dams, however, there was a disparity between levels of IL-6 in maternal sera and amniotic fluids of (poly)I:C-injected dams. In matings between IL-6 KO dams (IL-6^−/−) and wild-type males (IL-6^+/+) there was no IL-6 in sera from (poly)I:C-injected dams, but there were high levels of IL-6 in their amniotic fluids. Analysis of supernatants of cultured placental cell preparations from these IL-6 KO dams confirmed that the IL-6 was produced from the fetal (IL-6^+/−) component, and heterozygous IL-6^+/− offspring could also produce IL-6.     

Blockade of group II, but not group I, mGluRs in the rat nucleus accumbens inhibits the expression of conditioned hyperactivity in an amphetamine-associated environment

Environmental stimuli associated with amphetamine (AMPH) can elicit conditioned locomotion in rats, and the nucleus accumbens (NAcc) is known to be important in this process. This study examined the contribution of metabotropic glutamate receptors (mGluRs) in the NAcc to the expression of conditioned locomotion in an AMPH-associated environment. Rats in different groups were administered injections in five 3-day blocks: Paired, AMPH (1.0mg/kg, IP) in locomotor activity boxes on day 1 and saline in their home cages on day 2; Unpaired, saline in the activity boxes on day 1 and AMPH in their home cages on day 2; or Control, saline in both environments. No injections were administered on day 3 of each block. One week after the last conditioning block, all rats were tested for their conditioned locomotor response in the activity boxes for 1h following an IP saline injection. In Paired rats, this injection was preceded by a bilateral microinjection into the NAcc of saline, the group I mGluR antagonist, AIDA (0.5, 5.0 nmol/side), or the group II mGluR antagonist, EGLU (0.5, 5.0 nmol/side). Unpaired and Control rats received NAcc saline. As expected, Paired rats showed both increased locomotor activity and rearing compared to rats in either the Unpaired or Control groups. However, the expression of this conditioned hyper-locomotion was dose-dependently inhibited by NAcc EGLU, but not by AIDA. These results suggest that activation of group II, but not of group I, mGluRs in the NAcc contributes to the expression of conditioned locomotion in an environment associated with amphetamine.     

Evaluation of maternal inflammation as a marker of future offspring ADHD symptoms: A prospective investigation

Early life predictors of attention-deficit/hyperactivity disorder (ADHD) are critically needed; they could inform etiological theory and may help identify new prevention targets. The current study examined prospectively whether maternal cytokine levels during pregnancy predict offspring ADHD symptoms at age 4–6 years. Secondarily, we evaluated maternal cytokine levels as a possible common pathway through which prenatal risks exert influence on child ADHD. Data came from a sample of women recruited during the 2nd trimester of pregnancy (N = 62) and followed postnatally until children were 4–6 years old. Maternal inflammation was assessed using 3rd trimester plasma concentrations of three indicators of nuclear factor kappa B signaling: interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 which were combined into a latent variable. Mothers and teachers reported on child ADHD symptoms, negative affect, and externalizing behaviors at 48–72 months of age. Maternal inflammation in the 3rd trimester predicted ADHD symptoms when children were 4–6 years old (β = 0.53, 95% CI = 0.154, 0.905, p = 0.006). Further, maternal inflammation mediated the effect of prenatal distress on child ADHD (β = 0.21, 95% CI = 0.007, 0.419, p = 0.04). The inflammation effect on ADHD was not explained by concurrent child negative affect, externalizing behavior, or familial ADHD status. This is the first human study to prospectively link maternal pregnancy cytokine levels and offspring ADHD symptoms, suggesting that cytokine levels are a possible marker of ADHD risk. Results also provide new evidence that maternal prenatal inflammation may be one common pathway by which prenatal risk factors influence offspring mental health outcomes.     

Gestational IV nicotine produces elevated brain-derived neurotrophic factor in the mesocorticolimbic dopamine system of adolescent rat offspring

Maternal smoking during pregnancy is associated with enduring psychopathology, such as increased likelihood of substance use, in offspring. Various animal models demonstrate that continuous nicotine exposure produces teratogenic effects in offspring, as well. In this experiment, a novel intravenous (IV) exposure model was used to determine if gestational nicotine (GN) treatment produced alterations in methamphetamine-induced sensitization and the expression of brain-derived neurotrophic factor (BDNF) in the mesocorticolimbic dopamine (DA) system of adolescent offspring. Dams were injected with IV saline or nicotine (0.05 mg/kg/injection) three times per day on gestational days 8-21. Habituation was measured on postnatal day (PND) 25-27 and baseline activity on PND 28. On PND 29-35, offspring were injected with saline or methamphetamine (0.3 mg/kg) and locomotor activity was measured after the first and seventh injections. On PND 36, brains were removed, flash frozen, and BDNF protein levels in the nucleus accumbens (NAcc), dorsal striatum (Str), frontal cortex (FC), and hippocampus (Hipp) were analyzed. GN did not affect habituation or the induction of methamphetamine-induced sensitization. Interestingly, GN, but not adolescent methamphetamine treatment, elevated levels of BDNF in the NAcc and Str; however, the GN-induced increase in BDNF in the FC was attenuated by adolescent methamphetamine treatment. Both GN and adolescent methamphetamine treatment increased BDNF in the Hipp. These findings indicate that GN exposure will result in increased levels of BDNF protein throughout the mesocorticolimbic DA system during adolescent development and suggests that methamphetamine abuse will modulate the expression of BDNF in motivational circuitries of adolescent offspring exposed to GN.     

Maternal pinealectomy increases depressive-like responses in Siberian hamster offspring

This study investigated the effect of maternal pinealectomy and postnatal pinealectomy on affective responses. Siberian hamsters were born to either pinealectomized or sham-operated dams and then underwent pinealectomy or a sham operation. Maternal pinealectomy increased depressive-like responses of offspring in the forced swim test. Maternal pinealectomy increased rearing behaviour and postnatal pinealectomy increased locomotor behaviour in the open field test. These results suggest that prenatal melatonin organizes adult affective responses.     

The neuropathological contribution of prenatal inflammation to schizophrenia

Maternal infection and/or inflammation during pregnancy has been repeatedly shown to elevate the risk of schizophrenia and related psychotic disorders in offspring. However, the relative contribution of such immune-related prenatal insults to specific neuropathological outcomes in schizophrenia remains essentially unknown. The study by Ellman et al. is the first to explore whether prenatal levels of the proinflammatory cytokine, IL-8, are associated with the volume of specific brain regions in patients diagnosed with schizophrenia spectrum disorder. The authors provide new data to support a significant association between higher prenatal IL-8 levels in the second/third trimester of pregnancy and greater ventricular cerebrospinal fluid volume in adult schizophrenia spectrum cases. In addition, the results provide evidence for a significant relationship between higher prenatal IL-8 levels and lower volumes in the left entorhinal cortex and right posterior cingulate. The findings provided by Ellman et al., together with the results obtained in other epidemiological studies and experimental animal research, should encourage basic researchers and clinicians alike to make efforts towards the investigation of maternal immunomodulatory interventions that may help alleviate abnormal brain development and long-term psychotic illness in offspring.     

Repeated ventral tegmental area amphetamine administration alters dopamine D1 receptor signaling in the nucleus accumbens

Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locomotor sensitization following the repeated intermittent systemic administration of amphetamine (AMPH). In the nucleus accumbens (NAc), such neuroadaptations include enhanced DA overflow in response to a subsequent AMPH challenge as well as increased sensitivity to the inhibitory effects of D1 DA receptor (D1R) activation and an altered profile of D1R-dependent induction of immediate early genes (IEGs). Previous results indicate that AMPH acts in the ventral tegmental area (VTA) to initiate those changes leading to sensitization of the locomotor activity and NAc DA overflow produced by systemic administration of this drug. These observations are intriguing, given that acute infusion of AMPH into the VTA does not stimulate locomotor activity or, as we report presently, increase extracellular NAc DA concentrations. Two experiments, therefore, assessed the ability of repeated VTA AMPH to produce adaptations in D1R signaling in the NAc. Rats were administered three bilateral VTA infusions of saline or AMPH (2.5 microg/0.5 microl/side, one every third day). In the first experiment, in vivo extracellular electrophysiological recordings revealed that previous exposure to VTA AMPH enhanced the sensitivity of NAc neurons to the inhibitory effects of iontophoretic application of the D1R agonist SKF 38393. This effect was observed early (2-3 days) and at 1 month of withdrawal, but not after 2 months. Similarly, in the second experiment it was found that the D1R-dependent induction by AMPH of Fos, FosB, and JunB, but not NGFI-A, in the NAc was enhanced in rats exposed 1 week earlier to repeated VTA AMPH. These findings indicate that repeated VTA AMPH administration initiates relatively long-lasting adaptations in D1R signaling in the NAc that may, together with presynaptic adaptations affecting DA overflow, contribute to the expression of locomotor sensitization by this drug.     

Amphetamine, cocaine, and fencamfamine: relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics.

Using in vivo microdialysis, the caudate and nucleus accumbens dopamine (DA) responses to the psychomotor stimulants amphetamine (AMPH), cocaine (COC), and fencamfamine (FCF) were evaluated in rats concurrent with characterization of their behavioral response profiles. Doses of each stimulant that produced either enhanced locomotion or a prolonged period of intense focused stereotypies were examined to evaluate the quantitative relationships between stimulant-induced behaviors and changes in DA dynamics and to test the hypothesis that a balance between mesostriatal and mesolimbic DA activity contributes to the appearance of specific stimulant-induced behaviors. Although 10 mg/kg COC and 1.7 mg/kg FCF promoted levels of locomotor activity substantially greater than 0.5 mg/kg AMPH, the magnitude of the DA increases in both caudate and accumbens were markedly less than was obtained following AMPH. Thus, stimulant-induced locomotion appears to be dissociated from the quantitative DA response in both brain regions. This behavioral/DA dissociation was also apparent at higher doses of AMPH (2.5 mg/kg), COC (40 mg/kg), and FCF (6 mg/kg), doses that promoted a behavioral pattern that included a prolonged period of intense stereotypy. Indeed, the regional DA responses to these high doses of COC and FCF were substantially less than the response to 0.5 mg/kg AMPH. Furthermore, there were no differences in the ratio of the caudate and accumbens DA responses as a function of dose for any of the three drugs. Thus, the balance between the regional DA activation does not appear to regulate the expression of the behavioral response. Additionally, the effects of these stimulants on regional DA metabolite concentrations were compared. The results indicate that AMPH promoted an identical pattern of effects on caudate and accumbens DA metabolites, suggesting that similar mechanisms govern the dynamics of DA in response to AMPH in both brain regions. In contrast, the DA uptake blockers promoted some region-specific effects on DA metabolites that may be due to regional differences in the DA metabolism and rates of impulse flow.     

Associations Between Maternal Prenatal C-Reactive Protein and Risk Factors for Psychosis in Adolescent Offspring: Findings From the Northern Finland Birth Cohort 1986

Prenatal infection is associated with brain structural and functional abnormalities and may increase the risk for psychosis through a direct effect on neurodevelopment. Various infections may exert their effect through a proinflammatory immune response but studies of prenatal maternal inflammatory markers and offspring neurodevelopment are scarce. Using the longitudinal Northern Finland Birth Cohort 1986 study, we examined the associations of maternal prenatal C-reactive protein (CRP) levels with psychosis risk factors in adolescent offspring. CRP was measured in maternal sera collected in pregnancy. In offspring, school performance was measured at age 7 years, while school performance, psychotic experiences, and cannabis use were measured at age 16 years. We tested associations of CRP with offspring measures using regression analysis controlling for offspring sex, maternal education level, and prenatal maternal body mass index, smoking and alcohol use in pregnancy, place of birth, maternal psychiatric admission, paternal psychiatric admission, mothers age at birth, and gestational week of CRP sample. We also tested if adolescent cannabis use mediated the associations between maternal CRP and offspring outcomes. Controlling for covariates, maternal CRP was associated with academic performance at age 16 years (beta = .062, 95% CI = 0.036–0.088), but not with possible psychotic experiences at 16 years (odds ratio [OR] = 1.09, 95% CI = 0.96–1.24). Maternal CRP was also associated with adolescent cannabis use (OR = 1.24, 95% CI = 1.07–1.43). These findings suggest that prenatal inflammation may influence later mental illness risk by affecting neurodevelopment and also indirectly by increasing the risk of exposure to cannabis.     

Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB? receptors

The potential involvement of the cannabinoid CB? receptors (CB?r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB?r (CB?xP) and in wild-type (WT) littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. In addition, we assessed whether CB?r were localized in neurons and/or astrocytes, and whether they colocalized with dopamine D1 and D2 receptors (D1Dr and D2Dr). Dopamine (DA) extracellular levels in the nucleus accumbens (NAcc), and gene expression of tyrosine hydroxylase (TH) and DA transporter (DAT) in the ventral tegmental area (VTA), and μ-opioid and cannabinoid CB? receptors in the NAcc were also studied in both genotypes. CB?xP mice showed decreased motor response to acute administration of cocaine (10-20?mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB?xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB?r were found in neurons and astrocytes and colocalized with D2Dr in the VTA and NAcc. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. Under baseline conditions, TH and DAT gene expression was higher and μ-opioid receptor gene expression was lower in CB?xP than in WT mice. However, both genotypes showed similar changes in TH and μ-opioid receptor gene expression after cocaine challenge independently of the pretreatment received. Importantly, the cocaine challenge decreased DAT gene expression to a lesser extent in cocaine-pretreated CB?xP than in cocaine-pretreated WT mice. These results revealed that CB?r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction.     

Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult DBA/2J mice: relationship with ventral striatum dopamine concentrations

The principal polyunsaturated fatty acid acids found in brain, arachidonic acid (AA) and docosahexaenoic acid (DHA), preferentially accumulate in synaptic membranes. Although neurochemical studies have found that dietary-induced deficits in rat brain DHA composition significantly alter mesocorticolimbic dopamine (DA) neurotransmission, its impact on DA-mediated behavior remains poorly understood. In the present study, we determined the effects of dietary-induced deficits in brain DHA composition on amphetamine (AMPH)-induced locomotor activity and sensitization in DBA/2J mice, an inbred strain previously found to be hyporesponsive to AMPH, as well as monoamine concentrations in the PFC and ventral striatum following the AMPH challenge. Chronic dietary omega-3 fatty acid deficiency significantly decreased PFC (-25%) and ventral striatum (-20%) DHA composition, increased PFC (+7%) and ventral striatum (+6%) AA composition, and increased the AA:DHA ratio in PFC (+30%) and ventral striatum (+24%). The development and expression of AMPH-induced sensitization was significantly increased in DHA-deficient mice, whereas novelty- and acute AMPH-induced locomotor activity were not altered. DHA-deficient mice exhibited significantly greater ventral striatum, but not PFC, DA and DA metabolite concentrations following the AMPH challenge, whereas serotonin and noradrenalin concentrations were not altered. Ventral striatum AA composition and the AA:DHA ratio were both positively correlated with DA concentrations, and both ventral striatum AA composition and DA concentrations were positively correlated with locomotor activity during the preceding AMPH challenge. These results demonstrate that dietary-induced brain DHA deficiency, and associated elevation in the AA:DHA ratio, augment AMPH-induced sensitization in DBA/2J mice, and that this augmented response is associated with selective alterations in the mesolimbic DA pathway.     

Neonatal ventral hippocampal lesions attenuate the nucleus accumbens dopamine response to stress: an electrochemical study in the adult rat

Neonatal damage to the ventral hippocampus (VH) can lead, during adulthood, to behaviours that are believed to reflect enhanced mesocorticolimbic dopamine (DA) transmission. In the present study, the effects of neonatal excitotoxic lesions to the VH on spontaneous locomotor activity and stress-elicited increases in extracellular nucleus accumbens (NAcc) DA levels were examined in adult rats. Male pups received, on postnatal day 7, bilateral injections of either an ibotenic acid solution (lesioned) or vehicle (sham-lesioned) into the VH. At 3-4 months of age, animals were assessed during five daily sessions for changes in spontaneous locomotor activity associated with habituation to a novel environment. Voltammetry was used in separate groups of sham- and VH-lesioned animals to monitor the NAcc DA response to each of five once-daily exposures to tail-pinch stress. The results indicate that while VH-lesioned animals seem to habituate to novelty, they remain hyperactive relative to sham-lesioned controls. In contrast, however, stress consistently elicited in VH-lesioned animals smaller and shorter-lasting increases in NAcc DA than in sham-lesioned controls. These data suggest that neonatal excitotoxic damage to VH leads to changes in DA function that persist into adulthood. The blunted response to stress seen in VH-lesioned animals indicates that one consequence of such damage is a functional hyporeactivity in meso-NAcc DA neurons. The fact that these animals are spontaneously more active suggests compensatory changes in DA function that are efferent to DA terminals in NAcc.     

Susceptibility to sensitization. I. Sex differences in the enduring effects of chronic D-amphetamine treatment on locomotion, stereotyped behavior and brain monoamines

There are sex differences in a number of behavior elicited by amphetamine (AMPH). The purpose of the present experiment was to determine if there are also sex differences in the sensitization of the locomotor activity and stereotypy produced by repeated intermittent AMPH treatment, and whether this is accompanied by sex differences in dopamine (DA) metabolism. It was found that female rats showed greater and more rapid sensitization of locomotor activity and stereotyped behavior than males. In addition, prior exposure to AMPH was associated with an elevation in resting striatal dihydroxyphenlacetic acid (DOPAC) to DA ratios in female, but not male rats, suggesting a sex difference in one neurochemical correlate of sensitization. As a group, males were more variable and heterogeneous in their response to repeated AMPH treatment, because they were divisible into two neurochemically distinct subgroups on the basis of their change in behavior and females were not. This heterogeneity may make it more difficult to identify neurochemical correlates of sensitization in males. It is suggested that there is a sex difference in the responsiveness of brain DA systems to repetitive activation, and this contributes to individual variation in the susceptibility to sensitization.