Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease.

Hyperphosphorylated tau in the locus coeruleus (LC) is ubiquitous in prodromal Alzheimer's disease (AD), and LC neurons degenerate as AD progresses. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons are unknown. We assessed single unit LC activity in anesthetized wild-type (WT) and TgF344-AD rats at 6 months, which represents a prodromal stage when LC neurons are the only cells containing hyperphosphorylated tau in TgF344-AD animals, and at 15 months when amyloid-ß (Aß) and tau pathology are both abundant in the forebrain. At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates but showed elevated spontaneous bursting properties. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and 15-month transgenic rats showing hypoactivity. Early LC hyperactivity is consistent with appearance of prodromal neuropsychiatric symptoms and is followed by LC hypoactivity which contributes to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.

A role for B cells in facilitating defense against an NK cell-sensitive lung metastatic tumor is revealed by stress.

Stressors impair immune defenses and pose risks among cancer patients. Natural Killer cells are not the sole immune defense against tumor development. Utilizing an NK-sensitive tumor model, this study evaluated immune effects to stress and determined whether lung metastasis resulted from B cells' inability to augment tumorlytic function. Lung metastasis directly correlated with delayed lung B cell accumulation compared to NK, and T cells. Decreased interleukin-12 cytokine and CD80+ molecule expression by B cells correlated with decreased tumor lysis and increased tumor development. Thus, tumor defenses in the lung given stress exposure can depend on the B cell function.

Reprint of: Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol.

Sprague-Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol.

Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol.

Sprague-Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol.

Antidepressant and anticonvulsant effects of exercise in a rat model of epilepsy and depression comorbidity.

The bidirectional comorbidity between epilepsy and depression is associated with severe challenges for treatment efficacy and safety, often resulting in poor prognosis and outcome for the patient. We showed previously that rats selectively bred for depression-like behaviors (SwLo rats) also have increased limbic seizure susceptibility compared with their depression-resistant counterparts (SwHi rats). In this study, we examined the therapeutic efficacy of voluntary exercise in our animal model of epilepsy and depression comorbidity. We found that chronic wheel running significantly increased both struggling duration in the forced swim test and latency to pilocarpine-induced limbic motor seizure in SwLo rats but not in SwHi rats. The antidepressant and anticonvulsant effects of exercise were associated with an increase in galanin mRNA specifically in the locus coeruleus of SwLo rats. These results demonstrate the beneficial effects of exercise in a rodent model of epilepsy and depression comorbidity and suggest a potential role for galanin.

Effects of chronic mild stress on rats selectively bred for behavior related to bipolar disorder and depression.

To test the possibility that chronic mild stress (CMS) might be unreliable in producing its often-intended outcome (i.e., decreased preference for sucrose, hypothesized to represent depression-relevant anhedonia) because it is typically applied to "normal" rats, a CMS procedure was applied to rats that may possess genetic susceptibility to affective disorders, having had been selectively-bred to show behavior indicative of such disorders. These rat lines were: Hyperactive (HYPER) rats, which show characteristics of bipolar disorder, Swim-test Susceptible (SUS) and Swim-test Resistant (RES) rats, being susceptible or resistant to effects of stress in the swim test, Swim High-active (SwHi) and Swim Low-active (SwLo) rats, which innately show high or low activity in the swim test. These selectively-bred lines were compared to normal, non-selectively bred (NS) rats. During CMS, HYPER rats, both females and males, as well as RES and SwHi rats, showed reduced consumption of a palatable 2% sucrose solution, and reduced preference for sucrose (vs. water) in comparison to non-stressed rats (no CMS) of the same lines. In contrast, CMS produced no decrease in sucrose consumption or in preference for sucrose in normal NS rats, and actually a caused a slight increase in sucrose consumption and preference in male NS rats. Other measures that indicate depression - food intake and motor activity in the home cage - were also assessed. SwLo and SwHi showed greater sensitivity to having their home-cage ambulatory activity reduced by CMS than did NS rats, but no other such differences relative to NS rats were seen for these other measures; thus, changes in sucrose intake or preference could not be explained by a change in caloric intake. These results suggest that the genetic attributes of animals can influence the outcome of CMS, and that the application of CMS to normal, non-selected rats may account, at least in part, for the unreliability of CMS in decreasing consumption of palatable substances and decreasing preference for such substances.

Sex and lineage interact to predict behavioral effects of chronic adolescent stress in rats.

Neuropsychiatric disorders often derive from environmental influences that occur at important stages of development and interact with genetics. This study examined the effects of stress during adolescence in rats selectively bred for different behavioral responses to stress. The effects of chronic adolescent stress were compared between rats selected for susceptibility to reduced activity following acute stress (Swim-test Susceptible rats) and rats resistant to activity reduction after acute stress (Swim-test Resistant rats). Consistent with lineage, exposure to chronic adolescent stress increased swim-test activity of the Swim-test Resistant rats while tending to reduce activity of the Swim-test Susceptible rats. Consistent with the increased activity demonstrated post-stress in the swim test, chronic adolescent stress increased total activity in the open field for Swim-test Resistant rats. Indicative of anhedonia, chronic adolescent stress exposure decreased sucrose consumption in both male and female Swim-test Resistant rats but only in female Swim-test Susceptible rats. Although chronic stress induced changes in behavior across both breeding lines, the precise manifestation of the behavioral change was dependent on both breeding line and sex. Collectively, these data indicate that selective breeding interacts with chronic stress exposure during adolescence to dictate behavioral outcomes.

Prenatal exposure to escitalopram and/or stress in rats: a prenatal stress model of maternal depression and its treatment.

RATIONALE: A rigorously investigated model of stress and antidepressant administration during pregnancy is needed to evaluate possible effects on the mother. OBJECTIVE: The objective of this study was to develop a model of clinically relevant prenatal exposure to an antidepressant and stress during pregnancy to evaluate the effects on maternal care behavior. RESULTS: Female rats implanted with 28-day osmotic minipumps delivering the SSRI escitalopram throughout pregnancy had serum escitalopram concentrations in a clinically observed range (17-65 ng/ml). A separate cohort of pregnant females exposed to a chronic unpredictable mild stress paradigm on gestational days 10-20 showed elevated baseline (305 ng/ml), and acute stress-induced (463 ng/ml), plasma corticosterone concentrations compared to unstressed controls (109 ng/ml). A final cohort of pregnant dams were exposed to saline (control), escitalopram, stress, or stress and escitalopram to determine the effects on maternal care. Maternal behavior was continuously monitored over the first 10 days after parturition. A reduction of 35 % in maternal contact and 11 % in nursing behavior was observed due to stress during the light cycle. Licking and grooming behavior was unaffected by stress or drug exposure in either the light or dark cycle. CONCLUSIONS: These data indicate that: (1) clinically relevant antidepressant treatment during human pregnancy can be modeled in rats using escitalopram; (2) chronic mild stress can be delivered in a manner that does not compromise fetal viability; and (3) neither of these prenatal treatments substantially altered maternal care post parturition.

Operant psychostimulant self-administration in a rat model of depression.

Depression and psychostimulant addiction are co-morbid conditions; depression is a significant risk factor for psychostimulant abuse, and the rate of depression in drug addicts is higher than in the general population. Despite the prevalence of this comorbidity, there are few animal models examining psychostimulant abuse behaviors in depression. We have shown previously that while rats selectively bred for depression-like phenotypes (SwLo) have blunted mesolimbic dopamine (DA) signaling and locomotor responses to dopaminergic drugs, they voluntarily administer excessive amounts of psychostimulants compared to normal or depression-resistant (SwHi) rats in oral consumption paradigms. To determine whether this increased drug intake by depression-sensitive rats extends to operant self-administration, we assessed fixed ratio-1, progressive ratio, extinction, and reinstatement responding for cocaine and amphetamine in SwLo and SwHi rats. Contrary to the oral consumption results, we found that the SwHi rats generally responded more for both cocaine and amphetamine than the SwLo rats in several instances, most notably in the progressive ratio and reinstatement tests. Food-primed reinstatement of food seeking was also elevated in SwHi rats. These results provide further insight into the neurobiology of depression and addiction comorbidity and caution that oral and operant psychostimulant self-administration paradigms can yield different, and this case, opposite results.

Seizure susceptibility and epileptogenesis in a rat model of epilepsy and depression co-morbidity.

Although a strong co-morbidity exists clinically between epilepsy and depression, the cause of this co-morbidity remains unknown, and a valid animal model is crucial for the identification of underlying mechanisms and the development of a screening tool for novel therapies. Although some rodent models of epilepsy have been reported to display behaviors relevant to affective disorders, the seizure susceptibility of animals prone to depression-like behavior has not been characterized. Toward this end, we assessed several forms of seizure sensitivity and epileptogenesis in rats selectively bred for vulnerability (Swim Lo-Active; SwLo) or resilience (Swim High-Active; SwHi) to depression-like phenotypes. The SwLo rats exhibit decreased motor activity in a swim test and other depression-like phenotypes, whereas the SwHi rats display increased motor activity in a swim test. SwLo rats exhibited a decreased latency to limbic motor seizures following acute pilocarpine administration in the absence of differences in pilocarpine pharmacokinetics, and also had a decreased threshold to tonic seizures induced by electroshock. Approximately half of the SwLo rats, but none of the SwHi rats, had spontaneous limbic motor seizures 5 weeks following pilocarpine-induced status epilepticus. While the number of stimulations required to achieve full amygdala and hippocampal electrical kindling were similar in the two rat lines, SwLo rats had a lower final hippocampal kindling threshold and more wet dog shakes during both amygdala and hippocampal kindling. Combined, these results indicate that SwLo rats are a model of epilepsy and depression co-morbidity that can be used for investigating underlying neurobiological and genetic mechanisms and screening novel therapeutics.

Influence of chronic administration of antidepressant drugs on mRNA for galanin, galanin receptors, and tyrosine hydroxylase in catecholaminergic and serotonergic cell-body regions in rat brain.

Activity of locus coeruleus (LC) neurons and release of the peptide galanin (GAL), which is colocalized with norepinephrine (NE) in LC neurons, has been implicated in depression and, conversely, in antidepressant action. The present study examined the influence of chronic administration (for 14days, via subcutaneously-implanted minipump) of antidepressant (AD) drugs representing three different classes (tricyclic [desipramine], selective serotonin reuptake inhibitor [SSRI] [paroxetine], and monoamine oxidase inhibitor [MAOI] [phenelzine]) on mRNA for GAL, GAL receptors (GalR1, GalR2, and GalR3), and tyrosine hydroxylase (TH), the rate-limiting enzyme for NE synthesis, in four brain regions--LC, A1/C1, dorsal raphe (DRN), and ventral tegmentum (VTA) of rats. Consistent with previous findings that chronic administration of AD drugs decreases activity of LC neurons, administration of AD drugs reduced mRNA for both GAL and TH in LC neurons. GAL and TH mRNA in LC neurons was highly correlated. AD drugs also reduced GAL and TH mRNA in A1/C1 and VTA but effects were smaller than in LC. The largest change in mRNA for GAL receptors produced by AD administration was to decrease mRNA for GalR2 receptors in the VTA region. Also, mRNA for GalR2 and GalR3 receptors was significantly (positively) correlated in all three predominantly catecholaminergic brain regions (LC, A1/C1, and VTA). Relative to these three brain regions, unique effects were seen in the DRN region, with the SSRI elevating GAL mRNA and with mRNA for GalR1 and GalR3 being highly correlated in this brain region. The findings show that chronic administration of AD drugs, which produces effective antidepressant action, results in changes in mRNA for GAL, GAL receptors, and TH in brain regions that likely participate in depression and antidepressant effects.

Effects of fenfluramine, 8-OH-DPAT, and tryptophan-enriched diet on the high-ethanol intake by rats bred for susceptibility to stress.

The swim-test susceptible (SUS) line of rats has been bred in our laboratory for the characteristic of reduced motor activity in the swim test following exposure to an acute stressor. Testing of multiple generations of SUS rats has also revealed that they consume large amounts of ethanol voluntarily. As reported for lines of rats that show a propensity for high-ethanol intake, the SUS rats show evidence of low serotonergic function. Because serotonergic function has often been shown to be involved in the regulation of alcohol consumption, here we examined the effects of manipulations of serotonin transmission on intake of ethanol by SUS rats. Fenfluramine, a serotonin-releasing drug, was injected at various doses (0.625, 1.25, 2.5, and 5.0mg/kg) twice per day and ethanol intake was measured using a two-bottle free-choice method. The 8-OH-DPAT, a 5­HT(1A) agonist, was injected at various doses (0.03125, 0.0625, 0.125, 0.25, 0.5, and 1.0mg/kg) before a 1-h session of exposure to ethanol (single-bottle test, water available the other 23h per day). A diet enriched with 3% tryptophan (TRP), the amino acid precursor for serotonin synthesis, was administered in a restricted feeding schedule (5h per day) with ethanol intake measured the last 4h. Fenfluramine decreased ethanol intake at all doses tested. The 8-OH-DPAT increased ethanol intake at lower doses, presumably acting at autoreceptors, which inhibit serotonergic neurons, and decreased intake at higher doses, presumably acting at postsynaptic 5-HT(1A) receptors. TRP-enriched diet also significantly decreased ethanol intake. Food and water intake were less or unaffected by these three manipulations. With all three manipulations, ethanol intake remained suppressed one or more days after the day of tests that decreased ethanol intake. These data suggest that SUS rats, like many other lines/strains of rodents that consume large amounts of alcohol, show an inverse relationship between serotonin transmission and voluntary intake of ethanol.

Genetic propensities to increase ethanol intake in response to stress: studies with selectively bred swim test susceptible (SUS), alcohol-preferring (P), and non-preferring (NP) lines of rats.

RATIONALE: Swim test susceptible (SUS) rats selectively bred for reduced struggling in the forced swim test (FST) following stress show high voluntary ethanol intake like alcohol-preferring (P) rats selectively bred for ethanol preference. It is unknown whether stress enhances drinking in SUS rats or FST behavior in P and non-preferring (NP) rats. OBJECTIVES: The aim of this study was to assess the response to stress in male SUS, Sprague-Dawley (SD), P, and NP rats on 10% ethanol drinking and FST behavior. METHODS: In experiment 1, SUS and SD rats had limited access to ethanol and water following white noise, rehousing, and forced swim stress. In experiment 2, P and NP rats received footshock, white noise, restraint, or no stress prior to the FST. Rats then had continuous access to ethanol and water, and the effects of weekly exposures to stress were measured. RESULTS: SUS rats drank more ethanol (M = 2.98 g/kg) than SD rats (M = 1.26 g/kg) at baseline. Stress produced sustained increases (~33% of baseline) in ethanol intake in SUS rats. NP rats spent twice as much time immobile as P rats in the FST. Stress did not alter FST behavior in P or NP rats. Only footshock produced an increase (~29%) in ethanol intake in P rats. CONCLUSIONS: Selection for stress-induced depressive-like behavior in SUS rats is associated with enhanced stress-induced ethanol drinking. However, the selection for alcohol preference is not associated with stress-induced depressive-like behavior but is associated with footshock stress-induced ethanol drinking. In these experiments, relationships among stress, depressive-like behavior, and alcohol preference were not symmetrical.

Several stressors fail to reduce adult hippocampal neurogenesis.

Neurogenesis in the dentate gyrus of the hippocampus of adult laboratory animals has been widely reported to be vulnerable to many psychological and physical stressors. However, we have found no effects of acute restraint stress, acute or subchronic tailshock stress, or acute, subchronic, or chronic resident-intruder stress on neural progenitor cell (NPC) proliferation, short or long term survival of newborn cells, or brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats. In addition, we did not observe any effect of chronic resident-intruder stress on NPC proliferation in adolescent rats. A selectively bred stress-sensitive line was also found to exhibit no alterations in NPC proliferation following tailshock stress, although this line did exhibit a lower proliferation rate under baseline (unstressed) conditions when compared with non-selected rats. These results challenge the prevailing hypothesis that any stressor of sufficient intensity and duration has a marked negative impact upon the rate of hippocampal neurogenesis, and suggest that some yet unidentified factors related to stress and experimental conditions are crucial in the regulation of neurogenesis.

Effects of chronic antidepressant drug administration and electroconvulsive shock on activity of dopaminergic neurons in the ventral tegmentum.

Increasing attention is now focused on reduced dopaminergic neurotransmission in the forebrain as participating in depression. The present paper assessed whether effective antidepressant (AD) treatments might counteract, or compensate for, such a change by altering the neuronal activity of dopaminergic neurons in the ventral tegmental area (VTA-DA neurons), the cell bodies of the mesocorticolimbic dopaminergic system. Eight AD drugs or vehicle were administered to rats for 14 d via subcutaneously implanted minipumps, at which time single-unit electrophysiological activity of VTA-DA neurons was recorded under anaesthesia. Further, animals received a series of five electroconvulsive shocks (ECS) or control procedures, after which VTA-DA activity was measured either 3 d or 5 d after the last ECS. Results showed that the chronic administration of all AD drugs tested except for the monoamine oxidase inhibitor increased the spontaneous firing rate of VTA-DA neurons, while effects on 'burst' firing activity were found to be considerably less notable or consistent. ECS increased both spontaneous firing rate and burst firing of VTA-DA neurons. It is suggested that the effects observed are consistent with reports of increased dopamine release in regions to which VTA neurons project after effective AD treatment. However, it is further suggested that changes in VTA-DA neuronal activity in response to AD treatment should be most appropriately assessed under conditions associated with depression, such as stressful conditions.

Antidepressant drugs with differing pharmacological actions decrease activity of locus coeruleus neurons.

Previous studies suggest that all effective antidepressant (AD) drugs decrease activity of locus coeruleus (LC) neurons. However, little data exist regarding blood levels of drug in these studies, and what data do exist suggest blood levels might have been very high. To assess whether decreased LC activity is produced by drugs that selectively block reuptake for either norepinephrine or serotonin at therapeutically relevant blood levels, effects of chronic administration of desipramine, paroxetine, and escitalopram on LC activity were measured across a range of doses and blood levels of drug. Further, effects of a range of doses of mirtazapine were examined; in that mirtazapine blocks alpha2 adrenergic receptors, it might be anticipated to increase rather than decrease LC activity. Finally, to begin to assess whether the response of LC to ADs was specific to these drugs, effects of four non-AD drugs (single dose) were measured. Drugs were administered via osmotic minipump for 14 d. Electrophysiological recording of LC activity (assessment of both spontaneous firing rate and sensory-evoked 'burst' firing) then took place under isoflurane anaesthesia on the last day of drug treatment. The blood level of drugs present at the end of the recording session was also measured. All AD drugs tested decreased LC spontaneous and sensory-evoked 'burst' firing, and this was observed across a wide range of blood levels for the drugs. Non-AD drugs did not decrease LC activity. The findings of this investigation continue to support the possibility that all effective AD drugs decrease LC activity.

Behavioral effects of the CRF1 receptor antagonist R121919 in rats selectively bred for high and low activity in the swim test.

This study assessed effects of a CRF(1) receptor antagonist, R121919, on the behavior of rats that have been selectively bred to exhibit very high or very low activity in a swim test. Following treatment with R121919 (10 mg/kg, s.c.) or vehicle, several types of behavior were examined including: (1) spontaneous ambulatory activity in a novel environment, (2) swim-test activity, (3), and responses in an elevated plus maze. The most pronounced effects were observed in the swim test. Although R121919 had little effect on the swim-test behavior of normal, non-selected rats, Swim High-active rats (SwHi), characterized by being very active and exhibiting pronounced struggling behavior in the swim test, showed increased activity (more struggling) after R121919; in contrast, Swim Low-active (SwLo) rats, characterized by being very inactive and exhibiting pronounced floating behavior in the swim test, showed decreased activity (more floating) after R121919. This effect was observed in both male and female rats. No differences between strains or the effects of R121919 were observed for spontaneous ambulation or in the elevated plus maze test.

Lung and splenic B cells facilitate diverse effects on in vitro measures of antitumor immune responses.

In vitro measures of immune responsiveness toward tumors provide relevant information regarding the prevention and metastatic potential of cancer. In addition, the compartmentalization of immune responses is likely to be an important factor in dictating host antitumor immune responses. We have previously demonstrated that injection of antibody against B cells diminished pulmonary antitumor defenses. In the current study, we determined the effect of B cells on antitumor cellular responses against a lung metastatic tumor, MADB106. Lung B cells displayed sustained surface expression of CD80 and CD86, as compared to spleen B cells, in the presence of MADB106 tumor. Removal of B cells from lung lymphocyte cultures resulted in diminished IFN-gamma secretion and tumor lysis, whereas removal of B cells from spleen lymphocytes exposed to tumor resulted in elevated IFN-gamma and increased tumor lysis. Furthermore, a correlative increase in CD80 and CD86 co-stimulatory molecule expression by lung B cells was observed in mice subjected to MADB106 tumor. These findings provide additional evidence of the importance of pulmonary B cell responses in tumor defenses.

Rats bred for susceptibility to depression-like phenotypes have higher kainic acid-induced seizure mortality than their depression-resistant counterparts.

Epidemiological evidence suggests that epilepsy and depression are comorbid diseases. In fact, depression is the most common neuropsychiatric disorder associated with epilepsy, particularly temporal lobe epilepsy, and individuals with a history of depression are at a higher risk for developing epilepsy than the general population. Despite the epidemiological evidence for this link, there has been little experimental evidence to support the connection or elucidate possible underlying mechanisms. In an effort to address this problem and develop an animal model of epilepsy and depression comorbidity, we assessed seizure susceptibility and severity parameters in rats selectively bred for either susceptibility (the SwLo, SUS, and HYPER lines) or resistance (the SwHi, RES, and MON RES lines) to depression-like phenotypes. We found that rats bred for susceptibility to depression-like phenotypes experienced higher mortality following kainic acid-induced seizures than their resistant counterparts. In contrast, most line differences were not recapitulated when flurothyl was used to elicit seizures. Stress reduced kainic acid-induced mortality rates in all lines except the HYPER rats, supporting previously established indications that the stress response of HYPER rats is abnormal. These combined results support a neurobiological link between epilepsy and depression, advancing us towards an animal model of their comorbidity.