Katherine A. Boss-Williams

Testing the hypothesis that locus coeruleus hyperactivity produces depression-related changes via galanin

This paper reviews progress made in testing the idea that depression-related behavioral changes can arise from hyperactivity of locus coeruleus (LC) neurons which consequently inhibits activity of mesocorticolimbic dopamine neurons in the ventral tegmentum (VTA) via release of galanin from terminals on LC axons in VTA. Results from pre-clinical testing are described, including the most recent findings indicating that, in an animal model that shows long-lasting symptoms of depression, recovery to normal activity in the home cage is accelerated by infusion of a galanin receptor antagonist, galantide (M15), into VTA. Data are also described suggesting that all effective antidepressant treatments decrease activity of LC neurons.

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.

Motor activation by amphetamine infusion into nucleus accumbens core and shell subregions of rats differentially sensitive to dopaminergic drugs

Selective breeding based on activity in a swim test has been used to produce lines of rats that show a high level of activity in the swim test (Swim High-active (SwHi) rats) and a low level of activity in the swim test (Swim Low-active (SwLo) rats). Previous studies have indicated that dopamine (DA) function is enhanced in SwHi rats and reduced in SwLo rats; a principal finding was that SwLo rats showed much smaller increases in ambulatory activity after systemic administration of amphetamine than did SwHi or non-selected rats. In light of the importance of the nucleus accumbens (NAC) in amphetamine-induced activity, the present study investigated whether DA function in NAC differs in SwHi and SwLo rats. Amphetamine was infused bilaterally into either the core or shell subregion of NAC, and ambulation or swim test activity was then measured. In SwLo rats, infusion of amphetamine (0.2-2.0 microg) into either NAC core or shell produced moderate increases in ambulation. In SwHi rats, infusion of amphetamine into NAC shell produced similar moderate increases in ambulation, but infusion into the core produced markedly larger dose-related increases in ambulation. In the swim test, infusion of amphetamine (1.0 microg) increased activity by affecting the dominant behavior of each line; i.e. struggling increased in SwHi rats and floating decreased in SwLo rats, with large effects seen in both lines with infusion into either NAC core or shell. These results support the idea that the distinct behavioral characteristics of SwHi and SwLo rats are mediated in part by differences in NAC-DA function.

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.

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.

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.

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.

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.

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.