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.

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.

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.

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.

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.

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.

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.

Intake of ethanol and reinforcing fluids in rats bred for susceptibility to stress.

Rats have been selectively bred in our laboratory based on how swim-test behavior is affected by stress. Following exposure to an acute stressor, active swim-test behavior is reduced in the swim-test susceptible (SUS) line but is not reduced in the swim-test resistant (RES) line. Earlier findings indicate that SUS rats have reduced central serotonin and dopamine levels relative to normal, random-bred (i.e., nonselected [NS]) rats and RES rats, suggesting that SUS rats might respond differently to reinforcing substances, particularly ethanol. We report here comparison of SUS, NS, and RES rats regarding consumption of ethanol. Also examined was consumption of saccharin, sucrose, and quinine. Testing involved a two-bottle, free-choice method of measuring intake of substances in a home cage. Intake of each substance was tested across a range of concentrations. The results indicate that the SUS rats, tested across 14 generations, consume markedly more ethanol than the other two lines; in fact, SUS rats consume amounts similar to that ingested by lines/strains of rats bred specifically for ethanol intake. Similar to other alcohol-preferring rats, SUS rats show an increased affinity for saccharin solutions and a marked increase in their total daily fluid intake when a sweet-tasting saccharin or sucrose solution is available. These results indicate that a propensity to drink alcohol occurs in a line of rats that were selectively bred, not for alcohol intake, but for vulnerability to stress.

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.

Neural substrates of coping behavior in the rat: possible importance of mesocorticolimbic dopamine system.

This study measured expression of Fos protein, an indicator of neural activation, in 116 brain regions of rats that were able to control a stressor (i.e., avoid and/or escape an electric shock), and compared the changes with those observed in yoked rats that received the same shocks but without having control over them. The authors' interest was to find brain regions where elevated activity occurs in conjunction with control. Activity in these brain regions might be responsible for the consequences of having control, such as reduction of stress responses. Eleven brain regions were found in which rats with control showed significantly more Fos expression than was seen in yoked rats that did not have control. Six of these brain regions were part of the mesocorticolimbic dopamine system. These results point to the mesocorticolimbic dopamine system as being importantly involved in the mediation and/or the consequences of coping behavior.

Effects of dopamine beta-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice.

RATIONALE: Dopamine beta-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE), thus playing a critical role in catecholamine metabolism. OBJECTIVES/METHODS: We examined the effects of Dbh gene dosage and the DBH inhibitor disulfiram in mice with zero, one, or two null Dbh alleles (+/+, +/-, and-/- mice). RESULTS: DBH protein levels in adrenal and prefrontal cortex (PFC) and adrenal DBH activity were proportional to number of wild-type alleles. Adrenal DA was slightly increased in+/- mice and markedly increased (80-fold) in -/- mice compared to wild-type animals. While adrenal NE and epinephrine (EPI) were undetectable in -/- mice, adrenal concentrations of NE and EPI were similar in +/+ and +/- mice, suggesting that the increase in DA maintains the normal rate of beta-hydroxylation in Dbh +/- mice. Disulfiram had little effect on adrenal catecholamine levels, regardless of genotype or dose. NE was absent in the PFC of -/- mice, but only slightly reduced in +/- animals compared to wild-type animals. PFC DA was increased twofold in +/- mice and fivefold in -/- mice, and the NE to DA ratio was reduced ( approximately 35%) in +/- mice, compared to wild-type mice. Disulfiram significantly decreased PFC NE and increased DA in +/+ and +/- animals, with the disulfiram and genotype effects on the PFC NE to DA ratio apparently additive. CONCLUSIONS: The data reveal potentially important and apparently additive effects of Dbh genotype and disulfiram administration on PFC catecholamine metabolism. These effects may have implications for genetic control of DBH activity in humans and for understanding therapeutic effects of disulfiram.

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.

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.

The effects of endogenous interleukin-1 bioactivity on locus coeruleus neurons in response to bacterial and viral substances.

In a previous study, we found that microinjection of the cytokine interleukin-1 (IL-1) into the locus coeruleus (LC) increased the electrophysiological activity of LC neurons. To determine if endogenous IL-1 similarly affects the LC, brain IL-1 was induced with lipopolysaccharide (LPS), a substance derived from Gram-negative bacteria. LPS microinjected directly into the LC increased the activity of LC neurons in anesthetized rats, and this effect was blocked by microinfusion of the IL-1 receptor antagonist (IL-1RA) protein into the LC indicating the involvement of IL-1 receptors. Similarly, intraperitoneal (i.p.) LPS injection increased the activity of LC neurons in a dose- and time-related manner that was sensitive to IL-1RA. The change in the activity of LC neurons caused by a single i.p. injection of LPS was surprisingly long-lasting, and evolved over a period of at least 3 weeks. Other microbial substances-namely, peptidoglycan from Gram-positive bacteria and poly-inosine/poly-cytosine (poly(I)/(C)), which resembles RNA viruses-were used to determine the generality of the findings with LPS. Both i.p. peptidoglycan and poly(I)/(C) increased LC activity but with lesser efficacy than LPS. IL-1RA reversed the increase in the activity of LC neurons caused by i.p. peptidoglycan treatment; however, that caused by i.p. Poly(I)/(C) was not diminished by IL-1RA. Thus, the increased activity of LC neurons caused by LPS and peptidoglycan requires IL-1 receptor binding, suggesting the involvement of endogenously-produced IL-1. In contrast, poly(I)/(C) increased the activity of LC neurons but this did not critically involve IL-1 receptors in the LC.

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.

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.

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.