The reward system and maternal behavior in an animal model of depression: a microdialysis study.

RATIONALE AND OBJECTIVES: Flinders sensitive line (FSL) rats, an animal model of depression, display a different pattern of maternal behavior compared to Sprague-Dawley (SD) controls. In this study, we examined the rewarding value of mother-infant interaction for FSL dams. MATERIALS AND METHODS: In the main study, we measured monoamine levels in the nucleus accumbens (NAc) of early postpartum FSL and SD dams during an interaction with pups, using the microdialysis technique. In addition, we compared the preference patterns of FSL and SD rats using the conditioned place preference paradigm, with pups as the unconditioned stimuli. RESULTS: Dopamine (DA) levels in dialysates from the NAc of SD dams but not FSL dams were elevated while interacting with pups but the metabolism of DA to dihydroxyphenylacetic acid was greater in FSL than in SD dams. While SD dams showed a conditioned preference for a region that was associated with SD pups, FSL dams did not show a preference for regions associated either with SD or FSL pups, but water deprived FSL rats demonstrated a preference to a region associated with water, eliminating an alternative explanation of learning deficit in FSL rats. CONCLUSIONS: Taken together, these results suggest that FSL dams are less rewarded by pups, compared to control dams.

DHEA, a neurosteroid, decreases cocaine self-administration and reinstatement of cocaine-seeking behavior in rats.

Dehydroepiandrosterone (DHEA), which can act as a potential antidepressant in both animals and humans, appears to lower distress involved with cocaine withdrawal. In fact, a role for neurosteroids in modulation of substance-seeking behavior is becoming increasingly clear. Therefore, we tested the effects of DHEA on the self-administration of cocaine (1 mg/kg/infusion) by rats. At maintenance, a relatively low dose of exogenous DHEA (2 mg/kg; i.p.) attenuated cocaine self-administration after several days of chronic treatment. More than 2 weeks (19 days) of daily DHEA injections were required to decrease the cocaine-seeking behavior of rats to less than 20% of their maintenance levels. DHEA does not seem to decrease cocaine self-administration by increasing the reinforcing properties of the drug, as indicated by a cocaine dose-response determination. After being subjected to extinction conditions in the presence of DHEA, rats demonstrated a minimal response to acute exposure to cocaine (10 mg/kg), which indicated a protective effect of DHEA on relapse to cocaine usage. Our results suggest a potential role for the neurosteroid DHEA in controlling cocaine-seeking behavior, by reducing both the desire for cocaine usage and the incidence of relapse.

Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response.

Dopaminergic mesolimbic and mesocortical systems are fundamental in hedonia and motivation. Therefore their regulation should be central in understanding depression treatment. This review highlights the dopaminergic activity in relation to depressive behavior and suggests two putative receptors as potential targets for research and development of future antidepressants. In this article we review data that describe the role of serotonin in regulating dopamine release, via 5HT2C and 5HT3 receptors. This action of serotonin appears to be linked to depressive-like behavior and to onset of behavioral effects of antidepressants in an animal model of depression. We suggest that drugs or strategies that decrease 5HT2C and increase 5HT3 receptor-mediated dopamine release in the limbic areas of the brain may provide a fast onset of therapeutic effect. Clinical and basic research data supporting this hypothesis are discussed.

Dehydroepiandrosterone (DHEA) attenuates cocaine-seeking behavior in the self-administration model in rats.

The aim of this study was to determine the possible involvement of the neurosteroid dehydroepiandrosterone (DHEA) in cocaine-seeking behavior in a self-administration model in rats. DHEA pretreatment (continued thereafter concomitantly with cocaine self-administration) attenuated cocaine-seeking behavior and elevated the levels of dopamine and serotonin in several brain regions relevant to cocaine addiction. Chronic cocaine self-administration induced elevation in brain DHEA, its sulfate ester, DHEAS, and pregnenolone. The increased brain DHEA following cocaine self-administration may serve as a compensatory protective mechanism geared to attenuate the craving for cocaine. Such anti-craving activity is further enhanced by DHEA treatment before and during cocaine self-administration.

The serotonin-dopamine interaction is critical for fast-onset action of antidepressant treatment: in vivo studies in an animal model of depression.

In the last decade, many new antidepressants have been developed that display a more rapid onset to clinical effects than classical antidepressants. However, the mechanism that enables some drugs to have a faster onset of action than others is poorly understood. The aim of the present study was to determine neural alterations that are specific to fast-acting antidepressant action using Flinders Sensitive Line (FSL) rats, an animal model of depression. Because of the central role of accumbal dopamine in the mediation of motivation and reward, our measurements were focused on dopaminergic neurotransmission in the nucleus accumbens (NAC). The authors found that 7-day treatment with nefazodone (a putative fast-onset antidepressant) but not with desipramine (a classical antidepressant) normalized immobility time in the swim test in FSL rats. Serotonin (5-HT)-induced dopamine release but not basal dopamine levels correlated with the improvement of depressive-like behavior. The authors conclude that the 5-HT-dopamine interaction is critical to the fast-onset action of antidepressant treatment.

Neutralization of endogenous digitalis-like compounds alters catecholamines metabolism in the brain and elicits anti-depressive behavior.

Depressive disorders are among the world's greatest public health problems. Na(+), K(+)-ATPase is the established receptor for the steroidal digitalis-like compounds (DLC). Alteration in brain Na(+), K(+)-ATPase and DLC have been detected in depressive disorders raising the hypothesis of their involvement in these pathology. The present study was designed to further elaborate this hypothesis by investigating the behavioral and biochemical consequences of neutralization in brain DLC activity attained by anti-ouabain antibodies administrations, in normal Sprague-Dawley (SD) and in the Flinders Sensitive Line (FSL) of genetically depressed rats. Chronic i.c.v. administration of anti-ouabain antibodies to FSL rats elicited anti-depressive behavior. Administration of anti-ouabain antibodies intracerebroventriculary (i.c.v.) to SD rats significantly changed the levels of catecholamines and their metabolites in the hippocampus, ventral tegmentum and nucleus accumbence. These results are in accordance with the notion that endogenous DLC may be involved in the manifestation of depressive disorders and suggests that alteration in their levels may be of significant therapeutic value.

Arachidonic acid-containing phosphatidylcholine species are increased in selected brain regions of a depressive animal model: implications for pathophysiology.

The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression. Following recent findings that the brain fatty acid composition of FSL is characterised by increased arachidonic acid (AA), we used electrospray tandem mass spectrometry and (1)H-NMR to examine lipid species in different brain areas. Cholesterol and sphingolipids were increased in the hypothalamus of the FSL rats. Furthermore, arachidonic acid-containing phosphatidylcholine (AA-PC) species were elevated with PC16:0/20:4, PC18:1/20:4 and PC18:0/20:4 (p<0.003) increased in the hypothalamus and striatum. In contrast, there was a decrease in some docosahexaenoic acid (DHA)-containing species, specifically PC18:1/22:6 (p<0.003) in the striatum and PE18:1/22:6 (p<0.004) in the prefrontal cortex. Since no significant differences were observed in the erythrocyte fatty acid concentrations, dietary or environmental causes for these observations are unlikely. The increase in AA-PC species which in this animal model may be associated with altered neuropathy target esterase activity, an enzyme involved in membrane PC homeostasis, may contribute to the depressive phenotype of the FSL rats.

DHEA lessens depressive-like behavior via GABA-ergic modulation of the mesolimbic system.

Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate gamma-aminobutyric-acid-type-A (GABA(A)R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (sigma 1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitive-line (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the delta-subunit of GABA(A), but not of sigma 1R mRNA, in FSL rats compared to SD rats. The delta-subunit controls the sensitivity of the GABA(A)R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA(A) agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA(A)), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA(A)Rs in the NAc and VTA.

Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression.

Depression may be associated with impaired membrane PUFA composition, especially decreased n-3 PUFA. This assumption has not been tested at the level of brain tissue. Moreover, most studies were confounded by dietary variability. We examined the FA composition of selected brain areas in an animal model of depression, the Flinders Sensitive Line (FSL) rat, and compared the findings with those in controls fed identical diets. In all brain regions studied, the concentration of arachidonic acid (AA) was significantly higher in the FSL rats: in the hypothalamus by 21%, in the nucleus accumbens by 24%, in the prefrontal cortex by 31%, and in the striatum by 23%. No significant differences were observed for n-3 PUFA or for the saturated and monounsaturated FAs. Our results confirm the existence of altered brain PUFA composition in an animal model of depression. The finding of increased AA, an n-6 PUFA, rather than decreased n-3 PUFA, emphasizes the importance of both PUFA families in the pathophysiological processes underlying depression. The FSL rat is a useful tool for further elucidation of the FA disturbances in depression.