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Initial antidepressant treatment can paradoxically worsen symptoms in depressed adolescents by undetermined mechanisms. Interestingly, antidepressants modulate GABAA receptors, which mediate paradoxical effects of other therapeutic drugs, particularly in females. Although the neuroanatomic site of action for this paradox is unknown, elevated GABAA receptor signaling in the nucleus accumbens can disrupt motivation. We assessed fluoxetine's effects on motivated behaviors in pubescent female hamsters — anhedonia in the reward investigational preference (RIP) test as well as anxiety in the anxiety-related feeding/exploration conflict (AFEC) test. We also assessed accumbal signaling by RT-PCR and electrophysiology. Fluoxetine initially worsened motivated behaviors at puberty, relative to adulthood. It also failed to improve these behaviors as pubescent hamsters transitioned into adulthood. Low accumbal mRNA levels of multiple GABAA receptor subunits and GABA-synthesizing enzyme, GAD67, assessed by RT-PCR, suggested low GABAergic tone at puberty. Nonetheless, rapid fluoxetine-induced reductions of α5GABAA receptor and BDNF mRNA levels at puberty were consistent with age-related differences in GABAergic responses to fluoxetine and disruption of the motivational state. Whole-cell patch clamping of accumbal slices also suggested low GABAergic tone by the low amplitude of miniature inhibitory postsynaptic currents (mIPSCs) at puberty. It also confirmed age-related differences in GABAergic responses to fluoxetine. Specifically, fluoxetine potentiated mIPSC amplitude and frequency at puberty, but attenuated the amplitude during adulthood. These results implicate GABAergic tone and GABAA receptor plasticity in adverse motivational responses and resistance to fluoxetine during adolescence. [ABSTRACT FROM AUTHOR]

Women are more likely than men to exhibit motivational disorders (e.g., anhedonia and anxiety) with limited treatment options, and to overconsume high-fat “comfort foods” to improve motivational disruptions. Unfortunately, neurobiological underpinnings for sex differences in motivational disruptions and their responses to dietary fat are poorly understood. To help bridge these fundamental knowledge gaps, we assessed behavioral and neurobiological responses to dietary fat in a hamster model of female-biased motivational lability. Relative to social housing, social separation reduced hedonic drive in a new behavioral assay, the reward investigational preference (RIP) test. Fluoxetine or desipramine treatment for 21, but not 7, days improved RIP test performance. Pharmacologic specificity in this test was shown by non-responsiveness to diazepam, tracazolate, propranolol, or naltrexone. In the anxiety-related feeding/exploration conflict (AFEC) test, social separation worsened latency to eat highly palatable food under anxiogenic conditions, but not in home cages. Social separation also reduced weight gain, food intake, and adiposity while elevating energy expenditure, assessed by caloric efficiency and indirect calorimetry. Furthermore, chronic high-fat feeding improved anhedonic and anxious responses to separation, particularly in females. In the motivation-influencing nucleus accumbens, females, but not males, exhibited a separation-induced anxiety-related decrease in Creb1 mRNA levels and an anhedonia-related decrease in ΔFosb mRNA levels. Consistent with its antidepressant- and anxiolytic-like effects on behavior, high-fat feeding elevated accumbal Creb1 and ΔFosb mRNA levels in females only. Another accumbal reward marker, Tlr4 mRNA, was elevated in females by high-fat feeding. These results show that social separation of hamsters provides a novel model of sex-dependent comorbid anhedonia, anxiety, and anorexia, and implicate accumbal CREB, ΔFosB, and TLR4. Moreover, the results validate a new assay for chronic antidepressant efficacy. [ABSTRACT FROM AUTHOR]