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Prog Neuropsychopharmacol Biol Psychiatry. 2016 Aug 1;69:19-30. doi: 10.1016/j.pnpbp.2016.04.001. Epub 2016 Apr 8.

Fluoxetine disrupts motivation and GABAergic signaling in adolescent female hamsters.

Author information

1
Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843, United States.
2
Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843, United States; Department of Neuroscience & Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX 77807, United States.
3
Department of Neuroscience & Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX 77807, United States.
4
Department of Nutrition & Food Science, Texas A&M University, College Station, TX 77843, United States.
5
Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843, United States; Department of Psychology, Texas A&M University, College Station, TX 77843, United States.
6
Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843, United States; Department of Nutrition & Food Science, Texas A&M University, College Station, TX 77843, United States. Electronic address: camorgan@akhutherapeutics.com.

Abstract

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.

KEYWORDS:

Accumbens; Anhedonia; Anxiety; GABAA receptor; Maturation

PMID:
27068049
DOI:
10.1016/j.pnpbp.2016.04.001
[Indexed for MEDLINE]

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