Sex Differences in Dopamine Release and Reward Memory in Older Adults
Poster No:
913
Submission Type:
Abstract Submission
Authors:
Claire Ciampa1, Thomas Morin2, Jourdan Parent2, Alex Adornato1, Jordyn Cowan1, Katherine O'Malley1, Arielle Tambini3, Cristina Cusin2, Jacob Hooker2, Anne Berry1
Institutions:
1Brandeis University, Waltham, MA, 2Mass General Hospital, Boston, MA, 3Nathan Kline Institute, Orangeburg, NY
First Author:
Co-Author(s):
Introduction:
Sex differences in dopaminergic transmission impact behavior and brain structure and function across the lifespan (Kaczkurkin et al., 2019; Manza et al., 2022), with implications for numerous neuropsychiatric disorders (Becker, 2016; McLean et al., 2011). Recent work in healthy young and middle-aged adults demonstrates higher dopamine release in ventral striatum for females compared with males (Manza et al., 2022). The goal of our study is to establish whether sex differences in dopamine release extend to older age, and whether greater dopamine release in females supports better memory performance.
Methods:
We investigated sex differences in reward memory and dopamine release in a sample of healthy older adults (n = 46, mean age = 69, 53% female). As done previously (Berry et al., 2018), we measured dopamine release using the positron emission tomography (PET) tracer [11C]raclopride (bolus injection, 10mCi), which is a weak D2/3 receptor antagonist that binds competitively with dopamine. Each participant underwent two simultaneous PET/fMRI scans following oral placebo and oral methylphenidate (20mg). Methylphenidate increases dopamine availability in the synapse by inhibiting the dopamine transporter, while rate of dopamine release is unaffected. Endogenous dopamine release is quantified as the within-subject percent change in [11C]raclopride binding from placebo to drug, as the competitive binding of [11C]raclopride is reduced on drug due to increased synaptic levels of dopamine. During placebo and drug PET/fMRI scans, participants encoded images overlaid on a "high reward" background ($5 for each subsequently remembered item; Fig. 1A) and a "low reward" background ($0.01 for each remembered item), with a surprise offline memory test 24 hours later. We also collected resting state scans immediately before and after the task to investigate changes in functional connectivity following encoding.
Results:
We first found that females had better memory than males on drug (p=.02), while there was no sex difference on placebo (p=.39). This difference was driven by better low reward memory for females relative to males on drug (p=.007; Fig. 1B) but not placebo (p=.68), while there were no sex differences for high reward on drug (p=.33) or placebo (p=.27). We next tested for sex differences in dopamine release ([11C]raclopride % change from placebo to drug) in ventral striatum (VST) and dorsal caudate (DCA; Fig. 2A). In line with previous work, females had higher VST dopamine release compared with males (p=.01), while there was no sex difference in DCA dopamine release (p=.53; Fig. 2B, top) and no sex differences in baseline [11C]raclopride (VST: p=.72, DCA: p=.20; Fig. 2B, bottom). Testing for relationships between dopamine release and memory, we found that higher VST dopamine release related to drug-induced enhancements in memory for females (p=.006) but not males (p=.55). Finally, resting state functional connectivity between hippocampus and VST was higher post-task relative to pre-task for females on placebo (p=.009), while on drug pre-task connectivity increased (p=.02) to be no different from post-task (p=.11). In contrast, males did not show a pre/post task difference on placebo (p=.09) or drug (p=.26).
·Sex differences in reward memory performance
·Sex differences in [11C]raclopride dopamine PET
Conclusions:
We demonstrate that females are more sensitive to the behavioral and neurobiological effects of methylphenidate. Sex differences in dopamine release may be driven in part by a larger number of ventral tegmental area (VTA) dopamine neurons in females relative to males (Kritzer & Creutz, 2008), regulation of VTA activity by estrogen (Vandegrift et al., 2020), and sex differences in dopaminergic genes (Ngun et al., 2011). Our findings are in line with this previous work and have implications for disorders associated with dysregulated dopamine and individual differences in effects of dopaminergic medications.
Emotion, Motivation and Social Neuroscience:
Reward and Punishment
Learning and Memory:
Long-Term Memory (Episodic and Semantic)
Lifespan Development:
Aging 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Systems
Novel Imaging Acquisition Methods:
Multi-Modal Imaging 2
Keywords:
Aging
Dopamine
FUNCTIONAL MRI
Memory
Positron Emission Tomography (PET)
Other - Sex Differences
1|2Indicates the priority used for review
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Provide references using APA citation style.
2. Berry, A. S. (2018). Dopamine synthesis capacity is associated with D2/3 receptor binding but not dopamine release. Neuropsychopharmacology, 43(6).
3. Kaczkurkin, A. N. (2019). Sex differences in the developing brain: Insights from multimodal neuroimaging. Neuropsychopharmacology, 44(1), 71–85.
4. Kritzer, M. F. (2008). Region and sex differences in constituent dopamine neurons and immunoreactivity for intracellular estrogen and androgen receptors in mesocortical projections in rats. Journal of Neuroscience, 28(38), 9525–9535.
5. Manza, P. (2022). Sex differences in methylphenidate-induced dopamine increases in ventral striatum. Molecular Psychiatry, 27(2), 939–946.
6. McLean, C. P. (2011). Gender differences in anxiety disorders: Prevalence, course of illness, comorbidity and burden of illness. Journal of Psychiatric Research, 45(8), 1027–1035.
7. Ngun, T. C. (2011). The genetics of sex differences in brain and behavior. Frontiers in Neuroendocrinology, 32(2), 227–246.
8. Vandegrift, B. J. (2020). Estrogen receptor α regulates ethanol excitation of ventral tegmental area neurons and binge drinking in female mice. Journal of Neuroscience, 40(27), 5196–5207.