Sex differences in amphetamine-induced dopamine release in the dorsolateral prefrontal cortex of tobacco smokers

Neuropsychopharmacology. 2019 Dec;44(13):2205-2211. doi: 10.1038/s41386-019-0456-y. Epub 2019 Jul 3.

Abstract

Sex differences exist in the neurochemical mechanisms underlying tobacco smoking and smoking-related behaviors. Men tend to smoke for the reinforcing effects of nicotine, whereas women tend to smoke for stress and mood regulation, and have a harder time maintaining long-term abstinence. The mesolimbic dopamine (DA) system drives the reinforcing effects of tobacco smoking, whereas the mesocortical DA system-including the dorsolateral prefrontal cortex (dlPFC)-is critical for stress-related cognitive functioning and inhibitory control. This study is the first to investigate dlPFC D2/3-type receptor (D2R) availability and amphetamine-induced cortical DA release in smokers and nonsmokers. Forty-nine subjects (24 tobacco smokers (12 females) and 25 sex- and age-matched nonsmokers) participated in two same-day [11C]FLB457 positron emission tomography (PET) scans before and 3-hours after amphetamine administration (0.4-0.5 mg/kg, PO). D2R availability (non-displaceable binding potential; BPND) was measured pre- and post-amphetamine. The percent fractional change in BPND (%ΔBPND) between pre- and post-amphetamine, an index of DA release, was compared between male and female smokers and nonsmokers. Smokers showed significantly lower dlPFC D2R availability (BPND = 0.77 ± 0.05) than nonsmokers (BPND = 0.92 ± 0.04), p = 0.016, driven by males. Female smokers showed significantly less amphetamine-induced DA release in dlPFC (%ΔBPND = 1.9 ± 3.0%) than male smokers (%ΔBPND = 14.0 ± 4.3%), p < 0.005, and female nonsmokers (%ΔBPND = 9.3 ± 3.3%), p < 0.005. This study shows that in the prefrontal cortex, smokers have lower D2R availability than nonsmokers and that female vs. male smokers have a blunted amphetamine-induced DA release. These findings demonstrate that tobacco smoking differentially affects the mesocortical DA system in men vs. women, suggesting a potential target for gender-specific treatments.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amphetamine / administration & dosage*
  • Dopamine / metabolism*
  • Female
  • Humans
  • Male
  • Positron-Emission Tomography
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism*
  • Receptors, Dopamine D2 / metabolism*
  • Sex Characteristics*
  • Smokers*

Substances

  • DRD2 protein, human
  • Receptors, Dopamine D2
  • Amphetamine
  • Dopamine