Abstract
Addiction to cocaine is associated with dysfunction of the dopamine mesocortical system including impaired dopamine-2 receptor (D2r) signaling. However, the effects of chronic cocaine on neuronal adaptations in this system have not been systematically examined and data available is mostly from males. Here, we investigated changes in the total neuronal density and relative concentration of D2r-expressing neurons in the medial prefrontal cortex (mPFC), dorsal striatum (Dstr), nucleus accumbens (NAc), and ventral tegmental area (VTA) in both male and female mice passively exposed to cocaine for two weeks. In parallel experiments, we measured mRNA levels for Drd2 and for opioid peptides (mPenk and mPdyn). Through a combination of large field of view fluorescent imaging with BAC transgenic D2r-eGFP mice and immunostaining, we observed that cocaine exposed mice had a higher density of D2r-positive cells that was most prominent in mPFC and VTA and larger for females than for males. This occurred amidst an overall significant decrease in neuronal density (measured with NeuN) in both sexes. However, increases in Drd2 mRNA levels with cocaine were only observed in mPFC and Dstr in females, which might reflect the limited sensitivity of the method. Our findings, which contrast with previous findings of cocaine-induced downregulation of D2r binding availability, could reflect a phenotypic shift in neurons that did not previously express Drd2 and merits further investigation. Additionally, the neuronal loss particularly in mPFC with chronic cocaine might contribute to the cognitive impairments observed with cocaine use disorder.
Highlights
Addiction is a chronic disease which manifests by compulsive drug seeking and use that is difficult to control despite harmful consequences (Koob and Volkow, 2016)
We assessed the effects of chronic cocaine (2 weeks passive exposure) on dopamine-2 receptor (D2r)-expressing neurons and the total neuronal population in the dopamine mesocortical system
Contrary to our hypothesis, we found a significant increase in the number of D2r-expressing neurons in medial prefrontal cortex (mPFC), dorsal striatum (Dstr), nucleus accumbens (NAc), and ventral tegmental area (VTA) in cocaine exposed mice that was stronger in females than males
Summary
Addiction is a chronic disease which manifests by compulsive drug seeking and use that is difficult to control despite harmful consequences (Koob and Volkow, 2016). Studies in laboratory animals have documented the involvement of the dopamine mesocortical system in addiction, including the substantia nigra (SN) and ventral tegmental area (VTA) midbrain regions with their striatal targets to dorsal striatum (Dstr) and nucleus accumbens (NAc) and cortical targets to the medial prefrontal cortex (mPFC) (Koob and Volkow, 2010). The systematic analyses of changes in D2r and neuronal loss in the various regions of the DA mesocortical system with chronic cocaine exposure as a function of sex to our knowledge has not been investigated This is relevant since women when compared to men transition faster from occasional to compulsive cocaine intake and those with cocaine use disorder experience more cravings, withdrawal symptoms, and worse outcomes (Griffin et al, 1989; Robbins et al, 1999; Van Etten and Anthony, 2001; Becker and Koob, 2016). Studies in laboratories animals have reported significant sex differences in the locomotor and rewarding effects of cocaine (Kokane and Perrotti, 2020)
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