Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users

Abstract

Interest in development of therapeutics targeting brain neuropeptide systems for treatment of cocaine addiction (e.g., kappa opioid agonists) is based on animal data showing interactions between the neuropeptides, brain dopamine, and cocaine. In this autopsied brain study, our major objective was to establish by radioimmunoassay whether levels of dynorphin and other neuropeptides (e.g., metenkephalin, neurotensin and substance P) are increased in the dopamine-rich caudate, putamen, and nucleus accumbens of human chronic cocaine users (n=12) vs. matched control subjects (n=17) as predicted by animal findings. Changes were limited to markedly increased dynorphin immunoreactivity in caudate (+92%), decreased caudate neurotensin (-49%), and a trend for increased dynorphin (+75%) in putamen. In other examined subcortical/cerebral cortical areas dynorphin levels were normal with the striking exception of the ventral pallidum (+346%), whereas cerebral cortical metenkephalin levels were generally decreased and neurotensin variably changed. Our finding that, in contradistinction to animal data, the other striatal neuropeptides were not increased in human cocaine users could be explained by differences in pattern and contingency between human drug users and the animal models. However, the human dynorphin observations parallel well animal findings and suggest that the dynorphin system is upregulated, manifested as elevated neuropeptide levels, after chronic drug exposure in striatum and ventral pallidum. Our postmortem brain data suggest involvement of striatal dynorphin systems in human cocaine users and should add to the interest in the testing of new dynorphin-related therapeutics for the treatment of cocaine addiction.

Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: Potential role for 5-HT1B receptor

“…(Note that, in contrast, enkephalin expression is very responsive to antipsychotic/D2 receptor antagonist treatment or dopamine loss (Steiner and Gerfen, 1998)). Importantly, increased dynorphin mRNA and peptide levels have also been demonstrated in human cocaine abusers (Hurd and Herkenham, 1993; Frankel et al, 2008). …”

The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

“…PDYN expression is enhanced in putamen ''patches'' but not in caudate or NAcc of cocaine users, whereas [ 3 H]DYN binding is increased in the caudate relative to controls [277]. Enhanced DYN immunoreactivity in the caudate and ventral pallidum but no changes in the putamen and prefrontal cortex of methamphetamine and cocaine users have been reported [295,296]. Methamphetamine users have decreased DYN immunoreactivity in the NAcc, medial pulvinar thalamic nucleus, and temporal/occipital association cortices [296]; changes not observed in cocaine users [295].…”

“…Enhanced DYN immunoreactivity in the caudate and ventral pallidum but no changes in the putamen and prefrontal cortex of methamphetamine and cocaine users have been reported [295,296]. Methamphetamine users have decreased DYN immunoreactivity in the NAcc, medial pulvinar thalamic nucleus, and temporal/occipital association cortices [296]; changes not observed in cocaine users [295]. A significant correlation between recent psychostimulant use and PDYN expression in cingulate and dorsal lateral prefrontal cortices has also been reported [280].…”

What is the role of the D3 receptor in addiction? A mini review of PET studies with [11C]-(+)-PHNO

“…Although mechanisms underlying D3 upregulation are still unclear, preclinical data suggest that it may result from repeated stimulation of D 1 receptors by dopamine during drug use, leading to the release of brain-derived neurotrophic factor (BDNF), which has, in turn, been linked to increased D 3 expression (Guillin et al, 2001) and was recently shown to be elevated in cocaine dependence in humans (D'Sa et al, 2011) (although it should be noted that no definite data support a causal role for BDNF in addiction, see (Pickens et al, 2011)). D 3 upregulation is thought to occur on GABAergic neurons containing D 1 receptors, substance P, and dynorphin (Frankel et al, 2008), as brain dynorphin concentrations are also elevated in human stimulant use (Frankel et al, 2007(Frankel et al, , 2008Kim et al, 2005). Inhibition of GABA neurons via increased transmission at D 3 could therefore modify the functional system responsible for the output of the limbic striatum, thereby modulating motivation to use drugs (see e.g.…”