Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Author Affiliations

1. Contributed by Joanna S. Fowler, June 20, 2014 (sent for review April 9, 2014; reviewed by Bertha Madras, Harvard University Medical School, and Karen Berman, National Institute of Mental Health)

Significance

Marijuana abusers show lower positive and higher negative emotionality scores than controls, which is consistent, on one hand, with lower reward sensitivity and motivation and, on the other hand, with increased stress reactivity and irritability. To investigate this aspect of marijuana’s impact on the human brain, we compared the brain’s reactivity in marijuana abusers vs. controls when challenged with methylphenidate (MP). We found that marijuana abusers display attenuated dopamine (DA) responses to MP, including reduced decreases in striatal distribution volumes. These deficits cannot be unambiguously ascribed to reduced DA release (because decreases in nondisplaceable binding potential were not blunted) but could reflect a downstream postsynaptic effect that in the ventral striatum (brain reward region) might contribute to marijuana’s negative emotionality and addictive behaviors.

Abstract

Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [11C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral (“self-reports” for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [11C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BPND)] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BPND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.

Footnotes

• ↵1To whom correspondence may be addressed. Email:nvolkow@nida.nih.gov or fowler@bnl.gov.

• Author contributions: N.D.V., G.-J.W., and J.S.F. designed research; G.-J.W., F.T., D.A., and M.J. performed research; D.A. contributed new reagents/analytic tools; M.J. recruited and screened volunteers; N.D.V., G.-J.W., J.L., C.W., and D.T. analyzed data; and N.D.V. and J.S.F. wrote the paper.

• No author conflict of interest response is available.