Effects of methylphenidate on resting-state functional connectivity of the mesocorticolimbic dopamine pathways in cocaine addiction

JAMA Psychiatry. 2013 Aug;70(8):857-68. doi: 10.1001/jamapsychiatry.2013.1129.

Abstract

Importance: Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems-level effects of methylphenidate in this population have not yet been described.

Objective: To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.

Design: Randomized, placebo-controlled, before-after, crossover study.

Setting: Clinical research center.

Participants: Eighteen nonabstaining individuals with cocaine use disorders.

Interventions: Single doses of oral methylphenidate (20 mg) or placebo were administered at each of 2 study sessions. At each session, resting scans were acquired twice: immediately after drug administration (before the onset of effects [baseline]) and 120 minutes later (within the window of peak effects).

Main outcomes and measures: Functional connectivity strength was evaluated using a seed voxel correlation approach. Changes in this measure were examined to characterize the neural systems-level effects of methylphenidate; severity of cocaine addiction was assessed by interview and questionnaire.

Results: Short-term methylphenidate administration reduced an abnormally strong connectivity of the ventral striatum with the dorsal striatum (putamen/globus pallidus), and lower connectivity between these regions during placebo administration uniquely correlated with less severe addiction. In contrast, methylphenidate strengthened several corticolimbic and corticocortical connections.

Conclusions and relevance: These findings help elucidate the neural systems-level effects of methylphenidate and suggest that short-term methylphenidate can, at least transiently, remodel abnormal circuitry relevant to the pathophysiologic characteristics of cocaine addiction. In particular, the effects of methylphenidate within striatal and cortical pathways constitute a potentially viable mechanism by which methylphenidate could facilitate control of behavior in cocaine addiction.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Brain / drug effects
  • Brain / physiology*
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / physiopathology*
  • Connectome* / instrumentation
  • Connectome* / methods
  • Cross-Over Studies
  • Dopamine / metabolism
  • Dopamine / physiology*
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Female
  • Humans
  • Magnetic Resonance Imaging / instrumentation
  • Magnetic Resonance Imaging / methods
  • Male
  • Membrane Potentials / physiology
  • Methylphenidate / administration & dosage*
  • Middle Aged
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Severity of Illness Index

Substances

  • Dopamine Uptake Inhibitors
  • Methylphenidate
  • Dopamine