title: Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volunteers.
abstract: BACKGROUND
  Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders. We previously showed that the cannabis receptor subtype (CB1) inverse agonist rimonabant, an antiobesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses (Horder et al., 2010). Unlike rimonabant, tetrahydrocannabivarin is a neutral CB1 receptor antagonist (Pertwee, 2005) and may therefore produce different modulations of the neural reward system. We hypothesized that tetrahydrocannabivarin would, unlike rimonabant, leave intact neural reward responses but augment aversive responses.
  
  
  METHODS
  We used a within-subject, double-blind design. Twenty healthy volunteers received a single dose of tetrahydrocannabivarin (10mg) and placebo in randomized order on 2 separate occasions. We measured the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (picture of moldy strawberries and/or a less pleasant strawberry taste) using functional magnetic resonance imaging. Volunteers rated pleasantness, intensity, and wanting for each stimulus.
  
  
  RESULTS
  There were no significant differences between groups in subjective ratings. However, tetrahydrocannabivarin increased responses to chocolate stimuli in the midbrain, anterior cingulate cortex, caudate, and putamen. Tetrahydrocannabivarin also increased responses to aversive stimuli in the amygdala, insula, mid orbitofrontal cortex, caudate, and putamen.
  
  
  CONCLUSIONS
  Our findings are the first to show that treatment with the CB1 neutral antagonist tetrahydrocannabivarin increases neural responding to rewarding and aversive stimuli. This effect profile suggests therapeutic activity in obesity, perhaps with a lowered risk of depressive side effects.
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom (Mr Tudge and Dr McCabe); Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom (Ms Williams and Prof Cowen).
authors.forename: Luke
authors.initials: L
authors.lastname: Tudge
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom (Mr Tudge and Dr McCabe); Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom (Ms Williams and Prof Cowen).
authors.forename: Clare
authors.initials: C
authors.lastname: Williams
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom (Mr Tudge and Dr McCabe); Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom (Ms Williams and Prof Cowen).
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Cowen
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom (Mr Tudge and Dr McCabe); Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom (Ms Williams and Prof Cowen). c.mccabe@reading.ac.uk.
authors.forename: Ciara
authors.initials: C
authors.lastname: McCabe
mesh_terms: D000328:Adult; D000339:Affect; D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001362:Avoidance Learning / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001931:Brain Mapping / Q000379:methods; D002099:Cacao; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005247:Feeding Behavior / Q000187:drug effects*; D005260:Female; D031985:Fragaria / Q000382:microbiology; D005638:Fruit / Q000382:microbiology; D005658:Fungi; D064368:Healthy Volunteers; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010775:Photic Stimulation; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012201:Reward; D013649:Taste; D055697:Taste Perception; D014796:Visual Perception; D055815:Young Adult
chemical_list: D019440:Anti-Obesity Agents; C571130:CNR1 protein, human; D063387:Cannabinoid Receptor Antagonists; D043884:Receptor, Cannabinoid, CB1; C003403:tetrahydrocannabivarin 9; D013759:Dronabinol
keywords: THCv; cannabinoid; fMRI; obesity; reward