Ecology and neurobiology of toxin avoidance and the paradox of drug reward

E. H. Hagen, R. J. Sullivan, R. Schmidt, G. Morris, R. Kempter, P. Hammerstein

Research output: Contribution to journalReview articlepeer-review


Current neurobiological theory of drug use is based on the observation that all addictive drugs induce changes in activity of dopaminergic circuitry, interfering with reward processing, and thus enhancing drug seeking and consumption behaviors. Current theory of drug origins, in contrast, views almost all major drugs of abuse, including nicotine, cocaine and opiates, as plant neurotoxins that evolved to punish and deter herbivores. According to this latter view, plants should not have evolved compounds that reward or reinforce plant consumption. Mammals, in turn, should not have evolved reinforcement mechanisms easily triggered by toxic substances. Situated in an ecological context, therefore, drug reward is a paradox. In an attempt to resolve the paradox, we review the neurobiology of aversive learning and toxin avoidance and their relationships to appetitive learning. We seek to answer the question: why does aversive learning not prevent the repeated use of plant drugs? We conclude by proposing alternative models of drug seeking and use. Specifically, we suggest that humans, like other animals, might have evolved to counter-exploit plant neurotoxins.

Original languageEnglish
Pages (from-to)69-84
Number of pages16
Issue number1
StatePublished - 21 Apr 2009
Externally publishedYes

Bibliographical note

Funding Information:
We thank Hagai Bergman, Dori Derdikman, Brian Hyland, Olof Leimar, Jonas Rose, Inbar Saraf-Sinik, Kay Thurley and anonymous reviewers for discussions and valuable comments on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (Emmy-Noether grant “Ke 788/1-4” to R.K.; SFB 618 “Theoretical Biology” to P.H. and R.K.) and the BMBF (Bernstein Center for Computational Neuroscience, Berlin, grant “01GQ0410” to R.K.). Funding for R.J.S. was provided by a 2008 CSUS Research Award. E.H.H. and R.J.S. are co–first authors; R.K. and P.H. are co–last authors.


  • aversive learning
  • dopamine
  • nicotine
  • pharmacophagy
  • psychoactive substance use
  • reward learning

ASJC Scopus subject areas

  • General Neuroscience


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