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Neuropsychopharmacology. 2010 January; 35(1): 337–338.
Published online 2009 December 10. doi:  10.1038/npp.2009.106
PMCID: PMC2882101
NIHMSID: NIHMS208731

Exploring the molecular basis of addiction: drug-induced neuroadaptations

Abuse of a number of psychoactive substances can eventually control an individual's behavior by producing dependence and/or addiction. Recent surveys estimate that there are about 200 million users of illegal drugs worldwide, which represent 3.4% of the world population. An ever-increasing number of neuroscientists are searching for clues regarding the molecular determinants of addictive behavior. The low-hanging fruit would be to study dopamine receptors and transporters in the nucleus accumbens (NAc); however, scientists are now exploring mechanisms far beyond dopaminergic targets.

For example, some scientists have chosen to target molecular mechanisms within the hippocampus because of its role in encoding and retrieving information in the central nervous system. In addition, this brain region sends and receives projections from the mesolimbic dopamine system so often implicated in addiction (Bannerman et al, 2004). Further, the hippocampus has been directly implicated in addiction behavior (Vorel et al, 2001), likely because of the fact that there is increasing evidence suggesting that drug addiction represents a conditioning phenomenon that is largely dependent on associations between drug effects and environmental cues (Berke and Hyman, 2000).

Coordinated hippocampal/accumbal regulation is likely at the heart of the protective addiction phenotype produced by environmental enrichment. We find that rats reared in an enriched condition (large cages with cohorts and novel objects) self-administer cocaine or amphetamine less readily than rats in the isolated control group (Green et al, 2009). This protective phenotype is likely mediated by a coordinated decrease in cAMP response element binding protein (CREB) activity in the accumbens coupled with an increase in the hippocampus. Further, CREB has been linked to neuronal excitability (Dong et al, 2006), suggesting that some yet to be identified CREB target gene may produce this protective phenotype by decreasing excitability in the accumbens and increasing excitability in the hippocampus.

Addiction-related molecular targets in the hippocampus are also being interrogated using proteomics approaches. It is known that exposure to drugs of abuse alters the expression of certain synaptic proteins. Indeed, a recent study uses this state-of-the-art technology to examine the effects of morphine administration on the protein expression profile at hippocampal synapses (Moron et al, 2007). This study finds that repeated morphine administration alters the synaptic distribution of endocytic proteins. This finding has functional implications, as receptor trafficking largely depends on endocytosis, and therefore morphine may alter receptor localization by affecting synaptic redistribution of the endocytic machinery. The idea that endocytic proteins, such as clathrin, may be involved in morphine-induced changes at hippocampal synapses is quite innovative and opens up a new direction for the study of the mechanisms underlying morphine-induced neuroadaptations. In addition, these findings suggest that the study of hippocampal neuroadaptations induced by repeated morphine treatment has great potential to reveal the mechanisms contributing to the development of opiate addiction.

Addiction is a complex polygenic psychiatric condition involving many brain regions, proteins and physiological effects, not to mention varied etiologies. Understanding the molecular mechanisms underlying addictive behavior will someday allow for therapeutic intervention that will be both efficacious and safe.

Footnotes

DISCLOSURE

The authors declare that except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services, and there are no financial holdings that could be perceived as constituting a potential conflict of interest.

References

  • Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T, et al. Regional dissociations within the hippocampus—memory and anxiety. Neurosci Biobehav Rev. 2004;28:273–283. [PubMed]
  • Berke JD, Hyman SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron. 2000;25:515–532. [PubMed]
  • Dong Y, Green T, Saal D, Marie H, Neve R, Nestler EJ, et al. CREB modulates excitability of nucleus accumbens neurons. Nat Neurosci. 2006;9:475–477. [PubMed]
  • Green TA, Alibhai IN, Roybal CN, Winstanley CA, Theobald DE, Birnbaum SG, et al. 2009. Environmental enrichment produces a consistent behavioral phenotype indicative of decreased cAMP response element transcriptional activity in the nucleus accumbens Biol Psychiatry(in press).
  • Moron JA, Abul-Husn NS, Rozenfeld R, Dolios G, Wang R, Devi LA. Morphine administration alters the profile of hippocampal postsynaptic density-associated proteins: a proteomics study focusing on endocytic proteins. Mol Cell Proteomics. 2007;6:29–42. [PubMed]
  • Vorel SR, Liu X, Hayes RJ, Spector JA, Gardner EL. Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science. 2001;292:1175–1178. [PubMed]

Articles from Neuropsychopharmacology are provided here courtesy of Nature Publishing Group