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The Journal of Neuroscience, March 8, 2006, 26(10):2788-2797; doi:10.1523/JNEUROSCI.4331-05.2006

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Behavioral/Systems/Cognitive
Properties and Opioid Inhibition of Mesolimbic Dopamine Neurons Vary according to Target Location

Christopher P. Ford,¹ Gregory P. Mark,² and John T. Williams¹

¹Vollum Institute, L474, and ²Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239

Correspondence should be addressed to John T. Williams, Vollum Institute, L474, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: williamj{at}OHSU.edu

The mesolimbic dopamine system, which mediates the rewarding properties of nearly all drugs of abuse, originates in the ventral tegmental area (VTA) and sends major projections to both the nucleus accumbens (NAc) and the basolateral amygdala (BLA). To address whether differences occur between neurons that project to these separate areas, retrograde microspheres were injected to either the BLA or the NAc of DBA/2J mice. Whole-cell recordings were made from labeled VTA dopamine neurons. We found that identified neurons that projected to the BLA and NAc originated within different quadrants of the VTA with neither group exhibiting large-amplitude h-currents. Neurons that projected to the NAc exhibited a greater outward current in response to the -opioid agonist (5,7,8)-(+)-N-methyl-N-[7-(pyrrolidinyl)-1-oxaspiro [4,5]dec-8-yl]-benzeneacetamide (U69593 [GenBank] ; 200 nM), whereas neurons that projected to the BLA exhibited greater inhibition to the µ/ opioid agonist [Met⁵] enkephalin (ME; 3 µM). In addition, we found that the presynaptic inhibition of GABAergic transmission at both GABA_A and GABA_B receptors was differentially regulated by U69593 [GenBank] between the two groups. When dopamine IPSCs were examined, U69593 [GenBank] caused a greater inhibition in NAc- than BLA-projecting neurons. ME had no effect on either. Finally, the regulation of extracellular dopamine by dopamine uptake transporters was equal across the VTA. These results suggest that opioids differentially inhibit mesolimbic neurons depending on their target projections. Identifying the properties of projecting mesolimbic VTA dopamine neurons is crucial to understanding the action of drugs of abuse.

Key words: morphine; withdrawal; -opioid; µ-opioid; ventral tegmental area; retrograde labeling

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Received Oct. 11, 2005; revised Jan. 31, 2006; accepted Feb. 2, 2006.

Correspondence should be addressed to John T. Williams, Vollum Institute, L474, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: williamj{at}OHSU.edu

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