We continued our examination of the decrease in binding of the cocaine derivative [3H]WIN 35,428 to the dopamine (DA) transporter in homogenized striatum and nucleus accumbens at several times after a series of IV infusions of cocaine. The binding of [3H]WIN 35,428 was reduced by 30% in the nucleus accumbens 10, 30, and 60 days after of cocaine, but not 1, 3 or 6 days later or after saline. No change occurred in the striatum at any time. These data suggest that the DA transporters in the two regions may be regulated differently. We completed two related studies. The first is an autoradiographic study of [3H]WIN 35,428 binding in brains of rats injected IV with the isotope 1 or 10 days after the last IV infusion of cocaine. There was a significant 25% reduction in the in vivo [3H]WIN 35,428 binding in the nucleus accumbens of rats withdrawn from cocaine for 10 days. Secondly, we determined the distribution of the MRNA for the DA transporter using in situ hybridization in the brains of rats withdrawn from cocaine for 10 days. DA transporter MRNA was reduced in two nuclei of the ventral tegmental area that project to nucleus accumbens. The magnitude of the decrease in MRNA was similar to that of the decrease in transporter binding. The peptide neurotensin (NT) resides in part in the mesocorticolimbic DA neurons. Multiple IV infusions of cocaine decreased NT binding at their cell bodies but increased it markedly at their terminal fields. Ten days after withdrawal of cocaine, NT binding had recovered at the cell bodies, but binding at the terminal fields was enhanced further, suggesting that withdrawal from cocaine might decrease the synthesis and/or release of NT. Our preliminary findings show that NT accumulates in the prefrontal cortex and in the substantia nigra, the terminal fields of these neurons, 10 days after cocaine is withdrawn. It seems that these neurons synthesize NT after withdrawal of cocaine, but may not be able to release it. We are continuing to analyze the persistence of these changes. Taken together, these data show that long-lasting changes occur in dopaminergic neurons in reward-relevant areas in rat brain and may underlie other drug-related phenomena.
