Pharmacological study on the mixed CCK8/DA meso-nucleus accumbens pathway: evidence for the existence of storage sites containing the two transmitters.

The mixed CCK8/DA meso-nucleus accumbens pathway was used as a model to study the effects of some pharmacological treatments on the two coexisting transmitters. Reserpine (7 mg/kg i.p.), which depletes monoamine vesicles, induced as early as 1 h following its injection a selective decrease (36%) of CCK8 levels in the posterior part of the nucleus accumbens, an area innervated by the mixed CCK8/DA projection. In contrast, this treatment was without effect on CCK8 levels in the anterior nucleus accumbens and the ventral striatum, two areas which contain distinct CCK8 and DA innervations. Apomorphine (5 mg/kg i.p.), which is known to inhibit the firing rate of DA cells, did not block the reserpine- induced decrease in CCK8 levels suggesting that reserpine is acting on CCK8 storage. This mechanism of action was further substantiated by results obtained with alpha-methyl-p-tyrosine (alpha-MpT, 200 mg/kg i.p.) since no change in CCK8 levels was observed 4 h after this treatment. However, a selective decrease (35%) in CCK8 levels was found in the posterior part of the nucleus accumbens 20 h after two successive alpha-MpT injections. This suggested that long-term interruption of DA transmission resulted in an activation of CCK8/DA cells leading to a release of CCK8. The partial effect of reserpine on total CCK8 stores in CCK8/DA fibers suggests that the peptide is distributed in two types of storage compartments, one of them being sensitive to reserpine and possibly corresponding to mixed CCK8/DA vesicles.