D₁ and D₂ dopamine receptors differentially increase fos-like immunoreactivity in accumbal projections to the ventral pallidum and midbrain

Alterations in dopaminergic neurotransmission have profound effects on neuronal expression of the putative activity marker, Fos, in both the dorsal and ventral striatum. Stimulants such as d-amphetamine and cocaine increase Fos-like immunoreactivity by enhancing the activation of D₁ dopamine receptors. In contrast, neuroleptics such as heloperidol and raclopride increase Fos-like immunoreactivity by blocking striatal D₂ dopamine receptors. In the dorsal striatum, D₁ receptor stimulation elevates Fos-like immunoreactivity predominantly in neurons projecting to the midbrain (substantia nigra), whereas D₂ receptor antagonism enhances Fos-like immunoreactivity principally in neurons projecting to the pallidum (globus pallidus). These findings are consistent with the proposal that D₁ receptors are located chiefly on striatonigral neurons, whereas D₂ receptors reside mainly on striatopallidal neurons. Since the nucleus accumbens (largest component of the ventral striatum) also sends projections to the midbrain (ventral tegmental area and substantia nigra) and pallidum (ventral pallidum), the present study utilized retrograde tract-tracing techniques to determine if there was a similar segregation of D₁ agonist- and D₂ antagonist-induced Fos-like immunoreactivity in these accumbal projections. In addition, we examined whether these relationships were the same in the core and shell regions of the nucleus accumbens. Like the dorsal striatum, D₁ agonists (d-amphetamine and CY 208-243, but not D₂ antagonists (haloperidol and clozapine), increased Fos-like immunoreactivity in accumbal neurons projecting to the midbrain (ventral tegmental area and substantia nigra). Also like the dorsal striatum, D₂ antagonist-induced Fos-like immunoreactivity was located preferentially in accumbal neurons projecting to the pallidum (ventral pallidum). However, unlike the dorsal striatum, where the vast majority of neurons which display D₁ agonist-induced Fos-like immunoreactivity project to the midbrain, nearly 50% of those neurons in the nucleus accumbens which were Fos-immunoreactive after d-amphetamine or CY 208-243 projected to the ventral pallidum. Thus, a similar number of accumbal neurons which expressed D₁ agonist-induced Fos-like immunoreactivity were retrogradely labelled from the midbrain and ventral pallidum. Accumbal projections to the midbrain and ventral pallidum were retrogradely labelled with different retrograde tracers in order to determine the degree of collateralization between these pathways. Approximately 20% of retrogradely labelled neurons displayed both tracers, indicating that collateralization and damage to fibres of passage could not account for all of those cases in which D₁ agonist-induced Fos-like immunoreactivity was detected in accumbal neurons projecting to the ventral pallidum. All results of the present study were the same for both the shell and core regions of the nucleus accumbens. Our findings suggest that, in contrast to the projection from the dorsal striatum to the globus pallidus, which is composed primarily of neurons that express the D₂ receptor, D₁ and D₂ receptors are located on a comparable number of accumbal neurons that project to the ventral pallidum. Given that dopamine receptors in the nucleus accumbens are thought to play an important role in mediating the rewarding effects of stimulants and the antipsychotic actions of neuroleptics, our results may have significant implications for the anatomical basis of these processes.