7‐OH‐DPAT Differentially Reverses Clozapine‐ and Haloperidol‐induced Increases in Fos‐like Immunoreactivity in the Rodent Forebrain

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Abstract
The pattern of neurons which display haloperidol‐induced Fos‐like immunoreactivity closely matches the distribution of striatal D2 dopamine receptors, whereas clozapine‐induced Fos‐like immunoreactivity occurs primarily in regions that contain high levels of the D3 dopamine receptor. These neuroanatomical correlations suggest that haloperidol and clozapine may elevate Fos‐like immunoreactivity by blocking D2 and D3 receptors respectively. In order to test this hypothesis, the abilities of prior administration of the D3 receptor‐preferring agonist 7–hydroxy‐N, N′‐di‐n‐propyl‐2‐aminotetraline (7–OH‐DPAT) to competitively reverse haloperidol‐ and clozapine‐induced increases in Fos‐like immunoreactivity were compared. Administration of 7–OH‐DPAT (0.05 mg/kg, s.c.) 30 min before clozapine (20 mg/kg, s.c.) produced a 60% reduction in the number of neurons that displayed clozapine‐induced Fos‐like immunoreactivity in the major island of Calleja, nucleus accumbens and medial aspect of the striatum, while prior administration of 0.5 mg/kg (s.c.) of 7‐OH‐DPAT completely reversed these increases in Fos‐like immunoreactivity. In contrast, the increases in Fos‐like immunoreactivity in the major island of Calleja, nucleus accumbens and striatum (medial and dorsal aspects) induced by haloperidol (0.1 mg/kg, s.c.) were only reduced by the high dose of 7‐OH‐DPAT (0.5 mg/kg, s.c.). Hence, clozapine‐induced increases in Fos‐like immunoreactivity were more readily reversed by 7‐OH‐DPAT than elevations in Fos‐like immunoreactivity produced by haloperidol. These results suggest that D3 receptor blockade plays a larger role in mediating clozapine‐ than haloperidol‐induced increases in Fos‐like immunoreactivity.