ABSTRACT Gene expression studies have suggested that dopamine (DA) depletion increases the sensitivity of striatal direct pathway neurons to the effects of serotonin (5-HT) via the 5-HT 2 receptor. The present study examined the possible influence(s) of 5-HT 2A or 5-HT 2C receptor-mediated signaling locally within the striatum on motor behavior triggered by 5-HT 2 receptor agonism in the neonatal DA-depleted rat. Male Sprague-Dawley rats were treated with 6-hydroxydopamine (6-OHDA; 60 g in 5 l per lateral ventricle) on postnatal day 3 to achieve near-total DA depletion bilaterally. Sixty days later, sham-operated (saline-injected) or 6-OHDA-treated rats were challenged with the 5-HT 2A/2C agonist DOI [(Ϯ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane] or saline either by systemic treatment or bilateral intrastriatal infusion. Motor behavior was quantified for 60 min after agonist injection using computerized activity monitors. Systemic DOI treatment (0.2 or 2.0 mg/kg i.p.) was more effective in inducing motor activity in the DA-depleted group compared with intact controls. Intrastriatal DOI infusion (1.0 or 10.0 g/side) also produced a significant rise in motor activity in the DA-depleted group during the 30-to 60-min period of behavioral analysis but did not influence behavior in intact animals. The effects of intrastriatal DOI infusion were blocked by intrastriatal coinfusion of the 5-HT 2 antagonist ketanserin (1. A loss of dopamine (DA) transmission to the rodent striatum during early postnatal development results in a compensatory increase in serotonin (5-HT) innervation to the dorsal striatum Several studies indicate that 5-HT 2A receptors are positioned to mediate the influences of enhanced 5-HT signaling in the DA-depleted striatum. First, 5-HT release agents and 5-HT 2 receptor agonists gain potency in inducing striatal preprotachykinin (PPT; encodes substance P and neurokini
