Exp Brain Res (1998) 120:153±163  Springer-Verlag 1998 RESEARCH ARTICLE E. Lopez-Martin ´ G. Rozas ´ J. Rodriguez M.J. Guerra ´ J.L. Labandeira-Garcia The corticostriatal system mediates the ªparadoxicalº contraversive rotation but not the striatal hyperexpression of Fos induced by amphetamine early after 6-hydroxydopamine lesion of the nigrostriatal pathway Received: 8 August 1997 / Accepted: 20 November 1997 E. Lopez-Martin ´ G. Rozas ´ J. Rodriguez ´ M.J. Guerra J.L. Labandeira-Garcia ( ) ) Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, E-15705 Santiago de Compostela, Spain e-mail: cmlaband@uscmail.usc.es, Fax: +34-81-583345 Abstract In rats with unilateral 6-hydroxydopamine (6- OHDA) lesion of the nigrostriatal pathway, amphetamine produces ipsiversive rotational behavior and activation of Fos in the intact striatum, but practically no activation of Fos in the denervated striatum. However, a seemingly paradoxical contraversive rotation, accompanied by in- tense striatal Fos activation in the lesioned striatum, has been observed during the first few days postlesion. In the present work, behavioral tests and immunohistochem- istry for Fos protein and tyrosine hydroxylase (TH) were combined to study striatal changes 36 h after 6-OHDA le- sion and particularly the possible involvement of gluta- matergic corticostriatal afferents. Injection of amphet- amine (0.5 mg/kg or 5 mg/kg) induced contraversive rota- tion and strong and evenly distributed Fos expression in the lesioned striatum; in the contralateral striatum, how- ever, Fos density was lower than in nonlesioned rats. Pre- treatment with the N-methyl-D-aspartate (NMDA) gluta- mate receptor antagonist MK-801 (either 0.5 mg/kg or 5 mg/kg) did not significantly affect the hyperexpression of Fos in the lesioned striatum, but suppressed the contr- aversive rotation. Similarly, rats that were subjected to corticostriatal deafferentation (confirmed by sensory ne- glect tests) and 6-OHDA lesion (1 week or 3 weeks later) showed no significant reduction in the striatal Fos hyper- expression induced by amphetamine (0.5 mg/kg or 5 mg/ kg) and no significant rotational asymmetry. In conclu- sion, the present results indicate that glutamatergic cor- ticostriatal afferents are essential for the contraversive ro- tational behavior but not the striatal hyperexpression of Fos observed in response to amphetamine early after 6- OHDA lesion, and suggest that intense dopaminergic stimulation of striatal neurons is sufficient for induction of Fos, but that concurrent glutamatergic stimulation is necessary for the motor response. Key words Amphetamine ´ Fos ´ Rotational behavior ´ Corticostriatal afferents ´ Rat Introduction Lesion of the nigrostriatal system with 6-hydroxydopa- mine (6-OHDA) is the most widely used animal model of parkinsonism. Though long-term changes induced by 6-OHDA lesion have been extensively studied, early le- sion-induced changes and the time course of these chang- es have received relatively little attention. These changes are of great interest, since Parkinsons disease progresses for years, so that recently dysfunctional dopaminergic (DAergic) fibers coexist alongside DAergic fibers that have been dysfunctional for a longer time. Activation of the immediate-early gene c-fos and ex- pression of the Fos nuclear protein are induced by a vari- ety of stimuli that provoke changes in striatal neuronal function and second messengers; therefore, striatal induc- tion of Fos can be used as a morphological indicator of these changes (Dragunow and Faull 1989; Morgan and Curran 1991; Sommer and Fuxe 1997). In a classic rota- tional behavior model, animals with chronic DAergic le- sions (i.e., at least two weeks old) turn away from the side on which DA receptor stimulation is heaviest. Thus, in rats with chronic (at least 2-week-old) unilateral 6-OHDA lesions, DA-releasing drugs such as amphetamine induce pronounced ipsiversive (i.e., lesion-ipsilateral) rotation and activation of c-fos in the medium spiny neurons of the intact striatum, but induce practically no Fos in the denervated striatum (Graybiel et al. 1990; Ungersted 1971; Ungersted and Arbuthnott 1970). However, a seem- ingly paradoxical, amphetamine-induced contraversive rotation has been observed during the postlesion week 1 (Carey 1992; Mintz et al. 1986; Oberlander et al. 1979), and the underlying mechanism has not been clarified. Re- cently, we have observed that this ªparadoxicalº, amphet- amine-induced contraversive rotation is accompanied by intense striatal activation of Fos in the lesioned striatum even in response to low doses of amphetamine that