RELATIONSHIP BETWEEN ASYMMETRIES IN STRIATAL DOPAMINE RELEASE AND THEDIRECTION OF AMPHETAMINE-INDUCED ROTATION DURING THE FIRST WEEK FOLLOWING A UNILATERAL 6-OHDA LESION OF THE SUBSTANTIA-NIGRA

In animals with a large unilateral 6-hydroxydopamine (6-OHDA) lesion o f the nigrostriatal dopamine (DA) system the traditional ''rotational behavior model'' states that amphetamine will induce circling behavior towards the denervated striatum (ipsiversive), that is, away from the side where there is greater amphetamine-stimulated DA release and gre ater DA receptor stimulation. It is puzzling, therefore, why amphetami ne induces contraversive rotation in rats tested 4 days after a unilat eral 6-OHDA lesion, despite a 90-95% loss of the dopaminergic input to the striatum by this time. Rats reverse their direction of amphetamin e-induced rotation by 8 days post-lesion and turn in the ipsiversive d irection thereafter. To try and resolve this paradox, bilateral striat al microdialysis was used to estimate the effects of amphetamine on DA neurotransmission on Day 4 and Day 8 following a large unilateral 6-O HDA lesion of the substantia nigra. On Day 4 post-lesion, amphetamine produced a moderate (around 50% of control) increase in the extracellu lar concentration of DA in the denervated striatum. This amphetamine-r eleasable pool of DA was exhausted by a single amphetamine challenge, because a second injection of amphetamine given 3 h after the first di d not produce a comparable increase in DA. It is suggested that on Day 4 post-lesion the amount of DA released by amphetamine in the denerva ted striatum is sufficient to produce greater DA receptor stimulation on that side, because of DA receptor supersensitivity, and this leads to contraversive rotation. On Day 8 post-lesion, amphetamine induced D A release in the intact striatum but had no effect on extracellular DA in the denervated striatum (DA was nondetectable). On Day 8, therefor e, DA receptor stimulation would be greatest in the intact striatum, l eading to ipsiversive rotation. In conclusion, it is suggested that th e seemingly paradoxical reversal in the direction of amphetamine-induc ed rotation that occurs over the first week following a unilateral 6-O HDA lesion is consistent with the traditional rotational model, and is due to time-dependent changes in the ability of amphetamine to releas e DA in the denervated striatum. (C) 1994 Wiley-Liss, Inc.