D-amphetamine-induced behavioral sensitization: Implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation

Behavioral sensitization to amphetamine is expressed as a progressive enhan cement of the behavioral activating effects of the drug when repeated injec tions are performed as well as a long-lasting hypersensitivity to later env ironmental or pharmacological challenges. The mesoaccumbens dopamine system has been proposed to be the major candidate so far responsible for the ind uction and expression of this process, which are dependent on the action of amphetamine in the ventral tegmental area and nucleus accumbens, respectiv ely. The development of this process has been proposed to be the result of an interaction between somatodendritically released dopamine and dopaminerg ic D-1 receptors localized on different inputs to the ventral tegmental are a, including glutamate afferents arising in part from mesocorticolimbic are as such as the medial prefrontal cortex and the amygdala, Three groups of e xperiments were designed to test the role of each of these components in th e behavioral sensitization to amphetamine. First, the intervention of the g lutamatergic transmission of the ventral tegmental area in the induction of sensitization to amphetamine was tested. The effects of an iv-methyl-D-asp artate antagonist, 3-(R-2-carboxypiperazin-4-yl) -propyl-1-phosphonic acid, on the behavioral sensitization induced by amphetamine administered repeat edly in the ventral tegmental area was tested. It was found that the blocka de of N-methyl-D-aspartate receptors with 3-(R-2-carboxypiperazin-4-yl)-pro pyl-1-phosphonic acid coadministered with amphetamine in the ventral tegmen tal area dose-dependently prevented the induction of sensitization. In a se cond step, the role of the structures which send glutamatergic inputs to th e ventral tegmental area in the process of behavioral sensitization was tes ted. We evaluated the effects of ibotenic acid lesion of the medial prefron tal cortex and the amygdala on behavioral sensitization induced by peripher al or intra-ventral tegmental area administration of amphetamine. We found that ibotenic acid lesion of the medial prefrontal cortex blocked the behav ioral sensitization induced by both intra-ventral tegmental area and periph eral treatment with amphetamine. In contrast, ibotenic acid lesion of the a mygdala produced no effect on behavioral sensitization induced peripherally or centrally. These experiments confirmed (i) that the ventral tegmental a rea, where dopaminergic cell bodies are located, is a critical site for the induction of behavioral sensitization, (ii) that this process implicates t he glutamatergic transmission in the ventral tegmental area, and (iii) that the medial prefrontal cortex is crucially implicated merely because of its direct glutamatergic inputs on to ventral tegmental area neurons. Together, these results reinforce the view that the behavioral sensitizatio n to amphetamine implicates not only the mesoaccumbens dopaminergic neurons , but also other structures of the mesocorticolimbic system, such as the me dial prefrontal cortex and more specifically its glutamatergic component. ( C) 1999 IBRO. Published by Elsevier Science Ltd.