Behavioral sensitization to amphetamine is expressed as a progressive enhancement of the behavioral activating effects of the drug when repeated injections are performed as well as a long-lasting hypersensitivity to later environmental or pharmacological challenges. The mesoaccumbens dopamine system has been proposed to be the major candidate so far responsible for the induction and expression of this process, which are dependent on the action of amphetamine in the ventral tegmental area and nucleus accumbens, respectively. The development of this process has been proposed to be the result of an interaction between somatodendritically released dopamine and dopaminergic D 1 receptors localized on different inputs to the ventral tegmental area, including glutamate afferents arising in part from mesocorticolimbic areas such as the medial prefrontal cortex and the amygdala. Three groups of experiments were designed to test the role of each of these components in the behavioral sensitization to amphetamine. First, the intervention of the glutamatergic transmission of the ventral tegmental area in the induction of sensitization to amphetamine was tested. The effects of an N-methyl-d-aspartate antagonist, 3-(R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, on the behavioral sensitization induced by amphetamine administered repeatedly in the ventral tegmental area was tested. It was found that the blockade of N-methyl-d-aspartate receptors with 3-(R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid co-administered with amphetamine in the ventral tegmental area dose-dependently prevented the induction of sensitization. In a second step, the role of the structures which send glutamatergic inputs to the ventral tegmental area in the process of behavioral sensitization was tested. We evaluated the effects of ibotenic acid lesion of the medial prefrontal cortex and the amygdala on behavioral sensitization induced by peripheral or intra-ventral tegmental area administration of amphetamine. We found that ibotenic acid lesion of the medial prefrontal cortex blocked the behavioral sensitization induced by both intra-ventral tegmental area and peripheral treatment with amphetamine. In contrast, ibotenic acid lesion of the amygdala produced no effect on behavioral sensitization induced peripherally or centrally. These experiments confirmed (i) that the ventral tegmental area, where dopaminergic cell bodies are located, is a critical site for the induction of behavioral sensitization, (ii) that this process implicates the 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 sensitization to amphetamine implicates not only the mesoaccumbens dopaminergic neurons, but also other structures of the mesocorticolimbic system, such as the medial prefrontal cortex and more specifically its glutamatergic component.