Differential effects of endomorphin-1 and-2 on amphetamine sensitization: Neurochemical and behavioral aspects

Mu-opioid receptors are known to modulate mesolimbic dopaminergic activity in the ventral tegmental area via disinhibition of GABA-containing neurons. Recently, two novel tetrapeptides, endomorphin-1 and endomorphin-2, were i dentified in the mammalian brain and reported to have high binding affiniti es toward mu -opioid receptors. To determine if endomorphins would modulate the development of amphetamine sensitization, we administered endomorphins locally into the rat brain followed by behavioral and neurochemical examin ations. The results indicate that rats pretreated with endomorphin-1 or -2 (5 mug per side for 7 days) in the ventral tegmental area developed locomot or sensitization to the challenge injection of amphetamine (1 mg/kg). On th e other hand, when endomorphins were given in the lateral ventricle (20 mug for 5 days) of amphetamine-sensitized rats (5 mg/kg X 14 days) during the withdrawal period (w5-w9), neither peptide had a modulatory effect on locom otor sensitization. Biochemical analyses revealed that treatment with endom orphins in the ventral tegmental area significantly increased the levels of glutamate in the medial prefrontal cortex and ventral and dorsal striatum to levels comparable to those observed in the amphetamine-sensitized rats. In the same animals, endomorphins also caused decreases in the levels of se rotonin and its metabolite, 5-hydroxyindoleacetic acid, in the medial prefr ontal cortex. Interestingly, although there was no behavioral significance, endomorphin-1 treatment in the lateral ventricle of control and amphetamin e-sensitized rats during withdrawal resulted in decreases of GABA, aspartat e, dopamine, and its metabolite 3,4-dihydroxyphenylacetic acid in the ventr al striatum. We conclude that endomorphins, by stimulating the mu -opioid r eceptors in the ventral tegmental area, could sensitize the behavioral resp onse to amphetamine. The results also demonstrate that there are differenti al responses between endomorphin-1 and -2 on behavioral amphetamine sensiti zation and the underlying neurochemical substrates. (C) 2001 Wiley-Liss, In c.