INCREASED IN-VIVO PHOSPHORYLATION STATE OF NEUROMODULIN AND SYNAPSIN-I IN STRIATUM FROM RATS TREATED WITH REPEATED AMPHETAMINE

Repeated, intermittent treatment of rats with amphetamine results in a sensitization of locomotor and stereotyped behaviors that is accompan ied by an enhancement in stimulus-induced dopamine release. The effect s of repeated treatment with amphetamine on the phosphorylation state of neuromodulin and synapsin I, proteins involved in neurotransmitter release, were investigated. Rats were injected with 2.5 mg/kg AMPH, tw ice a week for 5 weeks (intermittent treatment). One week after the la st injection, a challenge dose of 2.5 mg/kg AMPH was given 30 min befo re sacrifice. We previously reported an increase in neuromodulin phosp horylation with this sensitization paradigm. Site 3-phospho-synapsin I , site 1-phospho-synapsin I and phosphoser(41)-neuromodulin were detec ted with phosphoryla- tion state-specific antibodies. Acute treatment with amphetamine did not increase the state of synapsin phosphorylatio n at either site 1 or site 3, but both site I-phospho-synapsin I and s ite 3-phospho-synapsin I were increased (38% and 34%, respectively) af ter repeated, intermittent amphetamine. Immunoreactivity for phosphose r(41)-neuromodulin was increased by acute amphetamine. Site S-phospho- synapsin I, site 1-phospho-synapsin I and phosphoser(41) -neuromodulin were also measured in striatum from rats receiving a different regime n in which amphetamine is given in escalating doses for 4 weeks. With this regimen, behavioral sensitization and enhanced dopamine release a re exhibited in rats withdrawn 4 weeks, but not 3 days, after pretreat ment. Small but significant increases in site 3-phospho-synapsin I and phosphoser(41)-neuromodulin were found in rats withdrawn 4 weeks from the escalating dose regimen, but not in those withdrawn 3 days. The i ncrease in the phosphorylation state of synapsin I and neuromodulin re flect changes in the presynaptic signal transduction pathways which co uld play a role in the behavioral sensitization and contribute to the enhanced dopamine release reported in amphetamine-sensitized rats.