Differential actions of dizocilpine (MK-801) on the mesolimbic and mesocortical dopamine systems: role of neuronal activity

The significance of impulse activity in the dopamine neurons of the ventral tegmental area for the dopamine release evoked by systemic administration of the psychotomimetic drug dizocilpine (MK-801) was investigated. Dual pro be microdialysis was utilized in freely moving rats implanted with one prob e in the ventral tegmental area and a second ipsilateral probe in either th e nucleus accumbens or the medial prefrontal cortex. Dialysates were analyz ed with high-performance liquid chromatography with electrochemical detecti on for dopamine. The ventral tegmental area was perfused with the sodium ch annel blocker tetrodotoxin (1 mu M) or vehicle (perfusion solution). A tota l of 2 h after the onset of tetrodotoxin perfusion of the ventral tegmental area, MK-801 (0.1 mg/kg) was injected subcutaneously. Tetrodotoxin perfusi on of the ventral tegmental area significantly reduced dialysate levels of dopamine both in the nucleus accumbens and the medial prefrontal cortex to approximately 30% of baseline. When given alone, MK-801 caused a significan t, i.e. 50%, increase in extracellular dopamine levels in the nucleus accum bens, and an even larger increase in the medial prefrontal cortex, i.e. 150 %. Tetrodotoxin perfusion of the ventral tegmental area completely blocked the systemic MK-801 induced increase in extracellular concentrations of dop amine in the nucleus accumbens. However, the MK-801-evoked increase in dopa mine levels in the medial prefrontal cortex was not significantly affected. Thus, the present results allow the conclusion that basal dopamine output in mesolimbic and mesocortical dopamine nerve terminal regions is predomina ntly dependent on nerve impulses generated in the ventral tegmental area. M oreover, also the MK-801 evoked dopamine release in the mesolimbic projecti on is almost entirely dependent on the impulse activity of the dopamine neu rons, in agreement with our previous results. However, the MK-801 evoked do pamine release in the mesocortical projection is, in contrast. largely inde pendent of the nerve impulse activity in the dopamine cells. The dysfunctio ns of mesolimbic and mesocortical dopamine neurons induced by systemic admi nistration of non-competitive NMDA receptor antagonists may have direct bea ring on the neurobiology of psychotic statss, in particular as regards the generation of emotional and cognitive impairments. (C) 1999 Elsevier Scienc e Ltd. All rights reserved.