The phencyclidine model of schizophrenia : dysregulation of brain dopamine systems induced by NMDA receptor antagonists

Non-competitive NMDA receptor antagonists, such as phencyclidine (PCP) and dizocilpine (MK-801) can even acutely induce a drug induced psychotic state which closely resembles schizophrenia. The midbrain dopamine (DA) neurons, which originate in the ventral tegmental area (VTA), are involved in motivational, attentional and cognitive processes, and have also been profoundly implicated in schizophrenia. Therefore, the present work analyzed, in detail, the effects of these psychotomimetics on the mesocorticolimbic DA neurons in the rat and associated behavioral significance as well as potential reversal by different types of drugs; the objectives being to reveal potential pathophysiological mechanisms underlying psychotic states and to assist the development of improved pharmacotherapy in schizophrenia.

DA neuronal activity was studied by means of single cell recordings in vivo and DA and neurotensin (NT) release in nerve terminal regions was assessed with microdialysis in freely moving animals coupled to HPLC and RIA methodology. Behavioral techniques included measurements of locomotor activity, conditioned avoidance response (CAR) and catalepsy. Systemic administration of PCP and MK-801 produced an increased firing rate and decreased variability of firing in DA neurons. Burst firing was differentially affected in different subpopulations of VTA DA cells. A high frequency, burst-like firing pattern was obtained in neurons projecting to subcortical sites, e.g. to the nucleus accumbens (NAC). In contrast, burst firing was attenuated in DA cells which largely project to the medial prefrontal cortex (MPFC). PCP increased release of DA and the colocalized peptide NT in both the ventral striatum and the MPFC. The MK-801 evoked DA output in the NAC was blocked by inhibition of DA nerve impulse generation or by local antagonism of AMPA and kainate receptors in the VTA, a procedure which also blocked the locomotor stimulation. The MK-801 evoked DA output in the MPFC was, in contrast, not affected by inhibition of nerve impulses in the VTA. Pretreatment with the [alpha]1-adrenoceptor antagonist prazosin also antagonized the MK-801 induced increase in DA output in the NAC, and associated locomotor stimulation. Finally, systemic administration of the AMPA receptor antagonist LY326325 was found to specifically suppress the CAR without affecting escape behavior, and did not cause catalepsy.

PCP and MK-801 thus profoundly dysregulate mesocortical and mesolimbic DA neurons in a differential manner. The drugs cause a pronounced augmentation of mesocortical DA output, that is independent of nerve impulse activity, and is instead mediated at the nerve terminal level. In contrast, a nerve impulse dependent increase in mesolimbic DA output is obtained by systemic MK-801, that seems elicited in the VTA by AMPA and/or kainate receptor activation. Since both the [alpha]1-adrenoceptor antagonist and the AMPA receptor antagonist effectively reversed several of the behavioral and biochemical correlates to dysregulated mesocorticolimbic DA system induced by PCP-like drugs, an antipsychotic potential of both types of drugs is indicated, especially as shown by the suppression of CAR by LY326325.

List of scientific papers

I. Pawlowski L, Mathe JM, Svensson TH (1990). Phencyclidine activates rat A10 dopamine neurons but reduces burst activity and causes regularization of firing. Acta Physiol Scand. Jul;139(3):529-30.
https://pubmed.ncbi.nlm.nih.gov/91050618

II. Murase S, Mathe JM, Grenhoff J, Svensson TH (1993). Effects of dizocilpine (MK-801) on rat midbrain dopamine cell activity: differential actions on firing pattern related to anatomical localization. J Neural Transm Gen Sect. 91(1):13-25.
https://pubmed.ncbi.nlm.nih.gov/93199740

III. Hertel P, Mathe JM, Nomikos GG, Iurlo M, Mathe AA, Svensson TH (1995). Effects of D-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat. Behav Brain Res. Dec 14;72(1-2):103-14.
https://pubmed.ncbi.nlm.nih.gov/96380850

IV. Mathé JM, Nomikos GG, Hildebrand BE, Hertel P, Svensson TH (1996). Prazosin inhibits MK-801-induced hyperlocomotion and dopamine release in the nucleus accumbens. Eur J Pharmacol. Aug 1;309(1):1-11.
https://pubmed.ncbi.nlm.nih.gov/97018069

V. Mathé JM, Nomikos GG, Schilström B, Svensson TH (1998). Non-NMDA excitatory amino acid receptors in the ventral tegmental area mediate systemic dizocilpine (MK-801) induced hyperlocomotion and dopamine release in the nucleus accumbens. J Neurosci Res. Mar 1;51(5):583-92.
https://pubmed.ncbi.nlm.nih.gov/98170953

VI. Mathé JM, Nomikos GG, Hygge Blakeman K, Svensson TH (1998). Differential actions of dizocilpine (MK-801) on the mesolimbic and mesocortical dopamine systems: role of neuronal activity. [Submitted]

VII. Mathé JM, Fagerquist MV, Svensson TH (1998). Antipsychotic-like effects of the AMPA and kainate receptor antagonist LY326325 as indicated by suppression of conditioned avoidance response in the rat. [Manuscript]