Influence of kynurenic acid on dopamine neurotransmission : implications for schizophrenia

Kynurenic acid (KYNA) belongs to the kynurenines, a group of metabolically related compounds derived from the amino acid tryptophan. It is an antagonist of glutamate- and α7 nicotinic acetylcholine (α7nACh) receptors. Increased levels of KYNA have been observed in the cerebrospinal fluid and postmortem brains of patients with schizophrenia. An increased dopamine neurotransmission is suggested to underlie pivotal symptoms in schizophrenia and patients show an augmented dopamine response to amphetamine administration. Previous studies reveal that elevated levels of brain KYNA increase the firing activity of midbrain dopamine neurons. The aims of the present thesis were to investigate a) the receptors involved in the excitatory action of KYNA on midbrain dopamine neurons and b) the influence of elevated brain KYNA levels on the dopamine response to amphetamine.

Single unit recording techniques and microdialysis were used for measuring dopamine firing and terminal efflux, respectively. The excitatory effects on ventral tegmental area (VTA) dopamine neurons observed in rats with elevated levels of KYNA were mimicked by administration of 4-chlorokynurenine (4-CL-KYN). This compound is transformed in situ to 7-CL-KYNA, which specifically blocks the glycine-site of the NMDA-receptor without affecting α7nACh receptors. Further, administration of the selective NMDA receptor antagonist SDZ 220-581 also increased dopamine firing, while administration of the selective α7nACh receptor antagonist methyllycaconitin (MLA) was associated with a decreased VTA dopamine firing. These results argue that the excitatory effect on midbrain dopamine neurons by elevation of brain KYNA, is specifically related to a blockade of NMDA receptors.

Subchronic, but not acute, elevation of brain KYNA was associated with an enhancement of the amphetamine-induced dopamine response, with regard to both release and firing. This potentiated action of amphetamine on dopamine release appears related to an attenuated ability of the drug to inhibit firing of VTA dopamine neurons. Altogether, the present results support the hypothesis that increased levels of brain KYNA, potentiate the amphetamine response in VTA dopamine neurons primarily through a blockade of glutamatergic receptors, rather than cholinergic receptors. A reduced responsiveness of VTA dopamine neurons toward the inhibitory action of amphetamine might partly explain the excessive dopamine efflux occurring in a situation of elevated brain KYNA. Given the similarities in amphetamine response between patients with schizophrenia and rats with subchronically elevated levels of KYNA, one may propose that the latter condition may serve as a valuable animal model of schizophrenia.

List of scientific papers

I. Linderholm KR, ANDERSSON AS, Olsson S, Olsson E, Snoddgrass R, Engberg G, Erhardt S (2007) Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: A pharmacological analysis. Neuropharmacology 53: 918-924.
https://doi.org/10.1016/j.neuropharm.2007.09.003

II. Olsson SK, ANDERSSON AS, Linderholm KR, Holtze M, Nilsson-Todd LK, Schwieler L, Olsson E, Larsson K, Engberg G, Erhardt S (2009). Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: Implications for schizophrenia. International Journal of Neuropsychopharmacology 12: 501-512.
https://doi.org/10.1017/S1461145708009383