Abstract
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.
