Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

Abstract

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and a7* nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.

The metabolic syndrome in schizophrenia: is inflammation a contributing cause?

“…By blocking the NMDA glutamate and the alpha-7 nicotinic acid receptors psychotic symptoms could result (Schwieler and Erhardt, 2003). There is also experimental evidence to show that, at least in the rat, micro-molar concentrations of KYNA cause a disruption of the auditory sensory gating system (Shepard et al, 2003).…”

Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia

“…28,29 Pharmacologically altered levels of KYNA have also been shown to influence brain dopaminergic, cholinergic, and glutamatergic terminal efflux 18,19,23,32 as well as the pharmacological response to several drugs, eg, nicotine, clozapine, and amphetamine. 27,29,31,33,34 Furthermore, several studies during the last years also suggest a critical role of KYNA in cognitive functions. [8][9][10][11]21 Interestingly, mice with a targeted deletion of kynurenine aminotransferase II resulting in low levels of endogenous KYNA display increased performance in cognitive tests.…”

Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

“…However, the present data suggest that more prolonged exposure to nicotine may have the opposite, detrimental effects on sensory and cognitive modalities since brain KYNA levels are elevated (cf Shepard et al, 2003). In fact, even relatively modest increases in brain KYNA are known to significantly influence the electrophysiological properties of monoaminergic neurons (Erhardt et al, 2000(Erhardt et al, , 2001b(Erhardt et al, , 2002Schwieler and Erhardt, 2003).…”

“…It will be especially important to evaluate whether concurrent treatment with antipsychotic drugs influences nicotine-induced changes in brain KYNA. Thus, neuroleptics are known to have reciprocal interactions with nicotine (Jann et al, 1986;Miller et al, 1990;Lee et al, 2001), affect smoking behavior (George et al, 1995) and, when administered chronically, reduce brain KYNA levels in rats (Ceresoli-Borroni et al, 1999b; cf also Schwieler and Erhardt, 2003). Evidence for interactions between prolonged nicotine and neuroleptic treatments in determining brain KYNA formation would further support the suggestion (Court et al, 1998) that smoking history be carefully assessed and considered in future biochemical studies in schizophrenic individuals.…”