Neurotransmitter interactions in schizophrenia—therapeutic implications

109

118

Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D 2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D 2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.

Section: Effect Of Antipsychotic Drugssupporting

confidence: 89%

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Gozzi

Large

Schwarz

et al. 2007

109

118

“…Nor is it likely to be a simple additive effect, as LY354740 alone, tested in one baboon, did not cause a decrease of [ 11 C]raclopride binding. The results of this study should be discussed in the context of the model of GLU-DA interaction introduced by Carlsson (Carlsson et al, 1999;Kegeles et al, 2000). According to this model, activity of midbrain DA neurons is modulated by cortical and limbic structures via both an activating pathway and an inhibitory pathway.…”

Section: Discussionmentioning

confidence: 90%

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

Berckel

Kegeles

Waterhouse

et al. 2005

Pharmacological evidence suggests that schizophrenia is associated with increased stimulation of dopamine (DA) D 2 receptors. Recently, several groups have demonstrated that amphetamine-induced DA release is increased in schizophrenia, providing direct evidence for dysregulation of DA systems in this condition. In healthy volunteers, pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine increases amphetamine-induced DA release to levels similar to those observed in patients with schizophrenia. Therefore, the dysregulation of DA function observed in schizophrenia might be secondary to NMDA hypofunction. In this study, the regulation of this response by glutamate (GLU) transmission was further characterized by using a metabotropic glutamate (mGlu) receptor group II agonist to inhibit GLU transmission. The amphetamine-(0.5 mg/kg intravenously (i.v.)) induced decrease in [ 11 C]raclopride equilibrium-specific binding (V 3 00 ) was measured under control conditions and following pretreatment with the mGlu2/3 receptor agonist LY354740 (20 mg/kg i.v.) in four baboons. Amphetamine reduced [ 11 C]raclopride V 3 00 by 2877% under control conditions. Following LY354740 pretreatment, amphetamine-induced reduction in [ 11 C]raclopride V 3 00 was significantly enhanced (3577%, p ¼ 0.002). The enhancement of the amphetamine-induced reduction in [ 11 C]raclopride V 3 00 by LY354740 was not a simple additive effect, as LY354740 alone did not reduce [ 11 C]raclopride V 3 00 . In conclusion, the results of this study further document the involvement of GLU transmission in regulating the effect of amphetamine-induced DA release, and provide additional support to the hypothesis that the dysregulation of DA function revealed by the amphetamine challenge in schizophrenia might stem from a deficit in GLU transmission. Neuropsychopharmacology (2006) 31, 967-977.

“…We find a very marked positive correlation between change in k D 3 and improvement in negative symptoms; that is, patients with the strongest decrease in thalamic k D 3 demonstrated the most pronounced decrease in the PANSS negative symptoms subscore. The thalamus seems to play a crucial role in the pathophysiology of schizophrenic symptomatology and is probably also an important site through which the clinical effects of antipsychotics are mediated (Carlsson et al, 1999b). It is an essential structure for controlling arousal and the transmission of sensory inputFboth from the outside world as well as from internal states of the bodyFto the cerebral cortex (Carlsson et al, 1999a).…”

Section: Discussionmentioning

confidence: 99%

Subchronic Haloperidol Downregulates Dopamine Synthesis Capacity in the Brain of Schizophrenic Patients In Vivo

Gründer¹,

Vernaleken²,

Müller³

et al. 2002

103

The antipsychotic effect of neuroleptics cannot be attributed entirely to acute blockade of postsynaptic D 2 -like dopamine (DA) receptors, but may arise in conjunction with the delayed depolarization block of the presynaptic neurons and reduced DA synthesis capacity. Whereas the phenomenon of depolarization block is well established in animals, it is unknown if a similar phenomenon occurs in humans treated with neuroleptics. We hypothesized that haloperidol treatment should result in decreased DA synthesis capacity. We used 6-[ 18 F]fluoro-L-dopa (FDOPA) and positron emission tomography (PET) in conjunction with compartmental modeling to measure the relative activity of DOPA decarboxylase (DDC) (k D 3 , min À1 ) in the brain of nine unmedicated patients with schizophrenia, first in the untreated condition and again after treatment with haloperidol. Patients were administered psychometric rating scales at baseline and after treatment. Consistent with our hypothesis, there was a 25% decrease in the magnitude of k D 3 in both caudate and putamen following 5 weeks of haloperidol therapy. In addition, the magnitudes of k D 3 in cerebral cortex and thalamus were also decreased. Psychopathology as measured with standard rating scales improved significantly in all patients. The decrease of k D 3 in the thalamus was highly significantly correlated with the improvement of negative symptoms. Subchronic treatment with haloperidol decreased the activity of DDC in the brain of patients with schizophrenia. This observation is consistent with the hypothesis that the antipsychotic effect of chronic neuroleptic treatment is associated with a decrease in DA synthesis, reflecting a depolarization block of presynaptic DA neurons. We link an alteration in cerebral catecholamine metabolism in human brain with the therapeutic action of neuroleptic medication.