Elsevier

Biological Psychiatry

Volume 62, Issue 7, 1 October 2007, Pages 739-746
Biological Psychiatry

Original Article
Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

https://doi.org/10.1016/j.biopsych.2006.12.003Get rights and content

Background

Several lines of evidence suggest that N-methyl-d-aspartate (NMDA) receptor hypofunction may be associated with schizophrenia. Activation of metabotropic glutamate 5 (mGlu5) receptors enhances NMDA receptor mediated currents in vitro, implying that allosteric modulation of mGlu5 receptors may have therapeutic efficacy for schizophrenia. The aim of this study was to determine if positive allosteric modulators of mGlu5 receptors are effective in reversing two cellular effects of NMDA receptor antagonists that are relevant to schizophrenia: increases in corticolimbic dopamine neurotransmission and disruption of neuronal activity in the prefrontal cortex (PFC).

Methods

In freely moving rats, we measured the effects of the positive modulator of mGlu5 receptor 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) alone or in combination with the NMDA antagonist MK801 on 1) spontaneous firing and bursting of medial PFC (mPFC) neurons, and 2) dopamine release as measured by microdialysis in the mPFC and nucleus accumbens (NAc).

Results

The predominant effect of CDPPB on mPFC neurons was excitatory, leading to an overall excitatory population response. Pretreatment with CDPPB prevented MK801-induced excessive firing and reduced spontaneous bursting. In contrast, CDPPB had no significant effect on basal dopamine release as compared with control rats and did not alter MK801-induced activation of dopamine release in the mPFC and NAc.

Conclusions

These results show that positive modulation of mGlu5 receptors reverses the effects of noncompetitive NMDA antagonists on cortical neuronal firing without affecting dopamine neurotransmission. Thus, these compounds may be effective in ameliorating PFC mediated behavioral abnormalities that results from NMDA receptor hypofunction.

Section snippets

Animals

A total of 76 adult male Sprague-Dawley rats (Harlan, Somerville, New Jersey), weighing 250 to 420 g were used in this study. Animals were housed on a 12-hour light/12-hour dark cycle (lights on at 07:00 am) for at least 1 week after their arrival in the animal facilities before surgery. Microdialysis and electrophysiological recordings were performed during the light phase on awake and freely moving animals. All experimental protocols were approved by the Institutional Animal Care and Use

Effects of CDPPB Treatment Alone

Single neurons showed different firing rate responses to CDPPB treatment (Figure 2A). K-means clustering identified five patterns of firing rate responses in single injection groups (CDPPB or vehicle) that included: 1) an early increase, 2) a sustained increase, 3) an early decrease, 4) a sustained decrease, and 5) no change in firing rate (Figure 2A, black lines). The distribution of these response types was significantly different between vehicle and CDPPB groups (Figure 2B, χ2 = 104.55, p <

Discussion

Positive allosteric modulation of mGlu5 receptors by CDPPB produced a predominately excitatory influence on population response and burst activity of mPFC neurons in awake rats. In contrast, CDPPB inhibited the profound excitatory effects of the NMDA antagonist MK801 on spontaneous activity of mPFC neurons. The CDPPB also normalized MK801-induced disruptions in burst activity. These effects of CDPPB were not related to changes in dopamine neurotransmission, as CDPPB alone did not change

Conclusions

Positive allosteric modulators of mGlu5 receptors have promising therapeutic potential for cognitive disorders including schizophrenia (Gasparini et al 2002, Moghaddam 2003, Marino and Conn 2006). The present study revealed that systemic treatment with CDPPB, a positive allosteric modulator of mGlu5 receptor, increased spontaneous firing and burst activity of PFC neurons in awake rats, suggesting that this class of compounds influences both the rate and pattern of firing of cortical neurons.

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      The recent targeting of an allosteric modulatory site on mGlu5 receptors, which potentiates receptor function, has been shown to improve cognitive performance of mice on the Morris water maze, five-choice serial reaction time test and novel object recognition test (Campbell et al., 2004; Schlumberger, Pietraszek, Gravius, & Danysz, 2010). Specifically, the mGlu5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazon-5-yl)benzamide (CDPPB) has been found to promote bursting activity and enhance firing capabilities of neurons within the PFC (Lecourtier, Homayoun, Tamagnan, & Moghaddam, 2007). Such an effect would elevate neuronal excitation, intracellular calcium levels and subsequent gene expression, which would help induce LTP.

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      We found that the CDPPB, a positive allosteric modulator of mGluR5, decreased K+-stimulated release of dopamine at all doses tested: to our knowledge, our study is the first to report the effect of mGluR5 activation on K+-stimulated dopamine release in NAc shell. This is consistent with the report that the mGluR5 antagonist, MPEP, enhanced dopamine release in the prefrontal cortex (Homayoun and Moghaddam, 2010), but contrary to the study of Lecourtier et al. (2007) who failed to show any effect of CDPPB on dopamine release in frontal cortex in vivo. However, the authors themselves suggested that their finding was ambiguous, as any drug-induced decrease would have been masked by a simultaneous increase caused by the dimethyl sulfoxide (DMSO) vehicle (Lecourtier et al., 2007).

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