Original ArticlePositive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex
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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2023, International Review of NeurobiologyCitation Excerpt :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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