Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices

Abstract

The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release.

Jian-Pi-Zhi-Dong-Decoction regulates the expression of glutamate transporters to attenuate glutamate excitotoxicity and exerts anti-tics effects in Tourette syndrome model rats

“…Meanwhile, a widespread interaction between DA and GLU systems has been reported. A recent study showed that intraventricular injection of DA increased the GLU levels in the brain of rats using cerebral microdialysis,55 whereas glutamate antagonist (phencyclidine) caused schizophrenia-related behavioral deficits due to DA release 56. Our findings demonstrated that Tia treatment downregulated the level of GLU in TS rats, but whether it regulates the GLU system directly or influences the DA system to improve glutamate metabolism is a question that needs to be further verified.…”

Modulation of stimulated dopamine release in rat nucleus accumbens shell by GABA in vitro: Effect of sub‐chronic phencyclidine pretreatment

“…We therefore sought to test the effect of PCP pretreatment, modeling schizophrenia on GABAergic control of dopamine release. Subchronic pretreatment with PCP, as used here, has been widely observed to cause behavioral changes resembling changes seen in schizophrenia (Cadinu et al., 2018; Javitt, 2007; Neill et al., 2010) and has been implemented as a relevant model for studying neurochemical and neurophysiological changes relevant to schizophrenia (Asif‐Malik et al., 2017; Gupta & Young, 2018; Yavas & Young, 2017, 2020). In slices taken from PCP‐pretreated rats, the level of stimulated release prior to acute drug infusion was similar to both non‐pretreated rats and saline‐pretreated rats, indicating that the pretreatment does not affect baseline stimulated release.…”

“…or saline (1 ml/kg, i.p.) twice daily (08:00 and 16:00) for 5 days, then left drug free in standard housing (as above) for at least 10 days, a procedure which produces reliable, long‐lasting behavioral changes resembling symptoms of schizophrenia (Grayson et al., 2007; Gupta & Young, 2018; Javitt, 2007; Neill et al., 2010). In each case, two saline pretreated and two PCP pretreated were housed together in the same cage.…”

“…In animals, they evoke behavioral changes which resemble schizophrenia (Javitt, 2007), providing a model with good construct validity, enabling mechanisms of dysfunction in schizophrenia to be probed in rats (Cadinu et al., 2018; Javitt, 2007; Neill et al., 2010). Rats treated with PCP twice daily for 5–7 days (termed subchronic), showed behavioral changes resembling deficits in schizophrenia (Grayson et al., 2007; Gupta & Young, 2018; Neill et al., 2010). The deficits endure long after the end of drug treatment, indicating that the changes are not simply due to the presence of the drug in the brain at the time of testing, but rather depend on long‐term conformational changes in brain physiology (Neill et al., 2010).…”

“…The deficits endure long after the end of drug treatment, indicating that the changes are not simply due to the presence of the drug in the brain at the time of testing, but rather depend on long‐term conformational changes in brain physiology (Neill et al., 2010). On this basis we have used this model extensively to probe long‐term neurochemical and physiological changes occurring after PCP pretreatment, which may indicate changes occurring in schizophrenia itself (Asif‐Malik et al., 2017; Gupta & Young, 2018; Yavas & Young, 2017, 2020).…”