Role of Dopaminergic System in Core Part of Nucleus Accumbens in Hyperlocomotion and Rearing Induced by MK-801 in Rats: A Behavioral and In Vivo Microdialysis Study

Abstract

ABSTRACT-We investigated modification of the MK-801 effect on motor activity and extracellular amines concentration by 6-hydroxydopamine (6-OHDA)-induced lesion of core nucleus accumbens (cACC) of rats. In vivo microdialysis-HPLC showed that the concentrations (fmol /ml) of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and serotonin were 0.738 ± 0.135, 155.34 ± 41.01 and 0.334 ± 0.024, respectively, in the cACC of intact rats. The DOPAC /DA ratio was 264.24 ± 94.01. Unilateral lesion of the cACC with 6-OHDA (8 mg/ml) substantially reduced DA (-93%) and DOPAC (-97%) in desipramine (30 mg /kg, i.p.)-pretreated rats (6-OHDA+DMI rats) as compared to the 65% reduction rate of both amines in salinepretreated rats (6-OHDA+saline rats). Moreover, DOPAC was reduced by 72% in 6-OHDA+DMI rats. MK-801 increased DOPAC (426 -467%) and DOPAC /DA ratio (180 -230%) in intact rats. On the other hand, MK-801 increased DA by 154% and 505% in 6-OHDA+saline and 6-OHDA+DMI rats, respectively. 6-OHDA reduced the effect of MK-801 on DOPAC and DOPAC /DA ratio. In the behavioral studies, MK-801 (0.01 -0.3 mg /kg, i.p.) increased locomotor activity and rearing of intact rats. Bilateral 6-OHDA+DMI lesion of the cACC caused greater reduction in the effect of MK-801 (0.1 mg /kg) than that of the shell nucleus accumbens. These results suggest that increased extracellular DOPAC concentration (but not DA) and DOPAC /DA ratio in the cACC plays an important role in MK-801-hyperactivity.Keywords: MK-801, Core nucleus accumbens (rat), Microdialysis, Motor activityThe nucleus accumbens (ACC) is a part of the mesocortical and mesolimbic dopaminergic system. The ACC receives dopaminergic inputs from the ventral tegmental area (VTA) and glutamatergic inputs that originate from cortical regions (including medial frontal), amygdala and midline thalamus (1). The ACC is involved in a variety of behavioral activities. The dopaminergic system in the ACC plays an important role in control of spontaneous, psychostimulants (2)-and MK-801 (3 -6)-induced locomotor hyperactivity. On the other hand, the allocortical-originated glutamatergic afferents could modulate the psychomotor activation and drug reinforcement (7). Moreover, the glutamatergic and dopaminergic systems not only separately alter the behavioral effects but could also act by interacting and modulating the function of each other. A functional interaction has been reported between the glutamatergic system (via Nmethyl-D-aspartate (NMDA) receptors) and the dopaminergic system at the striatal levels (8) with a negative modulatory effect of the glutamatergic system on the dopaminergic one (9). The consequence of glutamate block depends on which of glutamate receptors are blocked. In the ACC, it is suggested that antagonists that block only NMDA autoreceptors increase synaptic glutamate level and disinhibit dopaminergic terminals. On the other hand, NMDA and non-NMDA antagonists that block both the glutamate autoreceptors and postsynaptic receptors inactivate the dopaminergic terminals (10).Cytoarchite...

Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity

“…In the locomotor activity portion of the current study, we demonstrated that systemic treatment with MK-801 induced hyperlocomotion in a manner that is consistent with published literature ( Amalric et al, 1994 ; Ogren and Goldstein, 1994 ; Hatip-Al-khatib et al, 2001 ; Scorza et al, 2008 ).…”

“… Scorza et al (2008) demonstrated that systemic MK-801 injections induced robust locomotor increases, and that electrolytic mPFC lesions did not alter MK-801-induced hyperlocomotion. However, MK-801 infusions into the NAc increased locomotor behavior ( Raffa et al, 1989 ), and 6-OHDA lesions of the NAc block systemic MK-801-induced hyperlocomotion ( Hatip-Al-khatib et al, 2001 ). Taken together, these data suggest that although MK-801-induced attention impairment are mediated in part by the frontal cortex, its effects on locomotion are at least partially mediated by subcortical regions such as the NAc.…”

“…This mechanism would likely be active in the mPFC ( Riga et al, 2016 , 2017 ), a brain region that mediates at least some MK-801 effects on attention performance ( Totah et al, 2009 ; Pehrson et al, 2013a ; Auger et al, 2017 ) but is irrelevant for MK-801’s locomotor effects. Furthermore, vortioxetine’s 5-HT 3 receptor-dependent disinhibitory effects would be inactive in the NAc, which may mediate a portion of MK-801-induced hyperlocomotion ( Raffa et al, 1989 ; Hatip-Al-khatib et al, 2001 ). Thus, it is possible that the observed selective interaction between vortioxetine and MK-801 is caused by regionally circumscribed increases of excitatory neurotransmission by vortioxetine.…”

Combined administration of an mGlu2/3 receptor agonist and a 5-HT2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants

“…In support of this, lesions of the dopamine-containing cell bodies, as well as administration of dopamine synthesis inhibitors have been shown to attenuate the acute psychomotor-activating effects of stimulants (Dominic and Moore 1969;Hatip-Al-khati et al 2001;Hollister et al 1974;Ouagazzal et al 1994;Weissman and Koe 1965;Weissman et al 1966, but see Carlsson and Carlsson 1989). Furthermore, dopamine receptor antagonists block the psychomotor-activating effects of amphetamine and MK-801 (Hoffman 1992;Maj et al 1972;Schlechter and Butcher 1972) and stimulant-induced psychomotor activation is greatly attenuated in D1 and D2 dopamine receptor knockout mice (Chausmer et al 2002;Miyamoto et al 2001;Xu et al 2000).…”