Activation of D2-like receptors in rat ventral tegmental area inhibits cocaine-reinstated drug-seeking behavior

Abstract

Relapse is a hallmark of cocaine addiction. Cocaine-induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Preclinical evidence indicates that relapse to cocaine-seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because activity of dopamine neurons are regulated by D 2 -like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D 2 -like receptors in the ventral tegmental area can inhibit cocaine-induced reinstatement of extinguished cocaine-seeking behavior. Rats were trained to self-administer intravenous cocaine (0.25 mg/infusion) under a modified fixed-ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine-seeking behavior. Then the effect of quinpirole, a selective D 2 -like receptor agonist microinjected into the ventral tegmental area on cocaine-induced reinstatement was assessed. Quinpirole (0 -3.2 μg/side) dose-dependently decreased cocaineinduced reinstatement and such effects were reversed by the selective D 2 -like receptor antagonist eticlopride when co-microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D 2 -like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the prefrontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine-induced reinstatement. The role of potential changes in D 2 -like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed.

Regulation of cocaine-induced reinstatement by group II metabotropic glutamate receptors in the ventral tegmental area

“…Thus, AGS3-mediated uncoupling of mGluR2/3s and G i proteins could be a mechanism involved in enhanced glutamate release in the VTA after cocaine SA. This idea is consistent with our recent observation that activation of another G i protein-coupled receptors, D 2 -like DA receptors in the VTA produced a less potent effect on cocaineinduced reinstatement than on food-induced reinstatement (Xue et al 2011). Thus, further studies on the effect of cocaine SA on mGluR2/3-mediated signaling in the VTA are warranted.…”

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

“…Limited data suggest that D2/D3 autoreceptor function or expression may be a crucial factor contributing to drug reward. For instance, microinjection of quinpirole into the VTA, but not the SN, of rats dose-dependently decreases cocaine-induced reinstatement (Xue et al, 2011). Furthermore, the availability of midbrain D2/D3 autoreceptors is inversely correlated with drug reward and impulsivity (Bello et al, 2011;Buckholtz et al, 2010).…”

Acute fasting increases somatodendritic dopamine release in the ventral tegmental area

“…D2Rs that respond to somatodendritic dopamine release in the VTA play an important role in dopa-mine neuron function and influence numerous behaviors mediated by dopamine (Ford 2014). For example, injection of D2R agonists into the VTA decreases basal dopamine levels, inhibits food intake, stimulates conditioned-place aversion, and reduces reinstatement of cocaine self-administration (Liu et al 2008;Xue et al 2011). Recently, it has also been demonstrated that selective deletion of D2R autoreceptors in dopamine neurons (without affecting postsynaptic heteroreceptor D2Rs) increased dopamine release in the striatum and affected multiple aspects of the behavioral response to cocaine, including increased locomotor activity, conditioned-place preference, and self-administration (Anzalone et al 2012;Bello et al 2011).…”