Paladini, C. A. | bioRxiv Science

bioRxiv2018

Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

BackgroundThe D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinsons disease, and substance use disorders. However, studies investigating the modulatory impact of D3R antagonism on dopamine neurotransmission or the effects drugs of abuse have produced mixed results, in part because D3R-targeted compounds often also interact with D2 receptors (D2R). The purpose of this study was to compare the consequences of selective D2R or D3R antagonism on the behavioral effects of cocaine in mice, and to identify the neurobiological mechanisms underlying their modulatory effects.\n\nMethodsWe characterized the effects of selective D2R or D3R antagonism in mice on 1) basal and cocaine-induced locomotor activity, 2) presynaptic dopamine release and clearance in the nucleus accumbens using ex vivo fast scan cyclic voltammetry, and 3) dopamine-mediated signaling in D1-expressing and D2-expressing medium spiny neurons using ex vivo electrophysiology.\n\nResultsPretreatment with the selective D2R antagonist L-741,626 attenuated, while pretreatment with the selective D3R antagonist PG01037 enhanced, the locomotor-activating effects of acute and repeated cocaine administration. While both antagonists potentiated cocaine-induced increases in presynaptic DA release, D3R blockade uniquely facilitated DA-mediated excitation of D1-expressing medium spiny neurons in the nucleus accumbens.\n\nConclusionsSelective D3R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D2R antagonism or nonselective D2-like receptor antagonists, likely by facilitating D1-mediated excitation in the nucleus accumbens. These findings provide important insights into the neuropharmacological actions of D3R antagonists on mesolimbic dopamine neurotransmission.

neuroscience↗

bioRxiv2018

Ventral tegmental area astrocytes orchestrate avoidance and approach behavior

The ventral tegmental area (VTA) is a heterogeneous midbrain structure, containing neurons and astrocytes, that coordinates approach and avoidance behaviors by integrating activity from numerous afferents. Within neuron-astrocyte networks, astrocytes control signals from distinct afferents in a circuit-specific manner, but whether this capacity scales up to drive motivated behavior has been undetermined. Using genetic and optical dissection strategies in vitro and during behavior we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance. In this circuit, VTA astrocytes facilitate excitation of local GABA neurons to increase inhibition of dopamine neurons. The increased inhibition of dopamine neurons elicits real-time and learned avoidance behavior that is sufficient to impede expression of learned preference for reward. Despite the large number of functions performed by astrocytes, loss of one glutamate transporter (GLT-1) from VTA astrocytes selectively blocks these avoidance behaviors and spares preference for reward. Thus, VTA astrocytes selectively regulate excitation of local GABA neurons to drive a distinct learned avoidance circuit that opposes learned approach behavior.

neuroscience↗