Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control

Abstract

Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson's disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical and subcortical areas. Finally, we will delineate how the effect of DA on dendritic spines places this molecule at the interface between the motor and the cognitive systems. Specifically, we will be focusing on PD, vascular dementia, and schizophrenia.

Keywords: LTD; LTP; Parkinson’s disease; dopamine; motor control; reward; schizophrenia; synaptic plasticity; vascular dementia.

Figure 1

A simplified schematic of the major connections to and from the ventral tegmental area (VTA) and substantia nigra (SN) in the rodent brain. The primary reward circuit includes DAergic projections from the VTA to the nucleus accumbens (nAc), which release dopamine (DA) in response to reward-related stimuli. The nAc receives dense innervation from glutamatergic neurons from the medial prefrontal cortex (mPFC), hippocampus (Hipp) and amygdala (Amy), as well as other regions (Lateral Hypothalamus, LH). The caudate and putamen nuclei of striatum receive dense innervation from zona compacta of the SN and from PFC. The DAergic pathways control attention, addiction, reward, wakefulness, arousal, memory formation and memory consolidation. The illustration was prepared from scratch and created with our original design using Biorender.com.

Figure 2

Medium spiny neurons of nucleus accumbens (nAc) receive glutamatergic inputs from medial prefrontal cortex (mPFC) hippocampus and amygdala (Amy) and DAergic inputs from VTA. Glutamate acts on glutamate receptors (AMPA, NMDA), the activation of these receptors is responsible for basal excitatory synaptic transmission and many forms of synaptic plasticity such as Long-Term Potentiation (LTP) and Long-Term Depression (LTD). DA neurons from VTA project to nAc. Dopamine (DA) is synthetized from amino acid tyrosine; the tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, catalyzes the addition of a hydroxyl group to the meta position of tyrosine, yielding L-DOPA. The latter is rapidly converted to DA by dopa decarboxylase, which is located in the cytoplasm. After synthesis, the vesicular monoamine transporter 2 (VMAT2) transports DA from the cytoplasmic space into synaptic vesicles within presynaptic terminals. Once released, the DA can bind to and activate both presynaptic and postsynaptic DAergic receptors, D1 and D2-like receptors. D1R-like receptors generally couple to the Gs proteins that stimulate adenylate cyclase (AC) and cyclic adenosine monophosphate production. Conversely, D2R-like receptors by coupling to Gi proteins, induce inhibition of AC and PKA-dependent pathways. DA is taken back up into DAergic presynaptic terminals by the DA transporter (DAT). DA can modulate the postsynaptic terminal binding to D1-like receptors can potentiate AMPA and NMDA currents, and stimulate cAMP-dependent signaling. DA binding to D2-like receptors reduce AMPA and NMDA currents and inhibit cAMP-dependent signaling cascades. The illustration was prepared from scratch and created with our original design using Biorender.com.