Prefrontal Dopamine in Flexible Adaptation to Environmental Changes: A Game for Two Players

Abstract

Deficits in cognitive flexibility have been characterized in affective, anxiety, and neurodegenerative disorders. This paper reviews data, mainly from studies on animal models, that support the existence of a cortical-striatal brain circuit modulated by dopamine (DA), playing a major role in cognitive/behavioral flexibility. Moreover, we reviewed clinical findings supporting misfunctioning of this circuit in Parkinson's disease that could be responsible for some important non-motoric symptoms. The reviewed findings point to a role of catecholaminergic transmission in the medial prefrontal cortex (mpFC) in modulating DA's availability in the nucleus accumbens (NAc), as well as a role of NAc DA in modulating the motivational value of natural and conditioned stimuli. The review section is accompanied by a preliminary experiment aimed at testing weather the extinction of a simple Pavlovian association fosters increased DA transmission in the mpFC and inhibition of DA transmission in the NAc.

Keywords: dopamine; extinction; goal-directed; medial prefrontal cortex; nucleus accumbens; therapy.

Figure 1

Schematic representation of the main brain areas and connections of interest in this review: Dopaminergic neurons from the ventral tegmental area (VTA) project to the medial prefrontal cortex (mpFC)’s prelimbic (PL) and infralimbic (IL) subregions, along with the nucleus accumbens shell and core (NAcSh and NAcCo, respectively), all involved in specific ways in cognition, emotion, and motivation finalized to adaptive behavior. Dopamine projections from the substantia nigra pars compacta (SNpc) to the striatum (caudate–putamen, CP) are involved in voluntary movements, and their crucial role in Parkinson’s disease (PD) is well known. Moreover, the nigrostriatal system is crucial in behavioral disorders characterized by loss of flexibility, as well as in compulsive behavior characterizing neurodegenerative (PD) and neuropsychiatric disorders. Dopaminergic neurons in these brainstem regions receive direct and indirect excitatory glutamatergic afferents from the prefrontal cortex. Norepinephrinergic neurons in the locus coeruleus (LC) project to the mpFC where, synergically with dopamine, they modulate dopamine transmission in the accumbens, forming the prefrontal/accumbal catecholamine system [26]. The LC modulates the VTA, thus influencing dopamine transmission. DA: dopamine. NE: norepinephrine. GLU: glutamate.

Figure 2

Schematic drawing of the main prefrontal corticolimbic connections possibly involved in the attribution of motivational salience to stimuli, or in salience devaluation involved in extinction. In the present review, we focused on the prelimbic cortex (PL)’s regulation of dopamine in the mesoaccumbens; however, other brain areas and neurotransmitters are likely to play a role (see the limitations in the Discussion section). mpFC, medial prefrontal cortex; PL, prelimbic; IL, infralimbic; NAc, nucleus accumbens; Sh, shell; Co, core; LC, locus coeruleus; VTA, ventral tegmental area; AMY, amygdala; BLA, basolateral; CeA, central nucleus; NE, norepinephrine; DA, dopamine; GLU, glutamate; GABA, γ-aminobutyric acid present in some brain areas, represented by a G close to each area. Sky blue arrows represent reciprocal connections between the amygdala and other brain areas.

Figure 3

Effects of 80 min of re-exposure to CS+ or CS− on DA outflow in the prelimbic prefrontal cortex (PL) and nucleus accumbens core (NAcCo). CS+ = chamber associated with AMPH. CS− = chamber associated with saline. Results are expressed as pg/20 µL concentration (means ± SE); * p < 0.05 in comparison with basal levels, # p < 0.01 in comparison with CS− in the corresponding time block.

Figure 4

Schematic representation of our hypothesis of prefrontal (PL) dopamine (DA) modulation of DA transmission in the nucleus accumbens core (NAcCo). An inverse relationship between DA transmission in the PL and NAcCo modulates the goal values. High (+) DA in the PL causes a decrease (−) in DA in the NAcCo and a goal devaluation (low DA and goal devaluation in grey). The small rectangle shows the inverse relationship.