Endogenous Cholinergic Inputs and Local Circuit Mechanisms Govern the Phasic Mesolimbic Dopamine Response to Nicotine
Figure 1
Scheme of the ventral tegmental area and the states of nicotinic acetylcholine receptors.
(A) Afferent inputs and circuitry of the ventral tegmental area (VTA). The GABAergic neuron population (red) inhibits locally the dopaminergic neuron population (DA, green) [40], [43], [44]. This local circuit receives excitatory glutamatergic input (blue lines) from the prefrontal cortex (PFC) [68]–[71], the laterodorsal tegmental nucleus (LDT) and the pedunculopontine tegmental nucleus (PPT) [72]–[74]. The LDT and the PPT furthermore furnish cholinergic projections (cyan lines) to the VTA [8]. nAChRs are found at presynaptic terminals of glutamatergic projections (α7-containing receptors), on GABAergic neurons (α4β2 nAChRs) and DA neurons (α4β2 nAChRs). r is a parameter introduced in the model to change continuously the dominant site of α4β2 nAChR action. Dopaminergic efferents (green) project, amongst others, to the nucleus accumbens and the PFC. (B) Two-gate model of nicotinic acetylcholine receptors. Activation (horizontal) and desensitization (vertical) of nAChRs are two independent transitions in the model, i.e, the receptor can exist in four different states: (i) deactivated/sensitized (up-left), (ii) activated/sensitized (up-right), (iii) deactivated/desensitized (down-left), and (iv) activated/desensitized (down-right). Activation is driven by Nic and ACh and induces a transition from the deactivated/sensitized to the activated/sensitized state (green), the only open state in which the receptor mediates an excitatory current. Desensitization is driven by Nic and ACh if . a and s characterize the fraction of nAChRs in the activated and the sensitized state, respectively (modified from [22]). (C) α4β2 nAChR state occupation as described by the model for different Nic and ACh concentrations (
). The area of the circles represents the fraction of receptors in each of the four states (alignment as in panel B). The occupation of receptor states is shown for long-term exposures to low (0.1 µM) and high (100 µM) ACh, without and with 1 µM nicotine. A star means that the respective state is not occupied.