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.
Figure 2.
Nicotinic acetylcholine receptor model responses to nicotine and acetylcholine.
Response properties of α4β2 (panels A,C,E) and α7 nAChRs (panels B,D,E). (A&B) Dynamics of α4β2- (A) and α7-containing nAChRs (B) in response to Nic. The dynamics of the activation, a, (purple lines) and sensitization, s, (orange lines) are shown during and after the exposure to a constant Nic concentration of 100 µM for 200 ms starting at ms. The normalized receptor activation,
, is shown in blue and is proportional to the actual current. The inset shows the dynamics of the same variables on a longer time scale. (C&D) Dose-response curves of α4β2- (C) and α7-containing nAChRs (D) in response to Nic and ACh. The peak current mediated by the receptor during a 200 ms exposure to the respective agonist concentration is shown. The responses to Nic (ACh) are depicted in blue (red). The arrows indicate physiologically relevant nicotine concentrations [11], [31]. The half-maximum effective concentrations for ACh-evoked responses are indicated by the dotted black lines. (E) Reduction of the half-maximum response evoked by ACh in the presence of 0.5 µM Nic. The half-maximum effective concentration of the peak current in the absence of Nic is
µM for α4β2, and
µM for α7 nAChRs (green bars, see C and D). The red bars show the peak current in response to the same ACh concentration in the presence of a constant concentration of
µM. See Table 1 for parameters.
Table 1.
Parameters of nAChR activation and desensitization kinetics.
Figure 3.
Model VTA responses to nicotine in vitro.
Left hand panels (A,C,E and left side of panel G) show the results on GABAergic input changes to VTA DA cells, while the panels on the right-hand side (B,D,F and right side of G) depict results on glutamatergic input increases to VTA DA cells in response to 1 µM nicotine for 2 min starting at t = 1 min. (A&B) Illustration of the simulated experimental situation during in vitro experiments. Grey shaded parts and black crosses show pharmacologically blocked transmission pathways, and the scissors illustrate the truncation of the input pathways in vitro. (C&D) Time course of GABAergic, , (C) and glutamatergic input,
, (D) changes to VTA DA neurons during and after Nic exposure (black bar on top of the panels, Nic time-course shown in insets). The increase (green) and the decrease (magenta in C) of the input currents with respect to baseline are illustrated in both panels. (E&F) Maximal change of GABAergic (E) and glutamatergic input currents (F) as a function of the Nic concentration applied. The lines show the results of the model for control conditions (in green in both panels and magenta for decrease in panel E), with α4β2 nAChRs blocked (cyan in panel E, and green in panel F), and with α7 nAChRs blocked (green and magenta in panel E, orange in panel F). The squares show experimental results adapted from [19] (E) and [18] (F) for different experimental situations : control conditions - green squares; with α7 nAChR specific antagonist - orange squares; and with antagonist for non- α7 nAChRs - cyan squares. (G) Comparison of relative input changes between model and experiment for the case of 1 µM nicotine for 2 min. Model results are shown with shaded bars and experimental results with filled bars. Both, GABAergic- (left) and glutamatergic input changes (right) are shown for the three discussed cases : control conditions - green and magenta, α4β2 nAChR blocked - cyan, and α7 nAChR blocked - orange and magenta (experimental data adapted from [18], [19];
µM and
in all panels, see Table 1 and Models section for other parameters).
Figure 4.
Model VTA responses to nicotine in vivo.
Panels on the left-hand side (A,C,E) show results of the direct stimulation scenario (,
µM,
) and panels on the right-hand side (B,D,F) depict results for disinhibition (
,
µM,
). (A&B) Illustration of the simulated experimental situation in vivo. Note the difference in α4β2 nAChR distribution between the direct stimulation (A,
) and the disinhibition case (B,
). (C&E) Normalized DA (C) and GABA neuron activity (E) in response to the application of 1 µM nicotine in case of direct stimulation. The full lines show the time course of the normalized
(C) and
(E) for three different durations of nicotine exposure,
(as indicated by the bar on top of C). The full and the dashed blue lines depict the responses for low (
µM) and high endogenous cholinergic input rates (
µM), respectively (
min). (D&F) Normalized DA (D) and GABAergic neuron activity (F) in response to 1 µM nicotine for 2 min in case of disinhibition. The full lines show the time course of the normalized
(D) and
(F) for three different maximal desensitization time constants of α4β2 nAChRs,
(as indicated in the upper panel). The full and the dashed blue lines depict the responses for high (
µM) and low cholinergic input rates (
µM), respectively (
min). (G) Comparison of model results (purple and orange bars) and experimental data (green bars) on relative DA neuron activity changes in response to 1 µM nicotine. The maximal relative increase of DA activity in wild type (
min for direct stimulation; and
min with
min for disinhibition) and mutant mice is shown (experimental data adapted from [17]). (H) Comparison of the total duration of elevated DA neuron activity with respect to the duration of Nic application,
. The duration of elevated activity is taken to be the time between the two points where
attains half-of-maximum activity (as illustrated by arrows in C and D and depicted by square and circle, respectively). This duration is plotted for direct stimulation (purple) and disinhibition (orange).
Figure 5.
Predicted dynamics of the DA neuron population in the VTA in response to varying cholinergic input rates and Nic concentrations in case of direct stimulation (A,D) and disinhibition (B,E).
Nic was applied for 10 min in the direct stimulation scenario, and for 2 min in the disinhibition scenario, whereas the endogenous ACh input rate is modeled to be constant (see text). (A&B) Temporal dynamics of DA neuron activity in response to 1 µM nicotine and varying endogenous cholinergic input rates (ACh range: 0.1-blue lines, 0.5, 1.0, 1.5, 1.77-red lines, 2.0 µM). (C) Maximal increase of DA activity in response to 1.0 µM Nic as a function of the cholinergic input rate (,
). (D&E) Temporal dynamics of DA activity in response to 0.5 µM (blue lines) and 3 µM nicotine (red lines) in case of direct stimulation (D,
,
µM,
,
), or disinhibition (E,
,
µM,
,
). (F) The maximal DA response as a function of applied Nic concentration is depicted for direct stimulation (orange line) and disinhibition (purple line). Data point (green) adapted from [17].
Figure 6.
Temporal dynamics of DA neuron activity in response to 1 µM nicotine for 2 min for different values of r and afferent input strengths.
(A) The DA response in the presence of constant low cholinergic and glutamatergic afferent input to the VTA, i.e., in vitro like conditions ( µM,
). (B) The DA response in the presence of constant high cholinergic and glutamatergic afferent input to the VTA, i.e., in vivo like conditions (
µM,
). In both panels, the distribution of α4β2 nAChRs is changed by varying the control parameter r in steps of 0.2 from 0 to 1 (as indicated). The examples with values of r as used for the direct stimulation (
, red) and disinhibition (
, blue) cases in this study are highlighted.
Figure 7.
Temporal dynamics of GABA and DA neuron activity in response to 1 µM nicotine in case α4β2 receptor desensitization is driven by Nic and ACh.
(A,C) GABA (A) and DA (C) neuron activity in the direct stimulation case (same as in Fig. 4C,E full blue lines; ,
µM,
,
) for different efficacies of ACh to drive α4β2 receptor desensitization (η given in panel A). (B,D) GABA (B) and DA (D) neuron activity in the disinhibition case (
,
µM,
,
) for different efficacies of ACh to drive α4β2 receptor desensitization (η given in panel B, see Models).