Table 1.
Clinical data of chronic pharmacological perturbations and comparisons with simulation results
| Pharmacological agent | Pharmacological action# | Targeted regions | Chronic effects$ | Sim% | Ref |
|---|---|---|---|---|---|
| Ethanol (5 weeks) | Increased GABA binding (positive allosteric modulator) | Brain-wide | No change in DA or ACh release to PFC; decrease release of Glu and NE to PFC | √ | [44] |
| PCP (7 days, daily) | Glu (NMDA receptor antagonist) | Brain-wide | Enhanced activation of DA neurons in VTA | √ | [45] |
| Ketamine (7 or 10 days, daily) | Glu (NMDA receptor antagonist) | Brain-wide | increased DA release to striatum and mPFC; increased 5-HT release to mPFC; increased Glu release to mPFC | √ | [46–48] |
| Nicotine (7 or 13 weeks) | ACh (nAChR agonist) | Brain-wide | Increased DA release to striatum; increased Glu release to PFC; decreased ACh release to striatum | √ | [49–51] |
| 5,7-DHT | 5-HT (lesion) | Intracerebro-ventricular | Increased firing of DA neurons in VTA | √ | [52] |
| Tph2 (heterozygote) | 5-HT (reduced 5-HT synthesis) | Brain-wide | Decreased GABA in PFC | √ | [56] |
| Fluoxetine (2 or 3 weeks, daily) | 5-HT (reuptake inhibitor) | Brain-wide | No change in DA release to PFC; increased 5-HT release to PFC; decreased firing of NE neurons in LC; decreased firing of pyramidal PFC cells | √ | [53–55] |
| HT2c (null mutant) | 5-HT (5-HT2c receptor elimination) | Brain-wide | Increased DA release from SNpc to striatum | √ | [57] |
| Olanzapine (21 days) | 5-HT (5-HT2 antagonist) & DA (D2 antagonist) | Brain-wide | Increased firing of NE neurons in LC | √ | [54] |
| Clozapine (21 days) | 5-HT (5-HT2 antagonist) & DA (D2 antagonist) | Brain-wide | Increased DA release to mPFC; no change in DA release to striatum | √ | [58–60] |
| Venlafaxine (3 weeks, daily) | 5-HT & NE (reuptake inhibitor) | Brain-wide | Increased NE, DA, and 5-HT release to PFC | √ | [62] |
| Desipramine (2 weeks, daily) | NE (reuptake inhibitor) | Brain-wide | No change in DA release to striatum; increased DA and NE release to PFC | √ | [49, 62] |
| Nomifensine (22 days, daily) | NE & DA (reuptake inhibitor) | Brain-wide | Increased DA release to striatum; no change in DA release to PFC; Increased ACh release to PFC and striatum; no change in Glu release to PFC and striatum; no change in GABA release to PFC | √ | [63] |
| Mirtazpine (21 days) | NE (alpha2 antagonist) | Brain-wide | Increased firing of 5-HT and NE neurons | √ | [65, 66] |
| 6-OHDA | DA (lesion) | SNpc | Increased firing rate of pyramidal neurons in PFC; increased firing rate of neurons in STN | √ | [64, 67–70] |
| 6-OHDA | DA (lesion) | VTA | Increased firing of NE neurons | √ | [52] |
| 6-OHDA | DA (lesion) | Intracerebro-ventricular | Decreased spontaneous firing of 5-HT neurons | √ | [52] |
#
: Action sites show which neurotransmitter systems are targets of the pharmacological agent, and mechanisms (in parentheses) indicate the exact mechanisms of actions.
$
: Abbreviations: Phencyclidine (PCP), 5,7-Dihydroxytryptamine (5,7-DHT), medial prefrontal cortex (mPFC). For other abbreviations, please refer to the legend of Figure 1.
%
: Comparisons between clinical data and model simulations marked with a check mark indicate qualitative consistency.