There are multiple pathways to psychosis and schizophrenia, all associated with dopamine supersensitivity and elevated amounts of D2High receptors (Seeman et al., 2005; Seeman et al., 2006; Seeman, 2008; Seeman, 2010; Seeman, 2009). The present paper by Higley and Sabatini is consistent with the multiple-pathway hypothesis. They show that the dopamine D2 receptor, which is the main target for antipsychotic drugs (Seeman et al., 1975; Seeman et al., 1976), regulates the multiple pathways of glutamate and adenosine transmission. Their work is also consistent with the fact that a glutamate agonist can treat schizophrenia (Patil et al., 2007), especially when such a glutamate drug can stimulate glutamate receptors and partly inhibit dopamine D2High receptors (Seeman, 2008; Seeman, 2009; Seeman and Guan, 2009).
Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Männistö PT, Robinson S, Palmiter RD, Tallerico T. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005;102:3513-8. Abstract
Seeman P, Schwarz J, Chen JF, Szechtman H, Perreault M, McKnight GS, Roder JC, Quirion R, Boksa P, Srivastava LK, Yanai K, Weinshenker D, Sumiyoshi T. Psychosis pathways converge via D2High dopamine receptors. Synapse. 2006;60:319-46. Abstract
Seeman P. All psychotic roads lead to increased D2High dopamine receptors. A perspective. Clinical Schizophrenia & Related Psychoses. 2008 Jan;351-5.
Seeman P. All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2High receptors. CNS Neuroscience & Therapeutics. Epub 2010 June 18. Abstract
Seeman P. Schizophrenia model of elevated D2High receptors: Haloperidol reverses the amphetamine-induced elevation in dopamine D2High. Schizophr Res. 2009;91:191-2. Abstract
Seeman P, Chau-Wong M, Tedesco J, Wong K Brain receptors for antipsychotic drugs and dopamine: Direct binding assays. Proc Natl Acad Sci U S A. 1975;72:4376-80. Abstract
Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261:717-9. Abstract
Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007 Sep;13(9):1102-7. Epub 2007 Sep. 2. Erratum in: Nat Med. 2007 Oct;13(10):1264. Abstract
Seeman P. Glutamate agonists for schizophrenia stimulate dopamine D2High receptors. Schizophr Res. 2008;99(1-3):373-4. Abstract
Seeman P. Glutamate agonists for treating schizophrenia have affinity for dopamine D2High and D3 receptors. Synapse. 2009;63(8):705-9. Abstract
Seeman P, Guan H-C. Glutamate agonist LY 404,039 for treating schizophrenia has affinity for the dopamine D2High receptor. Synapse. 2009;63:935-9. Abs
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In a recent study by Kravitz et al., 2010, it is shown, also with optogenetic techniques (channelrhodopsin expressed in direct or indirect medium spiny neurons—MSNs—of transgenic mice), that specific stimulation of D2R-expressing indirect pathway MSNs (with an implanted laser) causes akinesia and rigidity in the animals as long as the laser stimulus is on. Once the illumination is turned off, the behavior returns to normal. Moreover, they show that stimulation of D1R-expressing direct pathway MSNs cause the opposite: hyperkinesia and hyperactivity. Furthermore, if a partial parkinsonism is induced in these mice, direct pathway stimulation rescues the animals from the pathological condition. These experiments give strong support to the basal ganglia pathophysiological model launched by Albin et al. (1989) more than 20 years ago. This model is based in the following assumptions: 1) dopamine acting on D1R stimulates direct pathway MSNs firing, and that facilitates movement; 2) dopamine acting on D2R represses indirect pathway MSNs, and that facilitates movement. Either D1R failing to facilitate or D2R failing to repress neuronal excitability results in akinesia and rigidity: less movement. But how does D2R action repress indirect pathway MSNs?
Higley and Sabatini, 2010, show without doubt that one way is the following: D2R inhibits calcium entry in MSNs, particularly in their dendrites and spines, where most synaptic inputs arrive. Inhibition of calcium entry would then repress the excitability of D2R-expressing MSNs from the indirect pathway. Calcium entry into D2R-expressing indirect pathway MSNs is controlled by modulating two effectors: NMDAR and R-type Ca2+ channels—a synaptic (extrinsic) channel and a voltage-gated (intrinsic) calcium channel. In addition, inhibition of Ca2+ entry by D2R can be compensated for by A2AR-activation, which enhances Ca2+ entry. Experiments to delimit the signaling cascades involved were preliminary and need further work to be completely established.
Thus, in the same year (2010), the classical basal ganglia model of Albin et al. (1989) receives two strong empirical supports: first, normal behavior is due to the balance between direct and indirect basal ganglia pathways (Kravitz et al., 2010), and, second, indirect pathway excitability induced specifically by cortical afferents activation and subsequent Ca2+ inflow is reduced by D2R activation (Higley and Sabatini, 2010). Cortical terminals expressing channelrhodopsin on a single spine are stimulated by light and/or spine/dendritic synapses are stimulated directly by released caged glutamate. Thus, both pre- and post-synaptic components of the D2R-response are tackled.
Hyperdopaminergic syndromes (e.g., schizophrenia) monitored in rodents by evaluating hyperkinesia and hyperactivity, among other tests, are due to a dopamine excess acting on D1R-expressing MSNs (see discussion above). Conversely hypodopaminergic syndromes (e.g., parkinsonisms) are assumed to be due to lack of dopamine that impedes activation of D2R expressed in indirect pathway MSNs, thus abolishing the control over the excitability of MSNs, which therefore become hyperexcitable and begin to lose spines and synapses (A HREF="/pap/annotation.asp?powID=142792">Day et al., 2008). What does hyperexcitability mean here? According to Higley and Sabatini, Ca2+ inflow is not controlled and an excess of it occurs. Diminished D2R leads to D2R-expressing indirect pathway MSNs’ hyperexcitability, leading to akinesia and rigidity.
However, several antipsychotics act by inhibiting D2R, thus mimicking a lack of dopamine on these receptors, increasing indirect pathway activation, and thus overpowering direct pathway activation. Therefore, D2R inhibition has collateral actions, i.e., parkinsonism. Conversely, Kravitz et al. (2010) suggest that to alleviate parkinsonian motor deficits, one should overactivate D1R-expressing neurons to overcome hyperexcitable D2R-expressing neurons. It can be predicted, then, that a probable collateral action would be to cause the symptoms of schizophrenia.
Thus, one cannot focus on just one of these receptors or pathways (direct or indirect) to alleviate a given syndrome, as they represent a control system that dynamically reaches a balance between them in every situation. Seeing the problem this way poses a hard challenge for treating pathophysiology.
A complication for Higley and Sabatini's work is that at some stimulation protocols, NMDAR-antagonists increase, rather than decrease excitability. The same happens with R-type channels. The explanation is that Ca2+ entry activates SK-channels, and, in fact, Ca2+ entry may serve to decrease excitability. However, with other stimulation protocols, EPSPs and EPSCs go along (increase) with Ca2+ inflow; thus, Ca2+ entry increases excitability. The problem is: what really happens physiologically?
Kravitz et al., 2010 could not answer this question, because their dopamine experiments involved activity on the microcircuit, and thus their results were unpredictable or unexplainable. However, some additional work may get around this setback: first, supra-threshold cortical stimulation, that is, a stimulus capable of generating firing of action potentials as an up-state does, is a response that directly answers what happens with the firing of MSNs after Ca2+ entry in each pathway, direct or indirect. Recent experiments using supra-threshold cortical stimulation readily distinguished between direct and indirect pathway neurons, and, in fact, D2R-expressing indirect pathway neurons manage Ca2+ inflow differently from D1R-expressing direct pathway neurons (Flores-Barrera et al., 2010): D2R-expressing neurons exhibit synaptically driven auto-regenerative Ca2+ spikes which may reflect all the Ca2+ sources that Higley and Sabatini mention in their work. D1R-expressing neurons do not exhibit these spikes under the same conditions. In fact, inhibition plays almost opposite roles in indirect and direct pathway neurons due to this difference in Ca2+ management.
This is an important difference between MSNs from both pathways and supports the work by Higley and Sabatini. Experiments are needed to know what the precise Ca2+ source is to trigger the dendritic spikes, or alternatively, if a non-linear cooperation among all sources occurs. That will answer whether a VGCC antagonist may help in controlling D2R-expressing neuron hyperexcitability, thus diminishing the probability of collateral effects accompanying D2R-blockage. It also would be pharmacologically relevant to review (experimentally) the possible VGCC blocking properties of different antipsychotic classes, or, alternatively, to develop a drug with both properties, thus increasing synergy and requiring lower dose.
Previous work on single cells and on synaptic terminals have reported similar findings to those from Higley and Sabatini: D1R-activation increases direct pathway excitability in part through the enhancement of NMDAR and VGCC currents, and D2R-activation decreases indirect pathway excitability through the negative modulation (inhibition) of NMDAR and VGCC currents. The difference is that these previous studies showed these differences by recording at the somata (Cepeda and Levine, 1998; Hernandez-Lopez et al., 1997; 2000) or at the synaptic terminals (Guzman et al., 2003; Salgado et al., 2005; Tecuapetla et al., 2007). The elegance of Higley and Sabatini's work lies in that they demonstrate the same phenomena in spines and dendrites while recording their impact at the soma using a combination of highly sophisticated techniques—perhaps the best combination that can be used today. Taking all these studies together, we can conclude that D2R activation decreases or regulates Ca2+ entry at the soma, dendrites, spines, and synaptic terminals of D2R-expressing MSNs. That being said, it is still not clear what the impact of D2R-activation would be at the circuit level (see Kravitz et al., 2010), since a decrease in dendritic excitability and firing, plus a decrease in Ca2+ entry at the terminals, may lead to less GABA-release within the striatal circuitry and into the striatal target (GPe). The end result may be an increase in circuit excitability.
In relation to this paradox, Singer and his group posit that behind many brain disorders, including schizophrenia and Parkinson disease, there is a problem in circuit organization, such that low frequencies engage neurons in a dominant, hyperexcitable, and synchronized state that impedes normal circuit processing (Uhlhaas and Singer, 2006). This has been recently proven for Parkinson disease (Jaidar et al., 2010). A similar work has to be done in schizophrenia (Uhlhaas and Singer, 2010). Thus, the clue for global understanding may not be located on somata, dendrites, spines, or terminals, although this work makes the necessary bricks for making a solid cellular foundation, but in the circuit (Yuste, 2008).
Finally, Higley and Sabatini (2010) complete the ongoing work of finding a role for the different VGCCs found in neurons. At least for the MSNs, L(D)-type channels help to fix the threshold for firing, the frequency-intensity relationship, whereas N- and P/Q-type channels activate Ca2+-dependent potassium currents and the after-hyperpolarization, thus fixing the firing frequency and the firing pattern (more or less spike frequency adaptation) (Perez-Garci et al., 2003). P/Q-type channels are also in charge of synaptic release (Salgado et al., 2005). Thanks to Higley and Sabatini's work, we now know that R- and possibly T-type channels control arriving synaptic inputs at the dendrites, either by shunting them through Ca2+-dependent potassium currents or by boosting them. In addition, L(C)-type channels may generate auto-regenerative spikes. Perhaps this depends on input convergence and strength (Flores-Barrera et al., 2010). Now, each VGCC has at least one role in MSNs, and a great step forward for Ca2+ channels pharmacology would be to control a cellular function by modifying the Ca2+ channel that controls it.
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