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    • br Dopamine The dopamine DA theory of schizophrenia

    2018-10-26


    Dopamine The dopamine (DA) theory of schizophrenia is a model that draws evidence from the findings that antipsychotics have DA blocking actions. Given the well-known role of DA in schizophrenia, what is the relationship between the substantia nigra and the PPN? Anatomically, the PPN is reciprocally connected to the substantia nigra, with the nigral input being inhibitory to PPN, mostly glutamatergic, neurons, and the PPN input to nigra being excitatory and emanating from both cholinergic and glutamatergic PPN sodium butyrate [108–110]. The excitatory input to the nigra from the PPN may be responsible for the activity manifested by nigral neurons, which are active during waking and REM sleep [111,112]. That is, it is likely that normal PPN activity during arousal states helps drive firing in the substantia nigra. However, the hypervigilance and increased REM sleep drive present in schizophrenia suggest that the PPN may overdrive the substantia nigra, thereby potentiating DA release in the striatum. Therefore, it would seem that down regulation of PPN output to the nigra may help alleviate some of the hyperarousal symptoms of the disease. The first generation antipsychotics included chlorpromazine and haloperidol, which showed DA D2 receptor blockade [113]. Due to limited clinical benefits and long-term side effects such as tardive dyskinesia, new agents had to be developed. A second generation antipsychotic named clozapine was found to act on the same DA receptors in the striatum to help decrease DA tone, but it was also found to affect muscarinic cholinergic and serotonergic receptors. In fact, clozapine was initially developed as an anti-muscarinic cholinergic agent intended to balance the decrease in DA present in Parkinson’s disease, i.e. by decreasing cholinergic tone the idea was to rebalance the striatum [114]. Clozapine thus appears to partially block muscarinic input to the nigra as well as DA input to the striatum. In addition, clozapine acts as a partial serotonin reuptake receptor blocker, thereby increasing inhibition of the PPN, further down regulating the raphe-PPN-nigra-striatum pathway. Despite the better beneficial effects than early antipsychotics, clozapine also shows major side effects, and fails to induce ameliorative effects in many patients. Drug companies have attempted to eliminate the side effects of clozapine, but only olanzapine has retained anti-muscarinic properties, and is, in fact, the most widely used third generation antipsychotic. This suggests that down regulating the muscarinic activation of the nigra by the PPN helps relieve the symptoms of the disease in at least some patients.
    Conclusion The PPN simultaneously modulates cortical arousal as well as posture and locomotion. Moreover, in response to sensory inflow, the PPN generates and maintains gamma band activity during waking. These membrane oscillations are mediated by voltage-dependent high threshold N- and P/Q-type calcium channels. It appears that these two types of channels with separate intracellular pathways are involved in selectively controlling high frequency activity. P/Q-type channels are modulated by CaMKII during waking, while N-type channels are modulated by cAMP during REM sleep [89]. In addition to intrinsic membrane oscillations, the maintenance of gamma band activity requires synaptic connectivity within the nucleus and between regions of the brain. PPN circuitry includes cholinergic, glutamatergic, and GABAergic neurons. Some GABAergic cells are electrically coupled to provide coherence [17], and the nucleus may include functional cell clusters [89]. From the moment we awaken, the nucleus ensures that the necessary background of activity is present in order to preconsciously evaluate the world around us [17,18,82,83,89]. Therefore, this process is embedded in the formulation of our perceptions and actions, and modulates higher-level gamma processing through its projections to the intralaminar thalamus, basal ganglia, hypothalamus, and basal forebrain. That is why it affects functions as disparate as waking and REM sleep, mood and perception, and homeostatic regulation. Consequently, dysregulation in PPN processing will be manifested in motor disorders, psychiatric disorders, neurological disease, all of which include sleep disturbances. These issues are discussed at length in a recent book [114].