HT2C Receptors Cognitive Impairment in Schizophrenia

The role of 5-HT2C receptors in attention and learning will be discussed in detail in Chaps. 23 and 24. As discussed previously, the ability of 5-HT2C receptor stimulation to tonically inhibit DA release in the frontal cortex and hippocampus, one of a number of mechanisms that fine-tune DA release in these two brain regions crucial for cognition, has been linked to the cognitive deficits in schizophrenia that are the principal cause of enduring disability in schizophrenia (Green 2006). The dentate gyrus of the hippocampus has been identified as an important locus of deficits in working, long-term verbal, and spatial memory in schizophrenia (Takao and Miyakawa 2009). The dentate gyrus is also a key region for neurogenesis, a process that may be disturbed in schizophrenia, along with plasticity at the synaptic level (Reif et al. 2007). In 5-HT2C null mice, Tecott et al. (1998) found that long-term potentation was impaired in the medial perforant pathway of the dentate gyrus. This was suggested to be the basis for impairment of performance by these mice in the Morris water maze, a measure of spatial learning and reduced aversion to a novel environment. No general deficit in learning or spatial discrimination was noted.

The PCP model of cognitive impairment is widely utilized to model some of the disturbances in cognition in schizophrenia. When given acutely or chronically, it causes a hypoglutamatergic deficit by blocking the NMDA receptor. 5-HT2C receptors were recently suggested to be important to reversal learning in female rats impaired in this task by subchronic PCP treatment (McLean et al. 2009). Reversal learning, a test of cognitive flexibility has been found to be impaired in patients with schizophrenia, possibly the result of abnormalities in frontal lobe functioning as well as other subcortical systems which are interconnected with the prefrontal cortex, e.g., the striatum, thalamus and dopaminergic systems. Adult female hooded Lister rats were trained to perform an operant reversal-learning task and then received subchronic PCP, which impaired reversal phase performance (p < 0.01 to 0.001), with no effect in the initial phase. Acute treatment with the selective 5-HT2C receptor antagonist SB 243213A (1.0, 3.0, and 10.0 mg/kg IP) significantly attenuated the deficit in reversal learning but only at the dose of 10 mg/kg (p < 0.05; Floresco et al. 2009). Thus, 5-HT2C receptor agonism may correct the hypogluta-matergic deficit postulated to be present in patients with schizophrenia (Bymaster et al. 2003; Richelson and Souder 2000).

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