Neurotransmitter interactions in schizophrenia-therapeutic implications

Abstract

The search for new and improved antipsychotic agents has increased in intensity during the past five years. The era of searching for non-toxic copies of clozapine has been followed by several different lines of research, some of which pursue the traditional dopamine track, although at a higher level of sophistication, whereas others focus on other neurotransmitters, such as serotonin and glutamate. Emerging knowledge about the interactions between different neurotransmitters in complex neurocircuits opens up possibilities for achieving antipsychotic activity by interfering with many different neurotransmitters. Most intriguing is the finding in animal experimental models, indicating that it should be possible to alleviate psychotic conditions by stabilizing rather than paralyzing neurocircuits, thus avoiding the risk of motor and mental side effects of the currently used drugs. Among these new classes, dopaminergic stabilizers and 5-HT2A receptor antagonists appear to offer the most promise at present. In a longer perspective, drugs interfering with glutamate function via different mechanisms may also turn out to be useful, especially in the control of negative symptoms.

Phencyclidine supersensitivity in rats with neonatal dopamine loss

“…Recent efforts in the field of schizophrenia have focused on elucidating the role of serotonergic and glutamatergic systems in both the symptomatology of the disease and the therapeutic efficacy of antipsychotic agents (e.g. review by Tamminga 1998;Carlsson et al 1999;Aghajanian and Marek 2000). One of the key observations supporting a role for altered excitatory amino acid neurotransmission in schizophrenia is that PCP and ketamine can produce both positive and negative schizophrenic symptoms in normal humans, and these effects seem to be mediated by blockade of the NMDA receptor (Javitt and Zukin 1991).…”

Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered

“…The dopamine (DA) hypothesis of SZ has been complemented during the last decade by the hypo-N-methyl-D-aspartic acid (NMDA) hypothesis, kindled by the observation that non-competitive NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) and ketamine provoke SZ-like symptoms in human volunteers and exacerbate symptoms in SZ patients, as well as by findings of abnormalities of glutamate neurotransmission in SZ patients (Abi-Saab et al 1998;Carlsson et al 1999;Javitt and Zukin 1991;Jentsch and Roth 1999;Tamminga 1998). Data from both healthy and affected populations converge to suggest that NMDAR blockade is highly relevant to negative and cognitive symptomatology.…”

A peripheral marker for schizophrenia: Increased levels of D 3 dopamine receptor mRNA in blood lymphocytes

“…Although its exact pathogenesis is still not known precisely, a common belief is that excessive activity at dopaminergic synapses in the brain plays a prominent role (1). To date, a definitive diagnosis of schizophrenia requires a 6-month duration of symptomatology and relies on heterogeneous symptoms.…”