Elsevier

Biological Psychiatry

Volume 46, Issue 9, 1 November 1999, Pages 1243-1252
Biological Psychiatry

Norepinephrine: New Vistas for an Old Neurotransmitter
The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease

https://doi.org/10.1016/S0006-3223(99)00232-2Get rights and content

Abstract

The role of noradrenergic neurotransmission in normal cognitive functions has been extensively investigated, however, the involvement of noradrenergic functions in the cognitive impairment associated with schizophrenia and Alzheimer’s disease has not been as intensively considered. The limited ability of atypical antipsychotics to treat the cognitive impairment of schizophrenia, and cholinomimetics to treat the cognitive impairment of Alzheimer’s disease, may be related to the influence of a multiplicity of neurotransmitter abnormalities including noradrenergic dysfunction, which these treatments do not address. The evidence of noradrenergic dysfunction occurring concomitantly with dopamine dysfunction in schizophrenia and acetylcholine dysfunction in Alzheimer’s disease supports therapeutic approaches using noradrenergic drugs in combination with neuroleptics and cholinesterase inhibitors, respectively, to enhance the treatment of cognitive impairment. Given the results of animal and human studies, it appears that α-2A agonists may be the optimal choice for this purpose.

Introduction

The role of noradrenergic neurotransmission in normal cognitive functions has been extensively investigated in numerous animal studies, leading to a better understanding of the contribution of noradrenergic dysfunction to certain neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and Korsakoff’s syndrome. The involvement of noradrenergic functions in the cognitive impairment associated with schizophrenia and Alzheimer’s disease (AD), however, has not been as intensively considered. Contemporary thinking focuses primarily on the disruption of normal dopaminergic functioning as the primary pathophysiologic mechanism underlying the cognitive impairment associated with schizophrenia. As a result, newer antipsychotic drugs are sought that enhance mesocortical dopamine activity, with the belief that cognitive functions in schizophrenic patients will be improved. Similarly, the development of therapeutics for patients with Alzheimer’s disease has been guided by the understanding that cholinergic dysfunction is central to the cognitive manifestations of this illness. Unfortunately, the use of atypical antipsychotics to address the cognitive deficits of schizophrenia, and cholinomimetics for the cognitive impairment of Alzheimer’s disease have met with only limited success. Clearly, one problem with each of these strategies is that they ignore the influence of a multiplicity of lesions on the manifestation of these illnesses. Among these, disruption of normal noradrenergic functions has been implicated in the pathophysiology of both schizophrenia and AD. This review examines the evidence implicating noradrenergic dysfunction in the cognitive dysfunction of schizophrenia and AD and explores the implications for the development of alternative approaches to their treatment.

Section snippets

Role of norepinephrine in cognition

The central noradrenergic system has two distinct projections: those originating from the ventrolateral tegmental noradrenergic cells, which are associated mainly with sexual and feeding behaviors; and those originating from the locus ceruleus (LC) cells, which are associated with certain cognitive functions Crow and TJ 1968, Mason and Iversen 1979. Furthermore, the prefrontal cortex (PFC) is rich in noradrenergic terminal fields from the LC, where it is believed that norepinephrine (NE) acts

Role of the α-2 adrenergic receptor in cognition

NE acts at four different adrenergic receptor families: α-1, α-2, β-1, and β-2, each of which has further subtypes. NE’s beneficial actions in the PFC result from stimulation of post-junctional α-2 receptors. Furthermore, a high density of α-2 receptors has been observed in the area of the principal sulcus of the PFC (Goldman-Rakic et al 1990). Indeed, α-2 agonists, such as the antihypertensive drug clonidine, have been the noradrenergic drugs of choice in studies of cognition in nonhuman

Role of the β-adrenergic receptor in cognition

Evidence suggests that the amygdala modulates some functions of the hippocampus required for memory formation. Electrophysiologic studies have shown that stimulation of the basolateral amygdala (BLA) facilitates the induction of hippocampal long-term potentiation (LTP) (Ikegaya et al 1996), a form of synaptic plasticity that may underlie learning and memory. The modulatory effects of the BLA on hippocampal LTP is mediated by the activity of β-adrenergic receptors in the BLA (Ikegaya et al 1997)

Noradrenergic involvement in the cognitive dysfunction of schizophrenia

The results of studies measuring NE activity in schizophrenic patients have been conflicting. CSF studies of NE initially identified generalized NE increases in chronic schizophrenic patients compared with age-matched normal control subjects Kemali et al 1982, Lake et al 1980. When medication and symptom status was factored into the analysis, medication-free relapsing patients demonstrated significantly higher levels of NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF van Kammen et al 1989a

Implications for a noradrenergic approach to the treatment of cognitive dysfunction in schizophrenia

The ability of α-2 agonists to improve cognitive performance in monkeys with lesions of the PFC has been demonstrated in humans with psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and Korsakoff’s syndrome, in addition to schizophrenia (Arnsten et al 1996). Studies of α-2 agonists in these clinical populations have demonstrated that these drugs can improve cognitive functions putatively mediated through the PFC, in humans as well as in animals. For example,

Noradrenergic involvement in the cognitive dysfunction of Alzheimer's disease

Cholinomimetic therapies for Alzheimer’s disease have met with only limited success (Mohs et al 1985). These results contrast with the impressive ability of cholinominetics to reverse the deficits in learning and memory that occur with an excitotoxic induced lesion of the nucleus basalis of Meynert (nbM) Haroutunian et al 1985, Haroutunian et al 1990, Murray and Fibiger 1985, Ridley et al 1986.

Despite the development of safer, easier to use cholinesterase inhibitors, such as donepezil,

l-deprenyl combined with cholinesterase inhibitors

One therapeutic option involves the combination of drugs, which would nonselectively increase noradrenergic activity, such as l-deprenyl, with a cholinesterase inhibitor. The results of a pilot study of l-deprenyl augmentation of tacrine or sustained-release physostigmine in 10 patients with AD (Schneider et al 1994) support this idea. The results demonstrated a statistically significant mean improvement on the cognitive subscale of the ADAS of 2.5 points with the addition of deprenyl.

These

Conclusions

The role of NE in normal cognitive functions and the cognitive impairments associated with schizophrenia and AD has been reviewed. These data highlight the multiplicity of neurotransmitter abnormalities involved in the pathophysiology of schizophrenia and AD, especially in the manifestation of cognitive impairments associated with these diseases. The evidence of NE dysfunction occurring concomitantly with DA dysfunction in schizophrenia, and ACh dysfunction in AD, supports therapeutic

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