Norepinephrine: New Vistas for an Old NeurotransmitterThe role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease
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
References (99)
- et al.
Peri-Karyal and synaptic localization of α-2A adrenergic receptorlike immunoreactivity
Brain Res
(1994) - et al.
α-1 Noradrenergic receptor stimulation impairs prefrontal cortical cognitive function
Biol Psychiatry
(1999) - et al.
Selective loss of neurons of origin of adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia
Lancet
(1981) - et al.
Number of neurons in nucleus locus ceruleus in demented and non-demented patientsRapid estimation and correlated parameters
Neurobiol Aging
(1986) - et al.
Effects of lesions to ascending noradrenergic neurons on performance of a 5-choice serial reaction task in rats. Implications for theories of dorsal noradrenergic bundle functions based on selective attention and arousal
Behav Brain Res
(1983) - et al.
Depletion of brain norepinephrine with DSP-4 does not alter acquisition or performance of a radial-arm maze task
Behav Neural Biol
(1985) - et al.
Clonidine improves memory function in schizophrenia independently from changes in psychosisPreliminary findings
Schizophr Res
(1988) - et al.
Behavioral and neurochemical effects following neurotoxic lesions of a major cholinergic input to the cerebral cortex in the rat
Pharmacol Biochem Behav
(1983) - et al.
“Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975) - et al.
Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT)
Neurobiol Aging
(1983)
Memory access pathwayRole of adrenergic versus cholinergic neurons
Pharmacol Biochem Behav
Pharmacological alleviation of cholinergic lesion-induced memory deficits in rats
Life Sci
Restoration of cholinomimetic activity by clonidine in cholinergic plus noradrenergic lesioned rats
Brain Res
Loss of pigmented dopamine-beta-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer’s type
Neurosci Lett
Short- and long-term memory are differentially regulated by monoaminergic systems in the rat brain
Neuobiol Learn Mem
Adrenergic receptors in aging and Alzheimer’s diseaseDecreased alpha 2-receptors demonstrated by [3H]p-aminoclonidine binding in prefrontal cortex
Neurobiol Aging
Plasma 3-methoxy-4-hudroxyphenylglycol (MHPG) and clinical symptoms in Alzheimer’s disease
Biol Psychiatry
Lesions of cholinergic forebrain nucleiChanges in avoidance behavior and scopolamine actions
Pharmacol Biochem Behav
Noradrenaline and spatial memory
Brain Res
Theories of dorsal bundle extinction effects
Brain Res Rev
Learning and memory deficits after lesions of the nucleus basalis magnocellularisReversal by physostigmine
Neuroscience
Development and plasticity of the locus coeruleusA review of recent physiological and pharmacological experimentation
Prog Neurobiol
Catecholaminergic neurons assessed ante-mortem in Alzheimer’s disease
Brain Res
Neurochemical activities in human temporal lobe related to aging and Alzheimer-type changes
Neurobiol Aging
Cerebrospinal fluid epinephrine in Alzheimer’s disease and normal aging
Neuropsychopharmacology
Oral physostigmine in Alzheimer’s diseaseEffects on norepinephrine and vasopressin in cerebrospinal fluid and plasma
Biol Psychiatry
Learning impairment following lesion of the basal nucleus of Meynert in the marmosetModification by cholinergic drugs
Brain Res
Neurotransmitters and CNS disease. Dementia
Lancet
Distribution of α-2 adrenergic receptor subtype gene expression in rat brain
Mol Brain Res
Effects of dihydrexidine, a full dopamine receptor agonist, on delayed response performance in chronic low dose MPTP-treated monkeys
Brain Res
Memory enhancement by central administration of norepinephrine
Brain Res
Cell loss in the locus coeruleus in senile dementia of Alzheimer type
J Neurol Sci
CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal
Biol Psychiatry
Clonidine treatment of schizophreniaCan we predict treatment response?
Psychiatry Res
Alpha-receptor-mediated facilitation of somatosensory cortical neuronal responses to excitatory synaptic inputs and iontophoretically applied acetylcholine
Neuropharmacology
Short- and long-term changes in tyrosine hydroxylase activity in rat brain after subtotal destruction of central noradrenergic neurons
J Neurosci
Changes in the brain catecholamines in patients with dementia of Alzheimer type
Br J Psychiatry
Impaired learning an decreased cortical norepinephrine afterbilater locus coeruleus lesions
Science
The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effectsEvidence for alpha-2 receptor subtypes
J Neurosci
Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates
Science
The contribution of α-2 noradrenergic mechanisms to prefrontal cortical cognitive function
Arch Gen Psychiatry
Physostigmine and recent memory effects in young and aged non-human primates
Science
Neurochemical correlates of dementia severity in Alzheimer’s diseaseRelative importance of the cholinergic deficits
J Neurochem
A pilot study of clonidine plus physostigmine in Alzheimer’s disease
Dementia
Brain norepinephrine and dopamine in schizophrenia
Science
Alzheimer’s diseaseCholine acetyltransferase activity in brain tissue from clinical and pathological subgroups
Ann Neurol
Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia
Neurology
Postmortem central catecholamines and ante mortem cognitive impairment in elderly schizophrenics and controls
Biol Psychiatry
Noradrenergic control of thalamic oscillationThe role of alpha-2 receptors
Eur J Pharmacol
Cited by (143)
Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing
2023, Neuroscience and Biobehavioral ReviewsClonidine augmentation in patients with schizophrenia: A double-blind, randomized placebo-controlled trial
2023, Schizophrenia ResearchThe role of norepinephrine in the pathophysiology of schizophrenia
2020, Neuroscience and Biobehavioral Reviews