α2-Adrenoceptors in the treatment of major neuropsychiatric disorders

doi:10.1016/j.tips.2015.02.006

Trends in Pharmacological Sciences

Volume 36, Issue 4, April 2015, Pages 196-202

https://doi.org/10.1016/j.tips.2015.02.006 Get rights and content

Highlights

•
Retrograde synaptic neurotransmission involves presynaptic autoreceptors.
•
Presynaptic receptors regulating neurotransmission exist for most neurotransmitters.
•
For norepinephrine, all presynaptic autoreceptors are of the α₂ subtype, regardless of the subtype mediating the postsynaptic response.
•
Several marketed CNS drugs possess significant effects mediated through presynaptic autoreceptors.
•
Presynaptic autoreceptors provide new pathophysiologically relevant targets for innovative drug discovery.

Presynaptic autoreceptors mediate a retrograde transfer of information by a negative feedback mechanism mediated by the transmitter of the neuron, and fulfill an autoregulatory function in neurotransmission in the peripheral and central nervous system (CNS). Starting with norepinephrine (NE), it was later reported that an autoreceptor-mediated negative feedback mechanism exists for other neurotransmitters, including dopamine (DA), serotonin, acetylcholine, histamine, GABA, and glutamate. This feedback mechanism regulates calcium-dependent transmitter release and synthesis through terminal presynaptic autoreceptors, while the firing rate of the neuron is regulated through somatodendritic autoreceptors.

Section snippets

Alpha-1 and alpha-2 receptor subtypes

The discovery of presynaptic α₂-autoreceptors opened up new pathophysiologically relevant opportunities for innovative drug discovery and has successfully led to improved pharmacotherapies of several major neuropsychiatric diseases in humans, including the α_2A-adrenoceptor agonists guanfacine and clonidine in attention deficit hyperactive disorder (ADHD) in children and young adolescents, and several α₂-adrenoceptor antagonists in schizophrenia, major depressive disorders (MDD), and bipolar

Presynaptic autoreceptors

Synapses are specialized sites for chemical transmission between two neurons or a neuron and an effector cell in the peripheral or CNS. Small-molecule neurotransmitters act on membrane-bound macromolecules called receptors to trigger a cascade of events in the postsynaptic cells to elicit a physiological response. Upon arrival of nerve impulses in each neuron, the neurotransmitter is released by exocytosis and traverses the synaptic cleft to activate receptors on the postsynaptic neuron or

Different receptor subtypes are involved in classical anterograde transmission versus retrograde autoregulation of neurotransmission.

Before the discovery of autoreceptors on noradrenergic neurons, it was generally accepted that α-adrenoceptors represented a homogeneous population. However, rigorous studies with α-adrenoceptor antagonists revealed up to a 100-fold potency difference between the concentrations of phenoxybenzamine required to block the postsynaptic α-adrenoceptors that mediate smooth muscle contraction in the perfused cat spleen and the presynaptic autoreceptors that regulate NE release in the same tissue 10, 11

Presynaptic autoreceptors exist for most neurotransmitters

As shown in Table 1, research has now convincingly demonstrated the presence of presynaptic inhibitory autoreceptors for other neurotransmitters, such as DA, acetylcholine, serotonin, histamine, glutamate, and GABA. In each case, the receptor subtype that mediates the presynaptic inhibition of transmitter release has been identified and characterized (Table 1).

It can be concluded that the autoreceptor-mediated regulation of neurotransmission represents a more general and fundamental

Presynaptic heteroreceptors can modulate the release of several neurotransmitters in the peripheral and CNS

As already discussed, presynaptic autoreceptors regulate the release and firing rate of the transmitter of the neuron (Figure 1, Table 1). In addition, the membrane of some nerve terminals has presynaptic heteroreceptors, which are sensitive to endogenous mediators that differ from that of the neuron. These different transmitters and endogenous mediators are released either from neighboring neurons, as in cholinergic–noradrenergic innervation in the salivary glands and the heart (reviewed in

ADHD

ADHD is a cognitive-behavioral developmental disorder that involves overactivity, impulsiveness, and deficient sustained attention. The behavioral disturbances of ADHD are associated with an imbalance between the noradrenergic and dopaminergic systems in the prefrontal cortex. In studies carried out in spontaneously hypertensive rats, an extensively validated animal model of ADHD, Svensson and his team demonstrated subsensitivity of α₂-adrenoceptor on LC neurons 30, 31. This finding could be a

Marketed drugs with significant effects on presynaptic receptors

Successful worldwide launching of a drug for a given indication, accompanied by solid evidence for the mechanism of action mediating its therapeutic effects, represents robust clinical proof of concept for the physiological and pharmacological relevance of presynaptic autoreceptors regulating neurotransmission. The evidence involving the physiological regulation of chemical neurotransmission through presynaptic autoreceptors is solidly documented in the selected eight examples listed in Table 3.

Concluding remarks

This review demonstrates that the discovery of retrograde neurotransmission and of the presynaptic α₂-adrenoceptor subtypes, subsequently called autoreceptors, provided novel targets to achieve improved efficacy in the pharmacotherapy for treatment of drug-resistant MDD, bipolar disorder, schizophrenia, ADHD, and possibly Alzheimer's disease.

The presynaptic regulation of neurotransmission is mediated through autoreceptors that differ pharmacologically from the postsynaptic receptors, and is

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Trends in Pharmacological Sciences

Reviewα2-Adrenoceptors in the treatment of major neuropsychiatric disorders

Highlights

Section snippets

Alpha-1 and alpha-2 receptor subtypes

Presynaptic autoreceptors

Different receptor subtypes are involved in classical anterograde transmission versus retrograde autoregulation of neurotransmission.

Presynaptic autoreceptors exist for most neurotransmitters

Presynaptic heteroreceptors can modulate the release of several neurotransmitters in the peripheral and CNS

ADHD

Marketed drugs with significant effects on presynaptic receptors

Concluding remarks

Biochem. Pharmacol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Neuroscience

Neuroscience

Neurosci. Biobehav. Rev.

Eur. J. Pharmacol.

Neuron

Biol. Psychiatry

J. Affect. Disord.

J. Affect. Disord.

J. Affect. Disord.

Neurosci. Biobehav. Rev.

Neuropharmacology

Eur. J. Pharmacol.

Schizophr. Res.

J. Neurol. Sci.

Brain Res.

Presynaptic receptors and their role in the regulation of transmitter release

Br. J. Pharmacol.

Presynaptic regulation of the release of catecholamines

Pharmacol. Rev.

Modulation of neurotransmitter release by presynaptic autoreceptors

Physiol. Rev.

Role of the α-adrenoceptor in regulating noradrenaline overflow by nerve stimulation

Br. J. Pharmacol.

Protection by phentolamine against the effects of phenoxibenzamine on transmitter release elicited by nerve stimulation in the perfused cat heart

Br. J. Pharmacol.

Physiological significance of α-adrenoceptor-mediated negative feedback mechanism regulating noradrenaline release during nerve stimulation

Nature

Negative feed-back regulation of noradrenaline release by nerve stimulation in the perfused cat's spleen: differences in potency of phenoxibenzamine in blocking the pre- and post-synaptic adrenergic receptors

J. Physiol.

Release of norepinephrine and dopamine-beta-hydroxylase by nerve stimulation. I. Role of neuronal and extraneuronal uptake and of α-presynaptic receptors

J. Pharmacol. Exp. Ther.

Adrenoceptor subtypes

Pharmacol. Rev.

Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents

Hypertension

Dopamine auto- and postsynaptic receptors: electrophysiological evidence for differential sensitivity to dopamine agonists

Science

Subsensitivity of the presynaptic α adrenoceptors after short-term surgical denervation of the cat nictitating membrane

J. Pharmacol. Exp. Ther.

Heteroreceptor-mediated modulation of noradrenaline and acetylcholine release from peripheral nerves

Rev. Physiol. Biochem. Pharmacol.

Inhibition by dopamine of 3H-noradrenaline release elicited by nerve stimulation in the isolated cat's nictitating membrane

Naunyn Schmiedebergs Arch. Pharmacol.

Frequency-dependence of Serotonin autoreceptor but not α-2 adrenoceptor inhibition of [3H]- serotonin release in rat hypothalamic slices

Naunyn Schmiedebergs Arch. Pharmacol.

Possible role of a beta-adrenoceptor in the regulation of noradrenaline release by nerve stimulation through a positive feed-back mechanism

Br. J. Pharmacol.

Morphine and beta-endorphin inhibit release of noradrenaline from cerebral cortex but not of dopamine from rat striatum

Nature

Pharmacological differentiation of presynaptic inhibitory α–adrenoceptors and opiate receptors in the cat nictitating membrane

Br. J. Pharmacol.

Dopamine and α adrenoceptor agonists inhibit neurotransmission in the cat spleen through different presynaptic receptors

J. Pharmacol. Exp. Ther.

Non-synaptic receptors and transporters involved in brain functions and target of drug development

Br. J. Pharmacol.

Review
α₂-Adrenoceptors in the treatment of major neuropsychiatric disorders

Frequency-dependence of Serotonin autoreceptor but not α-2 adrenoceptor inhibition of [³H]- serotonin release in rat hypothalamic slices