Receptor Supersensitivity

A prolonged decrease in the stimulation of the postsy-naptic receptors can result in a functional increase in receptor sensitivity. The best example of this is the denervation supersensitivity seen when a peripheral nerve is severed.7 In this situation, the lack of presynaptic neurotransmitter release results in a compensatory increase in postsynaptic receptor numbers on the muscle cell. Similarly, the loss of the endogenous neurotransmitter dopamine in neurodegenerative conditions such as Parkinson disease can result in supersensitivity of receptors for that neurotransmitter.14 This increased receptor sensitivity becomes problematic because administration of dopaminelike drugs can cause excessive or untoward responses (see Chapter 10).14 

A somewhat different type of denervation supersensitivity can also occur when receptor antagonist drugs are used for prolonged periods. Here the postsynaptic receptors are blocked by the antagonistic drug, and are unavailable for stimulation by the appropriate agonist. The postsynaptic neuron interprets this 

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The extent of receptor supersensitivity after unilateral nigrostriatal lesions can be quantified by measuring the extent of rotational behavior. After selective nigrostriatal lesions have been produced in rats by injections of 6-hydroxydopamine into the substantia nigra, the number of dopamine receptors in the ipsilateral corpus striatum increases markedly, and the increase in the number of receptors may correlate with the extent of behavioral supersensitivity as monitored by rotational behavior [52]. Thus, the increase in receptor density appears to play a role in the behavioral supersensitivity of these animals. 

Inhibits the synthesis of DA, decreases the number of /Tadrenergic receptors and inhibits DA2 and / adrenergic receptor supersensitivity ... 

Locomotor activity is measured in motility boxes equipped with photocells. Both horizontal and vertical movements can be registered in the modern boxes. Pretreatment with reserpine (18 h) renders the animals virtually without movement, an akinetic Parkinson-like state. It also makes postsynaptic D2 receptors supersensitive, since the receptors have been exposed to low concentrations of DA for a long period of time. The model is thus useful to reveal D2 agonists with a low degree of intrinsic efficacy and, the intrinsic efficacy of a series of partial agonists can be rated by this model. 

Treiser S, Kellar KJ Dthium effects on adrenergic receptor supersensitivity in rat brain. Eur J Pharmacol 58 85-86, 1979... 

Early research at our institute found that treatment with lithium decreased the b-adrenergic receptor number, consistent with the noradrenergic down-regulation hypothesis but difficult to reconcile with a complementary theory of mania ( 25). Lithium can also block dopamine receptor supersensitivity, and this is consistent with the postulate that mania is associated with an increased sensitivity of catecholamine receptors. 

Gerfen CR. D1 dopamine receptor supersensitivity in the dopamine depleted striatum animal model of Parkinson s disease. Neuroscientist. 2003 9 455-462. 

Kim, H. S., Jang, C. G., and Park, W. K. (1996). Inhibition by MK-801 of morphineinduced conditioned place preference and postsynaptic dopamine receptor supersensitivity in mice. Pharmacol. Biochem. Behav. 55, 11-17. 

Cowen PJ, Clifford EM, Walsh AE, Williams C, Fairbum CG. Moderate dieting causes 5-HT2C receptor supersensitivity. Psychol Med 1996 26 1155-1159. 

LaHoste GJ, Yu J, Marshall JF (1993) Striatal Fos expression is indicative of dopamine D1/D2 synergism and receptor supersensitivity. Proc Natl Acad Sci USA 90 7451-7455. 

Lithium s benefit in mania may be linked to effects on dopamine and norepinephrine, possibly by preventing dopamine receptor supersensitivity in the manic individual. Additionally, lithium blocks some cocaine- and amphetamine-induced symptoms of mania, which are thought to be mediated by stimulant-related increases in CNS dopamine concentration. The action of lithium on norepinephrine is variable, causing an initial prolonged increase in reuptake, although this effect is not evident with long-term administration (American Society of Hospital Pharmacists 1993). 

Tardive Dyskinesia and Dopamine Receptor Supersensitivity - Tardive dyskinesia is a major complication of long term treatment with neuroleptic drugs 24,25,26,27 it is characterized by abnormal movement of facial muscles and extremities which frequently worsen when the neuroleptic dose is lowered or terminated. Increasing the dose, however, may temporarily alleviate the symptoms. The chronic treatment of rats and mice with neuroleptics leads to an increased motor activity and enhanced sensitivity to the motor stimulant effects of apomorphine, a direct dopamine receptor agonist28 ... 

Evidence accumulated in 1978 for a catecholamine receptor supersensitivity theory of depression. 8 The therapeutic action of antidepressants may be due to delayed post-synaptic changes in receptor sensitivity, rather than to acute events like uptake. Various drugs, including TCA, mianserin, viloxazine and iprindol, as well as electroconvulsive therapy (ECT), but not selective 5-HT uptake inhibitors, caused central alpha-adrenoceptor subsensitivity in rats as measured by noradrenaline (NA)-associated adenylate cyclase or by receptor binding. In vivo, the effects were associated with chronic but not acute treatment, paralleling the clinical effects. MAOI may cause similar effects on chronic but not acute treatment. , 24-27 Brain NA turnover in rats was decreased by chronic desipramine and other TCA, but unaffected by iprindol and increased by mianserin.3,28... 

Graham WC, Crossman AR. Woodruff GN. Autoradiographic studies in animal models of hemi-parkisonism reveal dopamine D2 but not DI receptor supersensitivity. I. 6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat. Brain Res 1990 514 93-102. 

By removing the drug at intervals (a drug holiday ) in order to reduce the degree of receptor supersensitivity. 

Clonidine must be dosed at intervals that allow for a wearing off of the drug. This tends to decrease the effect of receptor supersensitivity and reflex overcompensation. 

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