Haloperidol-induced presynaptic dopamine supersensitivity is blocked by chronic lithium

Abstract

SUPERSENSITIVITY following the interruption of synaptic transmission within the dopamine (DA) system has now been established by behavioural^1–3, biochemical^4–6 and electrophysiological^7,8 evidence. Following production of lesions which interupt DA input¹, or treatment with pharmacological agents which chronically disrupt dopaminergic transmission^3,9,10, an increase in the sensitivity of postsynaptic (receiving input from dopaminergic neurones) responses of cells to DA and DA agonists has been observed. However, several studies have suggested that in vivo, presynaptic DA or ‘autoreceptors’ (that is, dopaminoceptive sites on DA-containing cells) may have an important physiological role in the modulation of DA synthesis and release^11–13. Thus, alterations in the sensitivity of presynaptic cells may have profound effects on the availability of the neurotransmitter. To date, only one study has attempted to investigate whether dopaminergic supersensitivity could be a presynaptic, as well as a postsynaptic, phenomenon; following long-term treatment of rats with a phenothiazine, an increase in the sensitivity of DA-containing neurones in the substantia nigra to the DA agonist, apomorphine, has been observed¹⁴. We present here electrophysiological evidence for increased presynaptic sensitivity following chronic haloperidol treatment, as measured by both the direct iontophoretic application of DA and the systemic administration of apomorphine to DA-containing cells in the zona compacta region of the substantia nigra. In addition, it has been found recently that rats treated concurrently with lithium and haloperidol fail to develop postsynaptic supersensitivity, as measured by alterations in behavioural sensitivity^15,16 and DA-receptor binding¹⁶. Several groups have theorised that alterations in catecholamine receptor sensitivity may be a factor in the aetiology of affective disorders, especially manic-depressive illness^17,18. As lithium therapy has been shown to be effective in preventing recurrent episodes of mania and depression in manic-depressive illness¹⁹, it is of interest to determine whether, at the level of individual DA neurones in the CNS, chronic lithium treatment could also affect the development of presynaptic supersensitivity. We provide here electrophysiological evidence for the blockade of presynaptic supersensitivity development following chronic lithium treatment.