Nicotine Dependence, Midbrain Dopamine Systems and Psychiatric Disorders

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Abstract
Compelling evidence exists that tobacco‐smoking represents a form of drug addiction to nicotine. Like several drugs of abuse, nicotine activates the mesolimbic dopamine system and this effect appears to be of critical importance for the reinforcing properties of the drug. Specifically, nicotine has been shown to increase burst activity in dopamine neurones of the ventral tegmental area, i.e. a mode of firing pattern in these cells which is physiologically associated with basic motivational processes underlying learning and cognitive behaviour. The stimulatory action of nicotine on mesolimbic dopamine neurones is exerted both at the somatodendritic and at the terminal levels. Yet, the release of dopamine in the nucleus accumbens induced by systemically administered nicotine is abolished by the nicotinic receptor antagonist, mecamylamine when administered locally in the ventral tegmental area, but not in the nucleus accumbens. Whereas continuous infusion of nicotine into the ventral tegmental area produces a long‐lasting increase in accumbal dopamine release, analogously to the effect of systemically administered nicotine, continuous infusion of nicotine into the nucleus accumbens produces a very short‐lasting dopamine release. Thus, nicotinic receptors in the ventral tegmental area appear to be more significant than those located in the nucleus accumbens for mediating the stimulatory effect of nicotine on dopamine release in the nucleus accumbens. The effect of nicotine on midbrain dopamine systems may help to explain the extremely high prevalence of tobacco‐smoking in schizophrenics, who frequently display so‐called hypofrontality, i.e. a reduced functional activity in the prefrontal cortex which provides a direct input to the ventral tegmental area dopamine cells. Specifically, the prefrontal cortex seems to control phasic activity, i.e. essentially burst firing, but not tonic activity in these neurones through glutamatergic pathways. Accordingly, impaired functional activity in the prefrontal cortex in the rat has been found to decrease burst firing in ventral tegmental dopamine cells, an effect which can be antagonized by nicotine pretreatment. Moreover, chronic, but not acute nicotine administration has been found to increase dopamine metabolism in the prefrontal cortex. Thus, the intense nicotine intake in psychotic individuals may, in effect, reflect an attempted self‐medication. The finding that cigarette‐smoking can help to normalize the impaired sensory gating in schizophrenic patients provides additional evidence for this notion. In summary, the physiological pattern of activation of dopamine neurones induced by nicotine may be particularly well suited for its ability to induce psychological dependence as well as to partly reverse a probably distorted dopamine signalling in psychotic individuals.
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