NICOTINE DEPENDENCE, MIDBRAIN DOPAMINE SYSTEMS AND PSYCHIATRIC-DISORDERS

Compelling evidence exists that tobacco-smoking represents a form of d rug addiction to nicotine. Like several drugs of abuse, nicotine activ ates the mesolimbic dopamine system and this effect appears to be of c ritical importance for the reinforcing properties of the drug. Specifi cally, 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 motivati onal processes underlying learning and cognitive behaviour. The stimul atory action of nicotine on mesolimbic dopamine neurones is exerted bo th at the somatodendritic and at the terminal levels. Yet, the release of dopamine in the nucleus accumbens induced by systemically administ ered nicotine is abolished by the nicotinic receptor antagonist, mecam ylamine when administered locally in the ventral tegmental area, but n ot in the nucleus accumbens. Whereas continuous infusion of nicotine i nto the ventral tegmental area produces a long-lasting increase in acc umbal dopamine release, analogously to the effect of systemically admi nistered nicotine, continuous infusion of nicotine into the nucleus ac cumbens produces a very short-lasting dopamine release. Thus, nicotini c receptors in the Ventral tegmental area appear to be more significan t than those located in the nucleus accumbens for mediating the stimul atory effect of nicotine on dopamine release in the nucleus accumbens. The effect of nicotine on midbrain dopamine systems may help to expla in the extremely high prevalence of tobacco-smoking in schizophrenics, who frequently display so-called hypofrontality, i.e. a reduced funct ional activity in the prefrontal cortex which provides a direct input to the ventral tegmental area dopamine cells. Specifically, the prefro ntal cortex seems to control phasic activity i.e. essentially burst fi ring, but not tonic activity in these neurones through glutamatergic p athways. Accordingly, impaired functional activity in the prefrontal c ortex in the rat has been found to decrease burst firing in ventral te gmental dopamine cells, an effect which can be antagonized by nicotine pretreatment. Moreover, chronic, but not acute nicotine administratio n has been found to increase dopamine metabolism in the prefrontal cor tex. Thus, the intense nicotine intake in psychotic individuals may, i n effect, reflect an attempted self-medication. The finding that cigar ette-smoking can help to normalize the impaired sensory gating in schi zophrenic patients provides additional evidence for this notion. In su mmary, the physiological pattern of activation of dopamine neurones in duced by nicotine may be particularly well suited for its ability to i nduce psychological dependence as well as to partly reverse a probably distorted dopamine signalling in psychotic individuals.