Smoking and mental health - NCSCT

Neurobiological and behavioural mechanisms linking smoking and mental disorders 3
reward), a major symptom of depression. This evidence suggests that nicotine
has antidepressant-like activity in experimental animal models, and that it may
act preferentially in animals which are particularly susceptible to a depressionlike
behavioural phenotype. 59
Nicotine injections also enhance the ability of the brain to respond to
pleasurable stimuli or events, and this reward enhancement has been observed
following both experimenter-administered 61 and self-administered 62,63 nicotine.
In intracranial self-stimulation, a procedure in which animals are trained to
perform a task that results in stimulation of small electrodes located in pathways
within the brain that mediate reward, nicotine injections decrease the electrical
current required to maintain responding, 64,65 whereas abrupt withdrawal of
nicotine, after a period of chronic infusion, increases the current required. 3,5 The
withdrawal-evoked increase in brain reward sensitivity induced by nicotine
self-administration persists for many days. 66 These findings indicate that the
antidepressant properties of nicotine may arise from its ability to enhance mood
by altering the way in which it is influenced by positive and negative stimuli, and
that nicotine withdrawal may exacerbate the influence of negative stimuli. If the
administration of the drug is controlled by the individual, its reward-enhancing
properties may be increased and prolonged and may, therefore, contribute
significantly to the addictive properties of the drug.
There is evidence that mesolimbic dopaminergic neurons play a pivotal role in
tobacco dependence (see Balfour 15 for a review), and that anhedonia and
depression are associated with reduced mesolimbic DA release. 67 Similar
mechanisms are thought to contribute to the psychopathology of nicotine
withdrawal. 68 Thus, it seems likely that increases in DA release evoked in the
nucleus accumbens, the principal terminal field of the mesolimbic
dopaminergic system, not only mediate the reinforcing properties of nicotine in
general but also contribute specifically to the amelioration of anhedonia in
depression. This hypothesis provides an explanation for the role of depression
in tobacco dependence that has clear face validity. However, it hides a
conundrum. Many depressed patients smoke heavily, in a way that is likely to
generate blood nicotine levels which desensitise many of the neuronal nicotinic
receptors in the brain and in turn mediate the effects of nicotine on DA
release. 15,69 Thus, the hypothesis above does not provide a complete explanation
for the mechanism through which tobacco smoke may serve as an
antidepressant.
In some of the forced swim test studies 56,58 nicotine was given either acutely or
repeatedly as a subcutaneous injection, a route of administration that is likely to
result in stimulation of neuronal nicotinic receptors. In other studies nicotine
was given in drinking water 57 or by continuous subcutaneous infusion, 70 thus
maintaining blood nicotine concentrations at a level that desensitises nicotinic
receptors but, perhaps, models more closely the pattern of exposure experienced
by heavy smokers. Interestingly, there is evidence that nicotinic receptor
antagonists also demonstrate antidepressant-like activity in this test, 54 which
© Royal College of Physicians 2013 43