**10. Importance of mode of nicotine administration**

Several human studies have assessed the effects of nicotine gum or patch in PD, most of which have not yielded positive results. The negative finding in these trials is likely due to the mode of administration of nicotine. Thus, it is very important to consider the route of nicotine administration, where its subdermal administration via patch may not achieve the desirable nAChR stimulation that is obtained via pulsatile nicotine administration (e.g., via inhalation). The very complex dynamic interaction of nicotine with its receptors, where initial stimulation can be followed by rapid and differential desensitization of receptor subtypes, must be critically considered in experimental paradigms so that maximal therapeutic outcome may be obtained. It may be concluded therefore, that pulsatile stimulation of specific nAChRs in selective brain regions such as the nigrostriatal pathway is critical for the therapeutic efficacy of nicotine or nicotinic agonists in PD. Pulsatile stimulation of central nicotinic receptors may be achieved by currently available nicotine inhaler of nicotine nasal spray. The necessity of pulsatile stimulation may explain the negative outcome of nicotine patch in PD trials. A recent clinical study using oral administration of nicotine (pulsatile), reported positive effects of nicotine on falls and freezing gait in PD. Furthermore, pulsatile nicotine preparations in forms of inhalers or nasal spray are available and approved by FDA for smoking cessation and could be re-purposed for PD pending evaluation of their effectiveness in clinical trials. In addition, pulsatile nicotine administration may also be helpful in improving non-motor symptoms (e.g., depression or cognitive decline) that are commonly associated with PD [12, 13].
