Nicotine Withdrawal-Induced Anhedonia

Urgent action is required to prevent the detrimental effects of tobacco smoking on global health. Currently available smoking cessation medication, however, remains largely ineffective for the majority of people that attempt to quit smoking. Development of new treatment options requires a gain in knowledge about the neurobiology underlying withdrawal from tobacco’s main psychoactive ingredient, nicotine. In humans, the early nicotine withdrawal syndrome is characterized by several affective and somatic symptoms. One of the symptoms of importance in the prevention of relapse is anhedonia, which is defined as the loss of interest or pleasure in activities that were previously perceived as rewarding. In animals, anhedonia can be reliably and quantitatively assessed using the intracranial self-stimulation (ICSS) procedure. Intracranial self-stimulation is an operant behavioral procedure in which laboratory rodents prepared with stimulating electrodes learn to deliver brief electrical pulses into brain structures that are part of the brain reward pathway. The present thesis aimed to assess the involvement of α7 and β4 nicotinic acetylcholine receptor (nAChR) subunits and metabotropic glutamate receptors (mGluRs) 5 and 7 on nicotine withdrawal by subjecting mice containing a null mutation for one of these genes to the intracranial self-stimulation procedure. After mice were trained and tested in the ICSS procedure, 40mg/kg/day nicotine (base) was chronically delivered through osmotic minipumps for 28 days. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps. The studies in α7 and β4 knockout mice indicated that targeting of the α7 and β4 nAChR subunits may alleviate the aversive anhedonic signs of the early nicotine withdrawal syndrome, thereby potentially increasing the chance of successful discontinuation of the tobacco smoking habit by decreasing the risk of relapse. Null mutation of mGluR5 and mGluR7 mice resulted in a longer-lasting attenuation of the anhedonic signs of nicotine withdrawal, indicating that blockade of these mGluRs may similarly alleviate the anhedonic signs of the nicotine withdrawal syndrome.