Nicotinic Acetylcholine Receptor Dysfunction in Addiction and in Some Neurodegenerative and Neuropsychiatric Diseases

Abstract

The cholinergic system plays an essential role in brain development, physiology, and pathophysiology. Herein, we review how specific alterations in this system, through genetic mutations or abnormal receptor function, can lead to aberrant neural circuitry that triggers disease. The review focuses on the nicotinic acetylcholine receptor (nAChR) and its role in addiction and in neurodegenerative and neuropsychiatric diseases and epilepsy. Cholinergic dysfunction is associated with inflammatory processes mainly through the involvement of α7 nAChRs expressed in brain and in peripheral immune cells. Evidence suggests that these neuroinflammatory processes trigger and aggravate pathological states. We discuss the preclinical evidence demonstrating the therapeutic potential of nAChR ligands in Alzheimer disease, Parkinson disease, schizophrenia spectrum disorders, and in autosomal dominant sleep-related hypermotor epilepsy. PubMed and Google Scholar bibliographic databases were searched with the keywords indicated below.

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…Due to the limited efficacy and/or complications of current interventions, extensive effort, particularly towards the prevention of neurodegeneration, has been expended. In this regard, neuronal nAChRs have emerged as a viable target [ 4 , 34 , 35 ]. Interestingly, a mutation in RIC3, a chaperone of neuronal nicotinic acetylcholine receptor subunit α-7 (CHRNA7), was implicated in PD [ 7 ].…”

“…It is now evident that nAChRs not only play an important role in neuronal function and the addiction to nicotine [ 151 , 152 ] but may also serve as targets for therapeutic intervention in various neuropsychiatric/neurodegenerative disorders, including PD [ 25 , 153 , 154 ], depression [ 153 , 155 , 156 ], obsessive–compulsive disorder [ 157 , 158 ], ADHD [ 159 ], Tourette syndrome [ 160 , 161 , 162 ], mild cognitive impairment or Alzheimer’s disease [ 163 , 164 , 165 , 166 ], ischemia [ 167 ], catalepsy [ 168 ], schizophrenia [ 4 , 166 , 169 ], pain [ 147 , 170 ], energy balance [ 171 , 172 ], autoimmune disorders [ 173 ], and even sleep–wake cycle dysregulation [ 174 ]. These receptors are also expressed abundantly in a variety of immune cells, including B cells, T cells, macrophages, and microglia, and are believed to contribute to the anti-inflammatory effects of nicotine [ 175 , 176 , 177 , 178 ].…”

“…Though many of the motor features of PD are dopamine (DA) responsive, some symptoms, including balance problems, do not respond well to such treatments. Non-motor symptoms such as cognitive difficulties, depression, fatigue, sleep problems, urinary problems, constipation, and variations in blood pressure do not respond to what might be termed as “DA-replacement therapy.” Thus, it is concluded that deficiencies in other neurotransmitter systems, including the nicotinic cholinergic system, may underlie these features [ 2 , 3 , 4 ]. As such, there is interest in targeting these other neurotransmitter functions to treat specific dopamine-resistant aspects of PD.…”

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…Due to the limited efficacy and/or complications of current interventions, extensive effort, particularly towards the prevention of neurodegeneration, has been expended. In this regard, neuronal nAChRs have emerged as a viable target [4,34,35]. Interestingly, mutation in RIC3, a chaperone of neuronal nicotinic acetylcholine receptor subunit α-7 (CHRNA7), has been implicated in PD [7].…”

“…Non-motor symptoms such as cognitive difficulties, depression, fatigue, sleep problems, urinary problems, constipation, and variations in blood pressure do not respond to what might be termed as "DA-replacement therapy." Thus, it is concluded that deficiencies in other neurotransmitter systems including nicotinic cholinergic system, may underlie these features [2][3][4]. As such, there is interest in targeting these other neurotransmitters functions to treat specific dopamine-resistant aspects of PD.…”