Nicotinic receptors are only one of the two main receptor subtypes in cholinergic receptor family. The other main type of cholinergic receptor is the muscarinic receptor. The prototypic nonselective muscarinic antagonist is scopolamine. Scopolamine is a classic amnestic drug. Low doses of scopolamine and mecamylamine have mutually augmenting effects impairing working memory function (Levin et al. 1989b). The α4β2 nicotinic desensitizing agent sazetidine-A significantly reversed scopolamine-induced attentional impairment in rats (Rezvani et al. 2011). The effects of sazetidine-A on memory function remain to be tested.

D₁ and D₂ dopamine receptors appear to have important interactions with nicotinic effects on memory function (Levin and Rose 1995). Nicotinic interactions with D₁ receptors appear to be more relevant to reference memory function (Levin et al. 1996b). Chronic systemic nicotine infusions blocked the reference memory improvement seen in rats given the D₁ antagonist SCH-23390 and potentiated the memory impairment caused by the D₁ agonist dihydrexidine in the 16-arm radial maze. No such interactions were seen with working memory performance (Levin et al. 1996b).

D₂ interactions with nicotinic receptor systems appear to be more closely related to working memory. The D₂ agonist quinpirole given systemically reversed the working memory impairment in the radial arm maze caused by high dose application of the general nicotinic antagonist mecamylamine (Levin et al. 1989a). Also, the finding that the D₂ antagonists raclopride and haloperidol potentiated working memory impairment with a subthreshold dose of mecamylamine supports the interaction of the nicotinic receptor system with D₂ receptors (McGurk et al. 1989a, b). The hippocampus might be an important site for these D₂/nicotinic interactions regarding working memory. We found that local hippocampal infusions of the D₂ antagonist raclopride impaired working memory in the radial arm maze and that local hippocampal infusion of the D₂ agonist quinpirole improves memory (Wilkerson and Levin 1999). We have also found that local hippocampal infusion of quinpirole significantly attenuates the working memory impairment caused by hippocampal infusion of the α4β2 nicotinic antagonist DHβE (unpublished data).

Serotonergic systems in the brain also interact with nicotinic systems involved in memory function. Nicotine-induced improvement in working memory is blocked by coadministration of the serotonin 5HT₂ antagonist ketanserin (Levin et al. 2005). The same is true with attentional function. Ketanserin blocked the nicotine-induced reversal of dizocilpine-induced attentional impairment (Rezvani et al. 2005). This 5HT₂ interaction with nicotinic effects may also explain why clozapine also blocks nicotine reversal of dizocilpine-induced attentional impairment given the substantial 5HT₂ antagonist effects of clozapine (Rezvani et al. 2008).

The most widespread excitatory and inhibitory neurotransmitter systems glutamate and GABA have been shown to interact with nicotinic effects on memory function. Blockade of NMDA glutamate receptors with dizocilpine (MK-801) causes impairments in working and reference memory in the 16-arm radial maze (Levin et al. 1998; Timofeeva and Levin 2008). These impairments are largely reversed by coadministration of nicotine. Local infusions of dizocilpine into the ventral hippocampus at doses that by themselves do not cause memory impairment reversed the effect of systemic nicotine from improving memory function to impairing it (Levin et al. 2003). The same dose range of dizocilpine infused into the amygdala significantly impaired memory function, an effect that was reversed by systemic nicotine (May-Simera and Levin 2003). The noradrenergic alpha2 receptor antagonist idazoxan blocked the nicotine-induced reversal of dizocilpine-induced memory impairment in rats (Timofeeva and Levin 2008).

Interactions between GABA and nicotinic systems are important as well. Acute nicotine administration reversed the working memory impairment caused by higher dose (1 mg/kg) administration of baclofen, a GABA-B receptor agonist. Interestingly, a lower (0.25 mg/kg) dose administration of baclofen caused a significant memory improvement. This was not additive with the nicotine-induced improvement. In fact, the low-dose baclofen-induced improvement blocked the nicotine-induced improvement in memory (Levin et al. 2004).

Nicotinic receptors in the brain have been found to be dramatically decreased in people with Alzheimer’s disease (Court et al. 2001). This is particularly apparent in the hippocampus and frontal cortex (London et al. 1989; Perry et al. 1986). In contrast, nicotinic receptors in the thalamus are often found to be relatively unaffected. Nicotine treatment significantly improves cognitive function in people with mild-to-moderate Alzheimer’s disease (White and Levin 1999). In addition, nicotine skin patches significantly improve cognitive performance in people with age-associated memory impairment (AAMI) (White and Levin 2004) or Mild Cognitive Impairment (MCI) (Newhouse et al. 2012).

Schizophrenia is characterized by substantial impairment in cognitive function related to abnormalities of α7 nicotinic receptors (Leonard et al. 1996; Martin et al. 2004). The great majority of people affected with schizophrenia smoke tobacco (Ripoll et al. 2004). There is some indication that they may use tobacco at least in part as a form of self-medication. Nicotine skin patch treatment has been shown to improve attention and memory in people with schizophrenia (Levin et al. 1996c). People with schizophrenia also take antipsychotic medications, many of which have antagonist effects at dopamine D₂, serotonin 5HT₂, and histamine H1 receptors among others (Schotte et al. 1993). These receptor actions are likely to have interactive effects with nicotinic treatment. Indeed, we have found that nicotine has important interactions with the antipsychotic drugs haloperidol and clozapine with regard to memory function. Haloperidol significantly impairs memory function in people with schizophrenia, an effect that was reversed by nicotine (Levin et al. 1996c). Many antipsychotic drugs, especially atypical antipsychotics, have effects of blocking serotonin 5HT₂ receptors. This effect seems to block nicotine-induced cognitive improvement. As described above, the 5HT₂ antagonist ketanserin when given to rats significantly blocks nicotine-induced working memory improvement (Levin et al. 2005). Thus, when testing cognitive improving effects of nicotinic drugs in people with schizophrenia, it is important to consider the interactions of antipsychotic drugs with nicotinic systems and how they may block nicotinic-induced cognitive improvement.

ADHD is the most prevalently diagnosed cognitive impairment among children and adolescents, and ADHD residual type is being increasingly diagnosed in adults. Tobacco use among people affected with ADHD is around double the rate of the general population (Pomerleau et al. 1995). As with schizophrenia, there is evidence that people with ADHD may be self-medicating by smoking tobacco, albeit in a particularly hazardous way (Newhouse et al. 2004). Nicotine skin patch treatment has been shown to significantly improve cognitive function in people with ADHD (Levin et al. 1996a). Interactions of nicotinic treatment with stimulant therapy, which affects dopamine and norepinephrine systems, needs to be more completely evaluated before new nicotinic treatments for ADHD can be advanced effectively.