It is well established that cigarette smoking is highly comorbid with a range of psychiatric conditions, including schizophrenia. However, whether this relationship is causal remains unclear. One possibility is that smoking may be a risk factor for schizophrenia (something I have blogged about in the past) while another is that smoking may represent a form of self-medication, whereby nicotine or other constituents of tobacco smoke may partially resolve some symptoms of schizophrenia. Critically, the two explanations aren’t mutually exclusive. For example, cognitive processes that rely on the prefrontal cortex are known to be impaired in schizophrenia, and this is associated with low activity of the default mode network (known as “hypofrontality”).
In this study, the authors used rodent models to explore the role of genetic influences that appear to influence both smoking and schizophrenia, in an attempt to understand this. Genetic variants within the CHRNA3-CHRNA5-CHRNB4 cluster of nicotine acetylcholine receptor genes contribute to the risk of heavy smoking, and have also been shown to influence the risk of schizophrenia. Genetic deletion of the alpha-5 nicotinic subunit in mice leads to prefrontal cortex-linked behavioural deficits, altered cholinergic excitation, and altered neuronal morphology in the prefrontal cortex. The authors developed a mouse line expressing the human alpha-5 variant to investigate the impact of this variant on behaviours associated with schizophrenia and to determine the neuronal and circuitry mechanisms underlying cognitive deficits.
The study is a complex one, reporting a large number of results from a series of linked experiments. Here I focus on three main questions addressed by the authors, looking at the role of the alpha-5 variant in:
- Behaviours related to social interaction
- Sensorimotor gating
- Neuronal response to nicotine
In all cases, mice carrying the alpha-5 variant, which alters the function of the corresponding nicotinic receptor in a manner similar to that seen in humans who carry the risk allele of this gene, were compared to wild type mice to examine the likely role of this variant on behaviour, cognition and neuronal activity.
1. Behaviours related to social interaction
Impaired social ability is a common feature of schizophrenia. The authors therefore used the three-chamber sociability test to determine whether alpha-5-SNP mice exhibit impairments in social interaction.
The results indicated that they do indeed have deficits in sociability. These differences in social interaction could not be attributed to the effects of differing genotypes on activity or general exploratory behaviour because the wild type and alpha-5-SNP mice did not differ in locomotor activity or combined time in the social and inanimate object interaction areas.
2. Sensorimotor gating
Prepulse inhibition (PPI) reflects the ability of an animal to inhibit the nature startle reaction in response to an acoustic tone (pulse) when the tone is preceded by a lower-intensity stimulus (prepulse). Deficiencies in this reflect impaired sensorimotor gating and are observed in schizophrenia.
The authors found that alpha-5-SNP mice showed decreased PPI across a range of prepulse intensities relative to their wild-type littermates, suggesting that sensorimotor gating is disrupted by the alpha-5 variant in a manner similar to that seen in schizophrenia and other psychiatric conditions.
3. Neuronal response to nicotine
Given evidence that smoking improves cognition, the authors also administered nicotine to wild type and alpha-5-SNP mice by mini-pump infusion and examined alterations in neuronal firing before and after infusion. The dose of nicotine was selected to maintain a plasma concentration analogous to that seen in smokers.
Pyramidal neuron activity significantly increased after two days of nicotine administration in wild-type mice and remained elevated after two weeks. They also found that nicotine treatment one to two weeks in duration increased pyramidal neuron activity in alpha-5-SNP mice to the levels of wild-type baseline activity.
This study provides the first experimental evidence that the alpha-5 human polymorphism, which is associated with heavier smoking, provokes a decrease in neuronal activity in mice that mirrors the hypofrontality observed in patients with psychiatric disorders, including schizophrenia. It also suggests that chronic nicotine treatment of mice carrying the alpha-5-SNP restores these neuronal activity deficits.
These findings suggest new avenues for investigating possible pharmacotherapies; positive allosteric modulators of specific nicotine acetylcholine receptor subunits (such as the alpha-5) would seem to be strong candidates. The results also support the hypothesis that individuals with the alpha-5 variant smoke, at least in part, in order to self-mediate symptoms of cortical dysfunction.
This study describes a complex and sophisticated series of experiments that provide further insight into the relationships between genetic risk, cigarette smoking and schizophrenia. The principal limitation is that animal studies, while valuable, need to be treated with caution when extrapolating the results to humans.
There is certainly evidence that smoking can improve cognitive abilities and can mitigate certain schizophrenia symptoms. However, in humans these studies are particularly challenging because it can be difficult to separate any beneficial effects of nicotine from the reversal of withdrawal-induced deficits.
The results indicate that nicotine (or nicotinic agonists) could normalise prefrontal cortex and reduce some of the cognitive deficits found in people with schizophrenia. However, this needs to be interpreted in the context of many human clinical trials, which have found little clear evidence of benefits of such treatments.
Koukouli F, Rooy M, Tziotis D, Sailor KA, O’Neill HC, Levenga J, Witte M, Nilges M, Changeux JP, Hoeffer CA, Stitzel JA, Gutkin BS, DiGregorio DA, Maskos U. (2017) Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nat Med, advance online publication. DOI: http://dx.doi.org/10.1038/nm.4274