Amyotrophic lateral sclerosis (ALS) involves the rapid degeneration of upper and lower motor neurons leading to weakening and paralysis of voluntary movements. Mutations in copper‐zinc superoxide dismutase 1 (SOD1) are a known genetic cause of ALS, and the SOD1 G93A mouse has been used extensively to investigate molecular mechanisms in ALS. In recent years, evidence suggests that ALS and frontotemporal dementia form a spectrum disorder ranging from motor to cognitive dysfunctions. Thus, we tested male and female SOD1 G93A mice for the first time before the onset of debilitating motor impairments in behavioural domains relevant to both ALS and frontotemporal dementia. SOD1 G93A males displayed reduced locomotion, exploration and increased anxiety‐like behaviours compared with control males. Intermediate‐term spatial memory was impaired in SOD1 G93A females, whereas long‐term spatial memory deficits as well as lower acoustic startle response, and prepulse inhibition were identified in SOD1 G93A mice of both sexes compared with respective controls. Interestingly, SOD1 G93A males exhibited an increased conditioned cue freezing response. Nosing behaviours were also elevated in both male and female SOD1 G93A when assessed in social paradigms. In conclusion, SOD1 G93A mice exhibit a variety of sex‐specific behavioural deficits beyond motor impairments supporting the notion of an ALS‐frontotemporal spectrum disorder. Thus, SOD1 G93A mice may represent a useful model to test the efficacy of therapeutic interventions on clinical symptoms in addition to declining motor abilities.

Schizophrenia is a severe psychiatric disorder which is worsened substantially by substance abuse/addiction. Substance abuse affects nearly 50% of individuals with schizophrenia, extends across several drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants) and worsens overall functioning of patients. Prominent theories explaining schizophrenia and addiction comorbidity include the primary addiction hypothesis (i.e. schizophrenia susceptibility primes drug reward circuits, increasing drug addiction risk following drug exposure), the two-hit hypothesis (i.e. drug abuse and other genetic and/or environmental risk factors contribute to schizophrenia development) and the self-medication hypothesis (i.e. drug use alleviates schizophrenia symptoms). Animal models can be used to evaluate the utility and validity of these theories. Since this literature was last reviewed by Ng and colleagues in 2013 [Neurosci Biobehav Rev, 37(5)], significant advances have been made to our understanding of schizophrenia and substance abuse comorbidity. Here we review advances in the field since 2013, focussing on two key questions: 1) Does schizophrenia susceptibility increase susceptibility to drug addiction (assessing the primary addiction hypothesis), and 2) Do abused drugs exacerbate or ameliorate schizophrenia symptoms (assessing the two-hit hypothesis and the self-medication hypothesis). We addressed these questions using data from several schizophrenia preclinical models (e.g. genetic, lesion, neurodevelopmental, pharmacological) across drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants). We conclude that addiction-like behaviour is present in several preclinical schizophrenia models, and drugs of abuse can exacerbate but also ameliorate schizophrenia-relevant behaviours. These behavioural changes are associated with altered receptor system function (e.g. dopaminergic, glutamatergic, GABAergic) critically implicated in schizophrenia and addiction pathology.