Drug addiction is a neuropsychiatric disorder with grave personal consequences that has an extraordinary global economic impact. Despite decades of research, the options available to treat addiction are often ineffective because our rudimentary understanding of drug-induced pathology in brain circuits and synaptic physiology inhibits the rational design of successful therapies. This understanding will arise first from animal models of addiction where experimentation at the level of circuits and molecular biology is possible. We will review the most common preclinical models of addictive behavior and discuss the advantages and disadvantages of each. This includes non-contingent models in which animals are passively exposed to rewarding substances, as well as widely used contingent models such as drug self-administration and relapse. For the latter, we elaborate on the different ways of mimicking craving and relapse, which include using acute stress, drug administration or exposure to cues and contexts previously paired with drug self-administration. We further describe paradigms where drug-taking is challenged by alternative rewards, such as appetitive foods or social interaction. In an attempt to better model the individual vulnerability to drug abuse that characterizes human addiction, the field has also established preclinical paradigms in which drug-induced behaviors are ranked by various criteria of drug use in the presence of negative consequences. Separation of more vulnerable animals according to these criteria, along with other innate predispositions including goal- or sign-tracking, sensation-seeking behavior or impulsivity, has established individual genetic susceptibilities to developing drug addiction and relapse vulnerability. We further examine current models of behavioral addictions such as gambling, a disorder included in the DSM-5, and exercise, mentioned in the DSM-5 but not included yet due to insufficient peer-reviewed evidence. Finally, after reviewing the face validity of the aforementioned models, we consider the most common standardized tests used by pharmaceutical companies to assess the addictive potential of a drug during clinical trials.

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Understanding Addiction Using Animal Models.

Receptor-type protein tyrosine phosphatase, receptor type D (PTPRD) has likely roles as a neuronal cell adhesion molecule and synaptic specifier. Interest in its neurobiology and genomics has been stimulated by results from human genetics and mouse models for phenotypes related to addiction, restless leg syndrome, neurofibrillary pathology in Alzheimer's disease, cognitive impairment/intellectual disability, mood lability, and obsessive-compulsive disorder. We review PTPRD's discovery, gene family, candidate homomeric and heteromeric binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes. We discuss the recently reported discovery of the first small molecule inhibitor of PTPRD phosphatase, the identification of its addiction-related effects, and the implications of these findings for the PTPRD-associated brain phenotypes. In assembling PTPRD neurobiology, human genetics, and mouse genetic and pharmacological datasets, we provide a compelling picture of the roles played by PTPRD, its variation, and its potential as a target for novel therapeutics.

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes.

AIMS To estimate trends in the prevalence of cannabis use and risk perceptions of cannabis use from 2005 to 2017 among United States people with and without depression. DESIGN Linear time trends of the prevalence of any, daily and non-daily past 30-day cannabis use and perceived great risk associated with regular cannabis use (outcome variables) among people with and without past-year depression were assessed using logistic regression with survey year as the predictor. All analyses were adjusted for gender, age, race/ethnicity and income; models assessing time trends of cannabis use prevalence were also adjusted for perceived risk. SETTING The United States: National Survey on Drug Use and Health, an annual cross-sectional survey, 2005-17 public use data files. PARTICIPANTS A total of 728 691 people aged ≥ 12 years. MEASUREMENTS Self-report of any, daily and non-daily past 30-day cannabis use and perceived great risk associated with regular cannabis use. FINDINGS The prevalence of any, daily and non-daily cannabis use in the past month was higher among those with depression versus those without [e.g. 2017 for any use: 18.94 versus 8.67%; adjusted odds ratio (aOR) = 2.17 (95% confidence interval (CI) = 1.92, 2.45)]. Any, daily and non-daily cannabis use increased among people with and without depression from 2005 to 2017, yet the increase in any (aORs = 1.06 versus 1.05; P = 0.008) and daily (aORs = 1.10 versus 1.07; P = 0.021) cannabis use adjusted for socio-demographic characteristics was more rapid among those with depression. Perception of great risk associated with regular cannabis use was significantly lower among those with depression (P < 0.001) and decreased significantly more rapidly over the study period among people with depression, compared with those without (aORs = 0.89 versus 0.92; P < 0.001). CONCLUSIONS The prevalence of cannabis use in the United States increased from 2005 to 2017 among people with and without depression and was approximately twice as common among those with depression. People with depression experienced a more rapid decrease in perception of risk, which may be related to the more rapid increase in any and daily past-month cannabis use in this group.

Rapid increase in the prevalence of cannabis use among people with depression in the United States, 2005-17: the role of differentially changing risk perceptions.

Suicidal behavior (SB) is a major problem in patients with substance use disorders (SUDs). However, little is known about specific SB risk factors in this population, and pathogenetic hypotheses are difficult to disentangle. This study investigated some SB and SUD-related endophenotypes, such as impulsivity, aggression, trait anger, and risk-taking behaviors (RTBs), in forty-eight patients with SUDs in relation to lifetime history of suicide attempts (SAs). Disorders related to alcohol, cannabis, cocaine, opiates, and hallucinogenic drugs were included. Lifetime SAs was significantly associated with both higher impulsivity and higher aggression, but not with trait anger. A higher number of RTBs were associated with lifetime SAs and higher impulsivity, but not with aggression and trait anger. Assessing these endophenotypes could refine clinical SB risk evaluation in SUDs patients by detecting higher-risk subgroups. An important limitation of this study is exiguity of its sample size. Its primary contribution is inclusion of all SUD types.

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Impulsivity and Impulsivity-Related Endophenotypes in Suicidal Patients with Substance Use Disorders: an Exploratory Study

Impulsivity traits and neurocognitive mechanisms conferring vulnerability to substance use disorders.

Impulsivity is strongly associated with substance use disorders (SUDs). Our review discusses impulsivity as an underlying vulnerability marker for SUDs, and treatment of co-occurring impulsivity in SUDs. Three factors should be considered for the complex relationship between impulsivity and a SUD: (1) the trait effect of impulsivity, centering on decreased cognitive and response inhibition, (2) the state effect resulting from either acute or chronic substance use on brain structure and function, and (3) the genetic and environmental factors (e.g., age and sex) may influence impulsive behavior associated with SUDs. Both subjective and objective measures are used to assess impulsivity. Together, treatment developments (pharmacological, behavioral, and neurophysiological) should consider these clinically relevant dimensions assessed by a variety of measures, which have implications for treatment matching in individuals with SUD. Despite its heterogeneity, impulsivity is a marker associated with SUDs and may be understood as an imbalance of bottom-up and top-down neural systems. Further investigation of these relationships may lead to more effective SUD treatments.

The neurobiology of impulsivity and substance use disorders: implications for treatment.

The present review will provide an overview of the neurobiology, epidemiology, clinical impact, and treatment of cannabis use disorder (CUD) in mood disorders. Patients with mood disorders including major depressive disorder (MDD) and bipolar disorder (BD) have higher rates of cannabis use, and CUD compared to the general population. Reasons for this association are not clear, nor are the putative therapeutic effects of cannabis use, or its components delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in these illnesses. The evidence surrounding treatments for patients with this comorbidity is lacking, with more support for psychotherapeutic treatments compared with pharmacological treatments. Cannabis use may be associated with mood disorders, but more research is needed to increase our understanding of the mechanisms for this association, and to develop more effective treatments for this comorbidity.

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Aliya M. Lucatch

Papers

The neurobiology of impulsivity and substance use disorders: implications for treatment.

Cannabis and Mood Disorders

Effects of Extended Cannabis Abstinence in Major Depressive Disorder