The gateway hypothesis  and the Common liability model 

Two distinct frameworks have been proposed to explain the development of drug involvement and co-occurrence of addiction to different drugs. The “gateway hypothesis” (GH) and the general common liability model (CLA).

According to the gateway hypothesis it is drug use itself that is viewed as the cause of drug use development. Likewise, the “stages” are defined in a circular manner: a stage is said to be reached when a certain drug(s) is used, but this drug is supposed to be used only upon reaching this stage. In other words, the stage both is identified by the drug and identifies that drug. In effect, the drug is identical to the stage (“marihuana is a crucial stage . . .”)  

 

(Illustration by Michael Helfenbein) 

In contrast to the GH, the concept of common (general) liability to addiction (CLA) involves mechanisms and biobehavioral characteristics that seek to           explain the entire course of development of the disorder and changes in the risk It also overlaps with the psychological and psychopathological constructs that have been previously used to explicate addiction and its mechanisms. For a particular individual that develops addiction the CLA describes the developmental trajectory phenotype, with genetic and environmental factors acting as vectors, whose salience changes over time.

Whereas the “gateway” hypothesis does not specify mechanistic connections between “stages”, and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co-occurrence, as well as targeted non-drug-specific prevention and early intervention. 

In a recent study a group of scientist combined the two frameworks and studied the epigenetic changes initiated by nicotine prime gene expression by cocaine. The showed that nicotine alters the brain to make it more susceptible to cocaine’s addicting effects, and suggest that interfering with this reprogramming may rein in cocaine abuse.The authors pretreated mice with nicotine to mimic the effects of smoking and detected an increase in the behavioral and neuronal activity responses that mice typically exhibit when given cocaine, relative to animals that had not been pretreated. In contrasty, cocaine did not have the reciprocal effect on nicotine responses. By taking a close look at histome proteins – which package DNA as chromatin- in the reward centers of the brain (the striatum), the authors found that certain histone were hyperacetylated, a state that results in augmented gene expression, consistent with the exaggerated response to cocaine.  

An epidemiological analysis described in the paper by Levine et al. reinforces the urgency of translating these results: most cocaine addicts began using the drug after they started smoking cigarettes, as would be expected if the mechanism operative in mice is mimicked in humans. Cocaine abusers are often administered nicotine replacement therapy to help curb their smoking habits; if the authors’ findings hold up in humans, nicotine replacement therapy might actually exacerbate the patient’s cocaine addiction, a highly undesirable effect. Finally, using cocaine while smoking increases the risk of becoming dependent on the drug: another healthy reason not to smoke.

 References  

Vanyukov MM, Tarter RE, Kirillova GP, Kirisci L, Reynolds MD, Kreek MJ, Conway KP, Maher BS, Iacona WG, Bierut L, Neale MC, Clark DB, Ridenour TA (2012). Common liability to addiction and “gateway hypothesis”: Theoretical, empirical and evolutionary perspective. Drug Alcohol Depend.2012;123:S3–S17. 

 Levine A, Huang Y, Drisaldi B, et al. (2011). Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine. Sci Transl Med.2011;3(107):107ra109. doi: 10.1126/scitranslmed.3003062.