Addiction Research

There are three defining features of addiction; the compulsion to take a drug, the loss of control of limiting intake and the emergence of a negative emotional state when the drug is withheld. Chronic dependency is associated with increased reward thresholds (i.e. decreased reward with a set concentration of a drug). This is seen in all common drugs of dependence and reinforces the addictive process.

Neurobiology of Addiction

At the cellular level, drug sensitization is associated with neuronal and synaptic plasticity, and structural changes in dendrites. In the ventral tegmental area (VTA), the level of neurofilament proteins is decreased by drug addiction. This is associated with decreased axonal transport of tyrosine hydroxylase and subsequently, a reduction of tyrosine hydroxylase transferred to dopaminergic nerve terminals in the nucleus accumbens (NAcc).

Dopamine is directly implicated in the positive reinforcement (reward) of drug addiction. The dopaminergic system, specifically the mesocorticolimbic pathway, is enhanced by all common drugs of abuse, including cocaine, amphetamines, ethanol, THC, opiates and nicotine. The mesocorticolimbic pathway originates in the VTA and projects to the NAcc, prefrontal cortex and other limbic areas, where increases in extracellular dopamine levels, due to inhibition of dopamine transporters, is observed in addiction. In addition, glutamatergic inputs into the VTA and NAcc from the amygdala, central GABAergic, cholinergic, serotonergic and noradrenergic systems, and stress peptides of the hypothalamic-pituitary-adrenal (HPA) axis have been shown to be involved in the underlying mechanics of drug addiction.

At the molecular level, the cAMP signaling pathway has long been suspected to be involved in tolerance and dependence of abused drugs, and protein kinase C (PKC) and cAMP response element-binding protein (CREB) are specific examples of molecules involved. Other molecules implicated in drug addiction, which act both upstream and downstream of PKC and CREB, include various neurotransmitters mentioned above, Gα_s and Gα_i proteins, protein kinases and phosphatases, ion channels, immediate early genes and transcription factors.

Pharmacological Interventions

Current pharmacological targets for addiction include acetaldehyde dehydrogenase (ALDH) inhibitors, indirect NMDA partial agonists and metabotropic glutamate receptor antagonists (alcohol addiction), long acting opioids and α₂-adrenoceptors agonists (opiate dependence) and nicotinic receptor antagonists (nicotine dependence). Novel pharmacological treatments are focusing on new targets that include dopamine receptor partial agonists, CRF antagonists, tachykinin receptor 1 (NK₁) antagonists, and glutamatergic and GABAergic signaling modulators.