Pharmacogenetic treatments for drug addiction: cocaine, amphetamine and methamphetamine

Abstract

Background: Pharmacogenetics uses genetic variation to predict individual differences in response to medications and holds much promise to improve treatment of addictive disorders.

Objectives: To review how genetic variation affects responses to cocaine, amphetamine, and methamphetamine and how this information may guide pharmacotherapy.

Methods: We performed a cross-referenced literature search on pharmacogenetics, cocaine, amphetamine, and methamphetamine.

Results: We describe functional genetic variants for enzymes dopamine-beta-hydroxylase (DbetaH), catechol-O-methyltransferase (COMT), and dopamine transporter (DAT1), dopamine D4 receptor, and brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP; C-1021T) in the DbetaH gene is relevant to paranoia associated with disulfiram pharmacotherapy for cocaine addiction. Individuals with variable number tandem repeats (VNTR) of the SLC6A3 gene 3'-untranslated region polymorphism of DAT1 have altered responses to drugs. The 10/10 repeat respond poorly to methylphenidate pharmacotherapy and the 9/9 DAT1 variant show blunted euphoria and physiological response to amphetamine. COMT, D4 receptor, and BDNF polymorphisms are linked to methamphetamine abuse and psychosis.

Conclusions: Disulfiram and methylphenidate pharmacotherapies for cocaine addiction are optimized by considering polymorphisms affecting DbetaH and DAT1 respectively. Altered subjective effects for amphetamine in DAT1 VNTR variants suggest a 'protected' phenotype.

Scientific significance: Pharmacogenetic-based treatments for psychostimulant addiction are critical for successful treatment.

FIG. 1

Hypothetical schematic of a DAergic synapse. Presynaptic neuron contains DA precursors leading to vesicular DA fusing with the presynaptic membrane and being released into the synaptic cleft. DA then stimulates DAergic receptors on the postsynaptic cell. DA is inactivated by being sequestered back into the presynaptic neuron by the DA transporter (DAT). DA may also be metabolized extra-synaptically by catechol-O-methyl transferase (COMT). DA present in the cytosol is taken up by the vesicular transporter (VMAT) for degradation and repackaging. Tyrosine hydroxylase is the rate-limiting enzyme in DA synthesis. Dopamine beta-hydroxylase (DβH) is responsible for the formation of norepinephrine (NE). Intracellular mechanisms associated with the cAMP-PKA-CREB pathway through DA D1-like and D2-like receptors are represented in the postsynaptic neuron. D1 stimulates through Gαs whereas D2 receptor activation inhibits cAMP levels via adenylate cyclase (AC) through Gαi G-proteins. cAMP enhances the dissociation of the regulatory subunit of proteins kinase A (PKA) from the catalytic subunit (Cα) causing activation. PKA-Cα may translocate to the nucleus where it phosphorylates cAMP-response element binding protein (CREB) that leads to cAMP response element (CRE)-mediated gene expression. PKA-Cα may phosphorylate other receptors or channels as well. This kinase also phosphorylates dopamine-and cAMP-regulated-phosphoprotein 32 kDa (DARPP-32) at position Thr34, that then leads to regulation of other intracellular proteins and effects on the neuron.

FIG. 2

Hypothetical schematic of a DAergic synapse representing various polymorphisms affecting proteins involved in psychostimulant action or altering response to medications for psychostimulant addiction. Cocaine pharmacotherapy is influenced by C-1021T SNP (1) of the DβH gene that alters enzyme levels and disulfiram’s action on this enzyme. DAT gene variable number tandem repeats of the SLC6A3 (2) affects treatment response to methylphenidate and possibly cocaine and amphetamine (AMPH). DAD4 receptor 7-repeat (exon III) polymorphism (3) may alter clozapine action for the treatment of methamphetamine (METH)-induced psychosis. The purported functional polymorphism of the BDNF gene val66met (4) may offer a pharmacogenetic target for METH addiction. Val158met (5) may alter COMT enzyme levels and is associated with AMPH and METH use. Genetically predetermined decreases in DRD2 receptors (6) in chronic drug abusers across classes offers a possible pharmacotherapeutic target.