Figure 1.

Profiling of the receptor psychopharmacology of efavirenz demonstrates its interaction with cloned serotonin 5-HT_2A receptors, catecholamine and indoleamine neurotransmitter transporters (dopamine (DAT), serotonin (SERT), and vesicular monoamine transporter 2 (VMAT2)), and γ-aminobutyric acid type A (GABA_A) (α₁,β₂, and γ₂) receptors in heterologous cellular expression systems. (a) Efavirenz (10 μM) displaces specifically bound [³H]radioligand from cloned serotonin 5-HT_2A and 5-HT_2C receptors expressed in HEK293 cells (n=3, *P<0.05 significant displacement compared to specific binding in the absence of efavirenz; one-way ANOVA with Bonferroni post hoc analysis), but not from CB₁ cannabinoid, dopamine D₁, D₂, D₃, and D₄, serotonin 5-HT_1A, opioid (μ, δ, and κ), histamine H₁, adrenergic α_2C, γ-hydroxybutyrate, or Sigma₁ receptors. (b) Agonist-stimulated Gq-coupled phospholipase C activity was measured as inositol phosphate accumulation. Efavirenz acts as a partial agonist of cloned serotonin 2A (5-HT_2A) receptors, and blockade of this receptor by pretreating with methysergide (10 μM) antagonizes its partial agonist effect (n=3–5, **P<0.01, ***P<0.001, NS means not significantly different from basal control levels; one-way analysis of variance (ANOVA) followed by a Dunnett's post hoc analysis). Lysergic acid diethylamine (LSD) (10 μM) acts as a full agonist of cloned 5-HT_2A receptors relative to the full agonist reference compound 5-HT (10 μM) effect (n=3, ***P<0.001, significantly greater levels than basal control). (c) Efavirenz (10 μM) significantly blocks the transport of DAT-mediated [³H]dopamine and SERT-mediated [³H]serotonin (n=2, *P<0.05, significant reduction in [³H]serotonin uptake compared with control uptake in the absence of test compound (defined as 100% uptake) and relative to complete inhibition by 10 μM nomifensine for DAT, and 10 μM fluoxetine for SERT; one-way ANOVA followed by Dunnett's post hoc analysis). (Inset) Efavirenz (10 μM) displaces tetrabenazine-displaceable specifically bound [³H]ketanserin to isoform 2 of the VMAT2 naturally expressed at high levels in rabbit platelets. Note that VMAT1 is not expressed in rabbit platelets. (d) Efavirenz is an allosteric potentiator of cloned α₁β₂γ₂ GABA_A receptors. Whole-cell chloride currents mediated by these receptors are potentiated by efavirenz (⩾10 μM), although efavirenz alone has no activity at the GABA_A receptor (*P<0.05 significantly different from control currents; Student's t-test).