FIGURE 32–3 Disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA) through drugs that act via Gio-coupled receptors. Top: Opioids target μ-opioid receptors (MORs) that in the VTA are located exclusively on γ-aminobutyric acid (GABA) neurons. MORs are expressed on the presynaptic terminal of these cells and the somatodendritic compartment of the postsynaptic cells. Each compartment has distinct effectors (insets). G protein-βγ-mediated inhibition of voltage-gated calcium channels (VGCC) is the major mechanism in the presynaptic terminal. Conversely, in dendrites MORs activate K channels. Together the preand postsynaptic mechanisms reduce transmitter release and suppress activity, ultimately taking away the inhibition by the GABA neurons. Middle: Δ9-tetrahydrocannabinol (THC) and other cannabinoids mainly act through presynaptic inhibition. Bottom: Gamma-hydroxybutyric acid (GHB) targets GABAB receptors, which are located on both cell types. However, GABA neurons are more sensitive to GHB than are DA neurons, leading to disinhibition at concentrations typically obtained with recreational use. CB1R, cannabinoid receptors.
studies show that these drugs also fail to stimulate dopamine release, further supporting the idea that only drugs that activate the mesolimbic dopamine system are addictive. Instead, hallucinogens increase glutamate release in the cortex, presumably by enhancing excitatory afferent input via presynaptic serotonin receptors (eg, 5-HT2A) from the thalamus.
LSD is an ergot alkaloid. After synthesis, blotter paper or sugar cubes are sprinkled with the liquid and allowed to dry. When LSD is swallowed, psychoactive effects typically appear after 30 minutes and last 6–12 hours. During this time, subjects have impaired ability to make rational judgments and understand common dangers, which puts them at risk for accidents and personal injury.
In an adult, a typical dose is 20–30 mcg. LSD is not considered neurotoxic, but like most ergot alkaloids, it may lead to strong contractions of the uterus that can induce abortion (see Chapter 16).
The main molecular target of LSD and other hallucinogens is the 5-HT2A receptor. This receptor couples to G proteins of the Gq type and generates inositol trisphosphate (IP3), leading to a release of intracellular calcium. Although hallucinogens, and LSD in particular, have been proposed for several therapeutic indications, efficacy has never been demonstrated.
In terms of numbers affected, addiction to nicotine exceeds all other forms of addiction, affecting more than 50% of all adults in some countries. Nicotine exposure occurs primarily through smoking of tobacco, which causes associated diseases that are responsible for many preventable deaths. The chronic use of chewing tobacco and snuff tobacco is also addictive.