Table 1.

Pharmacological targets of main classes of drugs of abuse

Drug Class	NT Mediators	Mechanism
Opioids	MOR → GABA↓ → DA↑	Opioids, like morphine, heroin, or fentanyl, are agonists at MOR (214). Opioid stimulation of MOR in the VTA increases striatal DA release.
Alcohol	EtOH → MOR↑, NMDA↓, DA↑, GABA↑, ECS↑	Unlike most addictive drugs that target specific receptors and transporters, EtOH affects a wide range of targets and indirectly increases DA in NAc (354).
Nicotine	nAChRs → DA↑	Nicotine’s interaction with specific nAChRs (i.e., α4β2) leads to NAc DA release directly by increasing neuronal activity in VTA DA neurons (13, 24) or indirectly by activating modulatory (i.e., GABA or Glu) neurons in VTA (76, 114).
Stimulants	DAT/VMAT2 → DA↑	Amphetamines block DAT and the VMAT2 (11, 96, 111), which increase synaptic levels of extracellular DA by DAT reversal and depletion of vesicular DA stores, which promotes DA release. Cocaine and methylphenidate block DAT inhibiting DA reuptake, thus increasing DA in NAc (171).
Cannabis	THC → Glu/GABA → DA↑↓	THC activation of CB1 receptors regulates the presynaptic release of both GABA and glutamate, influencing the activity states of the mesolimbic DA system (92, 299) (see FIGURE 1)
Classic hallucinogens	5-HT2ARs > DA↑; 5-HT2CRs > DA↓	Indolamines (e.g., psilocybin, LSD, Mescaline) that display high-affinity agonist activity at serotonin 5-HT2 G protein-coupled receptor subtypes (5-HT2A, 5-HT2B, and 5-HT2C) (51). These drugs do not trigger compulsive drug taking and are therefore not considered addictive. Instead, these drugs are predominantly used to alter mental state.
Inhalants	Multiple agents and targets, including volatile substances like toluene, which modulates NMDA↓, 5-HT3↑, Gly↑, GABAA↑, nACh↓, and DA↑ (39, 119, 249)	Abused inhalants (other than nitrites) have a wide range of effects on neurotransmitter release and receptors, with a few similar actions as those of benzodiazepines, alcohol, and barbiturates (15) and have been shown to enhance striatal DA release and have direct reinforcing effects (166).
Benzodiazepines and barbiturates	GABA↑ > DA↑	Benzodiazepines and barbiturates enhance GABA by increasing the frequency or the duration of the chloride ion channel opening at the GABAA receptor, respectively. Both drugs can increase the firing rate of DA neurons in VTA through disinhibition (86, 318).

MOR, mu opioid receptors; VTA, ventral tegmental area; DA, dopamine; NMDA, N-methyl-d-aspartate; ECS, endogenous cannabinoid system; NAc, nucleus accumbens; nAChRs, nicotinic acetylcholine receptors; DAT, dopamine transporter; VMAT2, vesicular monoamine transporter 2; THC, tetrahydrocannabinol.