Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity that is induced by activating glutamate receptors of the N-methyl-D-aspartate (NMDA) type. Since NMDA receptors are blocked by magnesium at negative potentials, their activation requires the concomitant release of glutamate (presynaptic activity) onto a receiving neuron that is depolarized (postsynaptic activity). Correlated preand postsynaptic activity durably enhances synaptic efficacy and triggers the formation of new connections. Because asso-ciativity is a critical component, LTP has become a leading candidate mechanism underlying learning and memory. LTP can be elicited at glutamatergic synapses of the mesolimbic reward system and is modulated by dopamine. Drugs of abuse could therefore interfere with LTP at sites of convergence of dopamine and glutamate projections (eg, ventral tegmental area [VTA], nucleus accumbens, or prefrontal cortex). Interest-ingly, exposure to an addictive drug triggers a specific form of synaptic plasticity at excitatory afferents (drug-evoked synaptic plasticity) and potentiates GABAA receptor-mediated inhibi-tion of the GABA neurons in the VTA and the ventral pallidum (VP), both primary targets of the medium spiny neurons of the nucleus accumbens. As a consequence, the excitability of dopa-mine neurons is increased, the synaptic calcium sources altered, and the rules for subsequent LTP inverted. In the nucleus accumbens, drug-evoked synaptic plasticity appears with some delay and mostly involves the D1 receptor-expressing neurons, which are the ones projecting back to the VTA to control the activity of the GABA neurons as well as to the VP. Manipula-tions in mice that prevent or reverse drug-evoked plasticity in vivo also have effects on persistent changes of drug-associated behavioral sensitization or cue-induced drug seeking, provid-ing more direct evidence for a causal role of synaptic plasticity in drug-adaptive behavior. Together, a circuit model of staged drug-evoked synaptic plasticity is emerging, whereby various symptoms are caused by changes in specific projections, even-tually combining into addiction.
Some drugs of abuse do not lead to addiction. This is the case for substances that alter perception without causing sensations of reward and euphoria, such as the hallucinogens and the dissociative anesthetics (Table 32–1). Unlike addictive drugs, which primarily target the mesolimbic dopamine system, these agents primarily target cortical and thalamic circuits. Lysergic acid diethylamide (LSD), for example, activates the serotonin 5-HT2A receptor in the prefrontal cortex, enhancing glutamatergic transmission onto pyramidal neurons. These excitatory afferents mainly come from the thalamus and carry sensory information of varied modalities, which may constitute a link to enhanced perception. Phencyclidine (PCP) and ketamine produce a feeling of separation of mind and body (which is why they are called dissociative anesthetics) and, at higher doses, stupor and coma. The principal mechanism of action is a use-dependent inhibition of glutamate receptors of the NMDA type. High doses of dextromethorphan, an over-the-counter cough suppressant, can also elicit a dissociative state. This effect is mediated by a rather nonselective action on serotonin reuptake, and opioid, acetylcholine, and NMDA receptors.