food or water reward (under food- or water- restricted conditions, respectively). Following this initial training, the reinforcer is replaced by a test drug to be administered by one of the following methods: oral, inhalation, intracerebral, intravenous. Intravenous catheterization is used most commonly because it maximizes bioavailability and has a rapid onset, although is inappropriate for drugs taken orally, such as alcohol. Humans suffering from addiction often resort to intravenous drug use for similar reasons, so this route of administration increases the face validity of the construct. Maintenance Upon presentation of the drug to the subject, a number of experimental variables might be manipulated to test hypotheses: Dose-response relationship Both humans and animals will adjust the rate and number of drug infusions to maintain stable rewarding blood levels of drugs, like cocaine. A dilute dose of cocaine will be administered intravenously at a faster rate than a concentrated dose of cocaine. Reinforcement schedules Continuous reinforcement: A single operant response triggers the dispense of a single dose of the reinforcer. A time-out period may follow each operant response that successfully yields a dose of reinforcer; during this period the lever used in training may be retracted preventing the animal from making further responses. Alternatively, operant responses will fail to produce drug administration allowing previous injections to take effect. Moreover, time-outs also help prevent subjects from overdosing during self-administration experiments. Fixed-ratio studies require a predefined number of operant responses to dispense one unit of the reinforcer. Standard fixed ratio reinforcement schedules include FR5 and FR10, requiring 5 and 10 operant responses to dispense a unit of reinforcer, respectively. Progressive ratio reinforcement schedules utilize a multiplicative increase in the number of operant responses required to dispense a unit of the reinforcer. For example, successive trials might require 5 operant responses per unit of reward, then 10 responses per unit of reward, then 15, and so on. The number of operant responses required per unit of reinforcer may be altered after each trial, each session, or any other time period as defined by the experimenter. Progressive ratio reinforcement schedules provide information about the extent that a pharmacological agent is reinforcing through the breakpoint. The breakpoint is the number of operant responses at which the subject ceases engaging in self-administration, defined by some period of time between operant responses (generally up to an hour). Fixed interval (FI) schedules require that a set amount of time pass