Binge/Intoxication Stage

Most cases of addiction are initiated by the abuse of substances that are sought because of their hedonic properties. However, drug experimentation also results from the reinforcing effects of conforming to social groups (peer pressure) with the eventual subsequent transfer of motivation to taking the drug for its reinforcing effects. Infrequently, the first use of a drug may be related to its therapeutic properties (such as opiate analgesics for pain or stimulants for attention-deficit hyperactivity disorder). As shown by preclinical studies, a key element of the reinforcing effects of drugs is broadly accepted to involve their ability to trigger large increases in extracellular dopamine in limbic regions (including the nucleus accumbens). Although acute drug self-administration is a good animal model for drug intoxication, using animal models to assess the subjective correlates of drug-induced dopamine increases is difficult. Brain imaging studies in humans have been instrumental in showing that drug-induced increases in dopamine in the striatum (including the ventral striatum where the nucleus accumbens is located) are associated with subjective descriptors of reward (eg, pleasure, high, euphoria; Volkow et al, 1996b). Moreover, these studies have shown that fast dopamine changes are associated with the subjective perception of reward, whereas slow and stable dopamine increases do not induce these subjective responses (Grace, 2000; Volkow and Swanson, 2003).

The pharmacokinetic properties of drugs, which influence the speed of delivery into the brain as well as the duration of their actions, are key elements of their addiction potential. Pharmacokinetic properties determine the doses, routes of administration, and frequency of drug use within a given binge episode. For example, comparison of the brain pharmacokinetics of cocaine and of methamphetamine reveals that both reach the brain very rapidly (although cocaine is somewhat faster than methamphetamine) but that cocaine clears out of the brain much faster than methamphetamine (Figure 3). This difference helps explain why cocaine is taken every 30?60 min during a binge, whereas methamphetamine is taken every couple of hours (Fowler et al, 2008). The importance of pharmacokinetics also helps explain why most abused drugs (with the exception of alcohol) are injected, smoked, or snorted. These routes allow for a much faster delivery of the drug to the brain than when taken orally (Volkow et al, 2000). Pharmacokinetics also help explain why stimulant drugs such as methylphenidate or amphetamine, which also increase dopamine, are not typically perceived as reinforcing when taken orally as prescribed therapeutically (Chait, 1994; Volkow et al, 2001b).

Figure 3

Brain images obtained at different times after administration for [¹¹C]-methamphetamine and for [¹¹C]cocaine (n=19 for each drug) showing axial planes at a level that transects the basal ganglia. Note the fast uptake of both drugs in the brain and the ...

Clinical studies have also shown that the expectation of the drug's effects significantly influences the rewarding responses to drugs, such that the behavioral as well as regional brain activation response of the brain to the drug tends to be more intense when a rewarding drug is expected compared with when the same drug is received unexpectedly (Volkow et al, 2003). The dependency of the drug's rewarding effects on context and expectation suggests the importance of other neurotransmitters such as glutamate, which modulates the reactivity of dopamine cells and dopamine release in the nucleus accumbens, in the rewarding effects of drugs of abuse (Kalivas and Volkow, 2005).

Date: 2016-06-12; view: 238