Addiction can be defined as the loss of control over drug use, and the compulsive seeking and taking of a drug despite adverse effects (Nestler, 2001). It is a serious major medical and social problem worldwide. For example, more than 20 million people in the United States are classified as having a substance use disorder, and among them >1 million are addicted to cocaine (Nielsen, Utrankar, et al., 2012). Approximately 7% or 17 million adults in the United States ages 18 years and older have an alcohol use disorder. In addition, >850,000 adolescents aged 12-17 years have such a diagnosis. Of note, drug taking does not always result in addiction. For example, only ~20% of cocaine users eventually become addicted, and the rate is much lower for alcohol (Anthony, Warner, & Kessler, 1994). As a result there has been a great deal of interest in understanding the transitions from drug use to addiction. Genetic factors are important, with ~50% of the risk for addiction to any drug being genetic. However, the specific genes that comprise this risk remain largely unknown. The other 50% is thought to reflect a range of environmental exposures. Presumably, environmental experience influences addiction risk through epigenetic mechanisms in the brain.

Great progress has been made over the past several decades in identifying brain regions that are important for addiction. The circuit that has received the most attention is referred to as the mesolimbic dopamine system (Kalivas & Volkow, 2011; Nestler, 2001). This system is composed of dopamine neurons in the ventral tegmental area (VTA) of the midbrain projecting to medium spiny neurons in the nucleus accumbens (NAc), a part of ventral striatum. This VTA-NAc circuit is crucial for the recognition of rewards in the environment and for initiating their consumption, but it also responds to aversive stimuli. VTA dopamine neurons innervate many other forebrain regions as well, including hippocampus, amygdala, and prefrontal cortex (PFC), among others. In turn, these cortical and subcortical regions provide gluta- matergic innervation of the NAc. Together, these various interconnected circuits are referred to as the brain’s reward pathway, crucial for mediating responses to natural rewards, but also the sites where drugs of abuse produce long-lasting changes to underlie addiction (Fig. 8.1).

Rodent models successfully recapitulate key features of drug addiction syndromes seen in humans. The best model is where animals can volitionally self- administer a drug to themselves; a subset of animals, depending on the experimental conditions, become compulsive drug users and show high rates of relapse during abstinence. However, drug self-administration paradigms are very labor intensive, and particularly difficult in mice due to the small caliber of their jugular veins, which hinders intravenous drug access. For these reasons, most studies continue to use experimenter-administered drug [eg, repeated intraperitoneal (IP) injections of cocaine]. Although such passive drug administration paradigms cannot capture

Reward circuitry of the rodent brain

Figure 8.1 Reward circuitry of the rodent brain. A simplified schematic of the major dopaminergic, glutamatergic, and GABAergic connections to and from the ventral tegmental area (VTA) and nucleus accumbens (NAc) (green, dopaminergic; red, glutamatergic; and blue, GABAergic) in the rodent brain. The primary reward circuit includes dopaminergic projections from the VTA to the NAc, which release dopamine in response to reward- (and in some cases aversion-) related stimuli. There are also GABAergic projections from the NAc to the VTA; projections through the direct pathway [mediated primarily by D1-type medium spiny neurons (MSNs)] directly innervate the VTA, whereas projections through the indirect pathway (mediated primarily by D2-type MSNs) innervate the VTA via intervening GABAergic neurons in ventral pallidum (not shown). The NAc also contains numerous types of interneurons (not shown). The NAc receives dense innervation from glutamatergic monosynaptic circuits from the medial prefrontal cortex (mPFC) and other prefrontal cortex regions (not shown), hippocampus (Hipp), and amygdala (Amy), among other regions. The VTA receives such inputs from Amy, lateral dorsal tegmentum (LDTg), lateral habenula (LHb), and lateral hypothalamus (LH), among others. These various glutamatergic inputs control aspects of reward-related perception and memory. The glutamatergic circuit from LH to VTA is also mediated by orexin (not shown). RMTg, rostromedial tegmentum (Russo & Nestler, 2013).

consequences of volitional control over drug use, they are rewarding and produce sensitized drug responses. Ultimately, findings from passive drug paradigms must be validated in self-administration models.

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