Binge/Intoxication Stage

Our understanding of the neurobiological substrates for the reinforcing effects of drugs of abuse can be traced to early work on the identification of a reward system in the brain with the discovery of electrical brain stimulation reward or intracranial self-stimulation by Olds and Milner (1954). Brain stimulation reward involves widespread neurocircuitry in the brain, but the most sensitive sites defined by the lowest thresholds involve the trajectory of the medial forebrain bundle that connects the ventral tegmental area (VTA) to the basal forebrain (Olds and Milner, 1954). All drugs of abuse, when administered acutely, decrease brain stimulation reward thresholds (ie, increased reward; Kornetsky and Esposito, 1979) and when administered chronically increase reward thresholds during withdrawal (ie, decreased reward; see below). Although much emphasis was focused initially on the role of the ascending monoamine systems in the medial forebrain bundle in reward, first norepinephrine (Stein, 1962) and then dopamine (Crow, 1973; Wise, 1978), other nondopaminergic systems in the medial forebrain bundle clearly have a key role in mediating brain stimulation reward (Hernandez et al, 2006). Indeed, much work suggests that activation of the midbrain dopamine system has multiple roles to give incentive salience to stimuli in the environment (Robinson and Berridge, 1993) to promote performance of goal-directed behavior (Salamone et al, 2007) or activation in general (Le Moal and Simon, 1991). More recently, the hypothesis has been raised that the time course of dopamine signaling is a key factor, with the fastest time course predominantly having a preferential role in reward and valuation of predicted outcomes of behavior and steady activation of dopamine release having a preferential role in providing an enabling effect on specific behavior-related systems (Schultz, 2007). Work in the domain of the acute reinforcing effects of drugs of abuse supports this hypothesis in which the mesolimbic dopamine system is critical for the acute rewarding effects of psychostimulant drugs but has a more enabling function for all drugs of abuse.

The acute rewarding properties of psychostimulant drugs have long been known to depend on activation of the mesolimbic dopamine system, but activation of this system is not necessarily critical for the acute reinforcing effects of other drugs of abuse (Koob, 1992; Nestler, 2005; Hnasko et al, 2005). Neurotoxin-selective lesions of the mesocorticolimbic dopamine system block the reinforcing effects of cocaine and -amphetamine (McGregor and Roberts, 1993). In contrast, neurochemically specific lesions of dopamine in the nucleus accumbens with 6-hydroxydopamine failed to block heroin or ethanol self-administration, supporting this hypothesis (Koob and Le Moal, 2006).

Using the technique of intracranial self-administration (Table 1) and intracranial place conditioning (Table 1), opioids and alcohol have been shown to be directly self-administered into the VTA. Opioids also produce conditioned place preference when injected into the VTA. Opioids, phencyclidine, and psychostimulants are directly self-administered into the nucleus accumbens, and psychostimulants produce a conditioned place preference when injected into the nucleus accumbens. Cocaine and phencyclidine are directly self-administered into the frontal cortex (McBride et al, 1999). The mesolimbic dopamine system is activated by acute administration of opioids, ethanol, nicotine, and Δ⁹-THC (Di Chiara and Imperato, 1988).

Intravenous nicotine self-administration is blocked by neurotoxin-specific lesions of the mesocorticolimbic dopamine system, and the neuropharmacological action has been hypothesized to be through nicotinic receptor activation of release of dopamine primarily in the VTA and also presynaptically in the nucleus accumbens (Watkins et al, 2000). However, nicotine reward measured by conditioned place preference appears to be independent of the mesocorticolimbic dopamine system (Laviolette et al, 2002). Other substrates implicated in nicotine reward include cholinergic inputs to the pedunculopontine nucleus (Yeomans and Baptista, 1997). In the VTA, activation of the β2 subunit of nicotinic receptors appears to be critical for nicotine activation of dopamine neurons (Mameli-Engvall et al, 2006). Neuropharmacological studies on cannabinoids have implicated both cannabinoid and opioid mechanisms. Opioid and cannabinoid CB₁ antagonists block intravenous self-administration of Δ⁹-THC in squirrel monkeys (Justinova et al, 2003). Similar to other drugs of abuse, Δ⁹-THC administration activates dopamine release in the nucleus accumbens shell (Tanda et al, 1997).

Thus, all drugs of abuse activate the mesolimbic dopamine system, but much evidence suggests that dopamine-independent reinforcement occurs at the level of the nucleus accumbens, suggesting multiple inputs to the activation of critical reinforcement circuitry in these brain regions (Koob, 1992; Nestler, 2005).

The central nucleus of the amygdala (CeA) also has a key function in the acute reinforcing actions of drugs of abuse. Microinjections of dopamine D₁ receptor antagonists into the CeA block cocaine self-administration (Caine et al, 1995; McGregor and Roberts, 1993). The most sensitive site for γ-aminobutyric acid (GABA) and opioid antagonism of oral alcohol self-administration in nondependent rats was the CeA (Hyytia and Koob, 1995; Heyser et al, 1999). Lesions of the CeA block oral self-administration of alcohol (Moller et al, 1997). Serotonin-3 antagonists injected into the CeA block oral ethanol self-administration in nondependent rats, an effect hypothesized to possibly involve the ability of serotonin-3 receptor antagonists to block drug-induced dopamine release (Dyr and Kostowski, 1995).

A major output from the nucleus accumbens is to the ventral pallidum/substantia innominata. Consistent with the nucleus accumbens as a key substrate for drug reward, lesions of the ventral pallidum are particularly effective in blocking the motivation to work for intravenous cocaine and intravenous heroin (Hubner and Koob, 1990; Robledo and Koob, 1993). In addition, blockade of dopamine and GABA_A receptors in the ventral pallidum blocks the reinforcing effects of alcohol (Melendez et al, 2004; June et al, 2003). Thus, elements of the ventral pallidum may not only be critical for further processing of the drug reward signal but may also be directly modulated by drugs of abuse.

The dorsal striatum does not appear to have a major role in the acute reinforcing effects of drugs abuse but appears to be recruited during the development of compulsive drug-seeking (Everitt et al, 2008). 6-Hydroxydopamine lesions of the dorsal striatum do not block cocaine-induced locomotor activity or cocaine self-administration (Roberts, 1992) but do block amphetamine-induced stereotyped behavior (Kelly and Iversen, 1976; Creese and Iversen, 1974). Using a second-order schedule (Table 1), lesions of the nucleus accumbens and basolateral amygdala blocked the acquisition of cocaine-seeking (Whitelaw et al, 1996). Similarly, when the nucleus accumbens core was selectively lesioned on one side of the brain and combined with dopamine receptor blockade in the contralateral dorsal striatum, no effect was observed in animals immediately after acquisition, but greatly decreased cocaine-seeking was observed in rats with stable responding on a second-order schedule (Belin and Everitt, 2008). These results suggest that the dorsal striatum may have a minor role in the acute reinforcing effects of psychostimulant drugs but a key role in the transition to compulsive use (Everitt et al, 2008).

Data with knockout mice also provide key insights into the role of dopamine in the rewarding effects of drugs of abuse. Genetically altered mice homozygous with a lack of the dopamine D₁ receptor do not self-administer cocaine (Caine et al, 2007). Although the initial report that dopamine transporter (DAT) knockout mice continued to self-administer cocaine (Rocha et al, 1998) questioned the function of the DAT in cocaine's reinforcing effects, a recent study showed that transgenic animals that expressed DAT that did not bind cocaine but that was functional as a dopamine reuptake carrier did not show cocaine reward measured by conditioned place preference (Chen et al, 2006a). These results support the hypothesis of a crucial role of the DAT in cocaine's reinforcing effects.

On the basis of this synthesis, an early neurobiological circuit for drug reward was proposed (Koob, 1992) that has been elaborated and expanded (Koob and Nestler, 1997; Figure 1). The starting point for the reward circuit was the medial forebrain bundle, composed of myelinated fibers connecting bidirectionally the olfactory tubercle and nucleus accumbens with the hypothalamus and VTA (Nauta and Haymaker, 1969) and including the ascending monoamine pathways such as the mesocorticolimbic dopamine system.

Figure 1

Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acute reinforcing actions of drugs of abuse. Cocaine and amphetamines activate the release of dopamine in the nucleus accumbens and ...

The initial action of drug reward was hypothesized to depend on dopamine release in the nucleus accumbens for cocaine, amphetamine, and nicotine; opioid peptide receptor activation in the VTA (dopamine activation) and nucleus accumbens (independent of dopamine activation) for opiates; and GABA_A systems in the nucleus accumbens and amygdala for alcohol. The nucleus accumbens is situated strategically to receive important limbic information from the amygdala, frontal cortex, and hippocampus that could be converted to motivational action through its connections with the extrapyramidal motor system. Thus, an early critical role for the nucleus accumbens was established for the acute reinforcing effects of drugs, with a supporting role for the CeA and ventral pallidum (Figures 1 and ​and2a2a).

Figure 2

Neural circuitry associated with the three stages of the addiction cycle. (a) Binge/intoxication stage. Reinforcing effects of drugs may engage reward neurotransmitters and associative mechanisms in the nucleus accumbens shell and core and then engage ...

Date: 2016-06-12; view: 253