Review. Neurobiological mechanisms for opponent motivational processes in addiction

Abstract

The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.

Figure 1

Diagram describing the addiction cycle—preoccupation/anticipation (‘craving’), binge/intoxication and withdrawal/negative affect—with the different criteria for substance dependence incorporated from the Diagnostic and statistical manual of mental disorders, 4th edn. (Adapted from Koob 2008.)

Figure 2

Opponent process theory of affective dynamics relevant to addiction. (a) The standard pattern of affective dynamics produced by a relatively novel unconditioned stimulus (first few stimulations). (b) The standard pattern of affective dynamics produced by a familiar, frequently repeated unconditioned stimulus (after many stimulations). (Adapted from Solomon 1980.)

Figure 3

Increases in drug intake associated with extended access and dependence. (a) Effect of drug availability on cocaine intake (mean±s.e.m.). In long-access (LgA) rats (n=12; filled circles) but not in short-access (ShA) rats (n=12; open circles), mean total cocaine intake started to increase significantly from session 5 (^*p<0.05; sessions 5–22 compared with session 1) and continued to increase thereafter (^*p<0.05; session 5 compared with sessions 8–10, 12, 13 and 17–22). (Adapted from Ahmed & Koob 1998.) (b) Effect of drug availability on total intravenous heroin self-infusions (mean±s.e.m.). During the escalation phase, rats had access to heroin (40 mg per infusion) for 1 hour (ShA rats, n=5–6; open circles) or 11 hours per session (LgA rats, n=5–6; filled circles). Regular 1-hour (ShA rats) or 11-hour (LgA rats) sessions of heroin self-administration were performed 6 days per week. The dotted line indicates the mean (±s.e.m.) number of heroin self-infusions of LgA rats during the first 11-hour session. ^*p<0.05 compared with first session (paired t-test). (Adapted from Ahmed et al. 2000.) (c) Effect of extended access to intravenous methamphetamine self-administration as a function of daily sessions in rats trained to self-administer 0.05 mg kg⁻¹ per infusion of intravenous methamphetamine during a 6-hour session. Short-access (open circles) group, 1-hour session (n=6). Long-access (filled circles) group, 6-hour session (n=4). All data were analysed using two-way ANOVA (dose×escalation session within ShA or LgA group). ^*p<0.05 and ^**p<0.01 versus day 1. (Adapted from Kitamura et al. 2006.) (d) Total 23-hour active (filled circles) and inactive (open circles) responses after repeated cycles of 72 hours of nicotine deprivation (ND) followed by 4 days of self-administration (^*p<0.05 versus baseline). (Adapted from George et al. 2007.) (e) Ethanol deliveries (mean±s.e.m.) in rats trained to respond for 10% ethanol and then either not exposed to ethanol vapour (control, n=5; circles) or exposed to intermittent ethanol vapour (14 hours on/10 hours off) for two weeks and then tested either 2 hours (n=6; squares) or 8 hours (n=6; triangles) after removal from ethanol vapour. No difference was observed between rats exposed to intermittent vapour and tested either 2 or 8 hours after ethanol withdrawal. (Adapted from O'Dell et al. 2004.)

Figure 4

(a) Effects of CRF₁ receptor small-molecule antagonist R121919 on ethanol self-administration in dependent (filled bars) and non-dependent (opened bars) rats. Ethanol dependence was induced by intermittent exposure to ethanol vapours for four weeks. Animals were subsequently tested for ethanol and water self-administration following 2 hours of acute withdrawal. Withdrawn, ethanol-dependent animals displayed a significant increase in ethanol lever pressing compared with non-dependent animals. R121919 significantly decreased ethanol self-administration in withdrawn, dependent but not non-dependent animals. Neither ethanol vapour exposure nor R121919 altered water responding. ^*p<0.001 compared with same drug dose in non-dependent animals. ^#p<0.0001 compared with vehicle treatment in dependent animals. (Adapted from Funk et al. 2007.) (b) Effects of CRF₁/CRF₂ peptide antagonist d-Phe CRF_12–41 administered directly into the central nucleus of the amygdala on ethanol and water self-administration in ethanol-dependent (filled bars) and non-dependent (open bars) rats. Ethanol dependence was induced by intermittent exposure to ethanol vapours for four weeks. Animals were subsequently tested for ethanol and water self-administration after 2 hours of acute withdrawal. Withdrawn, ethanol-dependent animals displayed a significant increase in ethanol lever pressing compared with non-dependent animals. d-Phe CRF_12–41 significantly decreased ethanol self-administration in withdrawn, dependent but not non-dependent animals when administered directly into the central nucleus of the amygdala. Neither ethanol vapour exposure nor d-Phe CRF_12–41 altered water responding. ^*p<0.0001 compared with same drug dose in non-dependent animals. ^#p<0.0001 compared with vehicle treatment in dependent animals. Error bars indicate s.e.m. (Adapted from Funk et al. 2006.)

Figure 5

Neurocircuitry associated with the acute positive reinforcing effects of drugs of abuse and the negative reinforcement of dependence and how it changes in the transition from (a) non-dependent drug taking to (b) dependent drug taking. Key elements of the reward circuit are DA and opioid peptide neurons that intersect at both the VTA and the nucleus accumbens and are activated during initial use and the early binge/intoxication stage. Key elements of the stress circuit are CRF and noradrenergic neurons that converge on GABA interneurons in the central nucleus of the amygdala that are activated during the development of dependence. CRF, corticotropin-releasing factor; DA, dopamine; GABA, γ-aminobutyric acid; NA, noradrenaline; VTA, ventral tegmental area. (Adapted from Koob & Le Moal 2008.)