Neuroadaptational Views of Addiction

Motivational View of Addiction

Rather than focusing on the physical signs of dependence, our conceptual framework has focused on the motivational aspects of addiction. The emergence of a negative emotional state (dysphoria, anxiety, irritability) when access to the drug is prevented is associated with the transition from drug use to addiction. The development of such a negative affective state can define dependence as it relates to addiction:

“The notion of dependence on a drug, object, role, activity or any other stimulus-source requires the crucial feature of negative affect experienced in its absence. The degree of dependence can be equated with the amount of this negative affect, which may range from mild discomfort to extreme distress, or it may be equated with the amount of difficulty or effort required to do without the drug, object, etc.”

(Russell MAH. What is dependence? In: Edwards G (ed) Drugs and Drug Dependence. Lexington Books, Lexington MA, 1976, pp. 182–187).

FIGURE 1.8 (A) The standard pattern of affective dynamics produced by a relatively novel unconditioned stimulus. (B) The standard pattern of affective dynamics produced by a familiar, frequently repeated unconditioned stimulus. [Taken with permission from Solomon RL. The opponent-process theory of acquired motivation: the costs of pleasure and the benefits of pain. American Psychologist, 1980, (35), 691–712.]

A key common element of all drugs of abuse in animal models is dysregulation of brain reward function associated with the cessation of chronic drug administration. Rapid acute tolerance and opponent-process-like actions against the hedonic effects of cocaine have been reported in humans who smoke coca paste (Figure 1.9). After a single cocaine smoking bout, the onset and intensity of the “high” are very rapid via the smoked route of administration. Rapid tolerance is evident, in which the “high” decreases rapidly despite significant blood levels of cocaine. Human subjects also report subsequent dysphoria, again despite significant blood levels of cocaine. Intravenous cocaine produces similar patterns (a rapid “rush” followed by an increased “low”) (Figure 1.10).

The hypothesis that the compulsive use of cocaine is accompanied by the chronic perturbation of brain reward homeostasis has been tested in an animal model of escalation in drug intake with prolonged access. Animals that have access to intravenous cocaine self-administration show increases in cocaine self-administration over days when given prolonged access (long-access [LgA] for 6 h) compared with short-access (ShA; 1 h access). This differential exposure to cocaine also has dramatic effects on intracranial self-stimulation (ICSS) reward thresholds. ICSS thresholds progressively increase in LgA rats but not ShA or control rats across successive self-administration sessions (see Psychostimulants). Elevations in baseline ICSS thresholds temporally precede and are highly correlated with escalated cocaine intake. Post-session elevations in ICSS reward thresholds then fail to return to baseline levels before the onset of subsequent self-administration sessions, thereby deviating more and more from control levels. The progressive elevation in reward thresholds is associated with a dramatic escalation in cocaine consumption. After escalation occurs, an acute cocaine challenge facilitates brain reward responsiveness to the same degree as before but results in higher absolute brain reward thresholds in LgA rats than in ShA rats.

FIGURE 1.9 Dysphoric feelings followed the initial euphoria in experimental subjects who smoked cocaine paste, although the concentration of cocaine in the plasma of the blood remained relatively high. The dysphoria was characterized by anxiety, depression, fatigue, and a desire for more cocaine. The peak feelings were probably reached shortly before the peak plasma concentration, but the first psychological measurements were made later than the plasma assay. The temporal sequence of the peaks shown cannot be regarded as definitive. [From Van Dyke C, Byck R. Cocaine. Scientific American, 1982, (246), 128–141. Reproduced with permission. © 1982, Scientific American Inc. All rights reserved.]

FIGURE 1.10 Average behavioral ratings after an infusion of cocaine (0.6 mg/kg over 30 s; n = 9). The rush, high, low, and craving ratings were averaged within each category for the subjects who had interpretable cocaine functional magnetic resonance imaging data after motion correction and behavioral ratings time-locked to the scanner. Both peak rush and peak high occurred 3 min post-infusion. Peak low (primary reports of dysphoria and paranoia) occurred 11 min post-infusion. Peak craving occurred 12 min post-infusion. No subject reported effects from the saline infusion on any of the four measures. Ratings obtained for rush, high, low, and craving measures were higher in subjects blinded to the 0.6 mg/kg cocaine dose compared with subjects unblinded to a 0.2 mg/kg cocaine dose. [Taken with permission from Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD, Goodman JM, Kantor HL, Gastfriend DR, Riorden JP, Mathew RT, Rosen BR, Hyman SE. Acute effects of cocaine on human brain activity and emotion. Neuron, 1997, (19), 591–611.]

With intravenous cocaine self-administration in animal models, such elevations in reward threshold begin rapidly and can be observed within a single self-administration session (Figure 1.11), bearing a striking resemblance to human subjective reports. These results demonstrate that the elevated brain reward thresholds following prolonged access to cocaine fail to return to baseline levels, thus creating a progressive elevation in “baseline” ICSS thresholds and defining a new set point. These data provide compelling evidence for brain reward dysfunction in escalated cocaine self-administration and strong support for a hedonic allostasis model of drug addiction.

FIGURE 1.11 Rats (n = 11) were allowed to self-administer 10, 20, 40, and 80 injections of cocaine (0.25 mg per injection), and intracranial self-stimulation thresholds were measured 15 min, 2 h, 24 h, and 48 h after the end of each intravenous cocaine self-administration session. The horizontal dotted line in each plot represents 100% of baseline levels. The data are expressed as the mean percentage of baseline intracranial self-stimulation thresholds. #p < 0.05, ##p < 0.01, compared with baseline; #p < 0.05, ##p < 0.01, compared with baseline. [Taken with permission from Kenny PJ, Polis I, Koob GF, Markou A. Low dose cocaine self-administration transiently increases but high dose cocaine persistently decreases brain reward function in rats. European Journal of Neuroscience, 2003, (17), 191–195.]

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