Animal Models of the Withdrawal/Negative Affect Stage of the Addiction Cycle

Measures of Anxiety-Like Responses

A common response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like responses, such as fear, panic, irritability, hypervigilance, sweating, increased heart rate, increased blood pressure, and distractibility. The dependent variable can be a passive response to a novel or aversive stimulus, such as an open field or the elevated plus maze. In such paradigms, the animal is simply placed on or in the apparatus, and its behavior is watched and recorded. Another kind of dependent variable is an active response to an aversive stimulus, such as in the defensive burying test. Withdrawal from repeated administration of cocaine, opioids, ethanol, and cannabinoids produces anxiogenic-like responses in both the elevated plus maze and defensive burying test (Box 3.1).

In the defensive burying test, a rat or mouse is placed in a box with woodchip bedding material. Protruding into the box is an electrified metal probe. Rodents have a natural defense reaction to unfamiliar and potentially dangerous objects. When the animal incidentally touches the probe, it receives a mild shock. The rat or mouse then vigorously pushes the bedding material to cover the probe (presumably in an effort to prevent itself from touching the probe). Researchers will watch this active response and record how long it takes the animal to start burying the probe (latency), the total time spent burying, the total number of burying acts, and the height of the bedding material deposited over the probe. All of these measures have been validated to reflect emotionality in this test (Andrews and Broekkamp, 1993).

The elevated plus maze is an ethologically based exploratory model of anxiety that measures how animals, typically rats and mice, respond to a novel approach/avoidance situation by measuring their relative exploration of two distinct environments. The elevated plus maze is elevated about 2 feet (60 cm) from the floor. It is shaped as a plus sign, consisting of a bright and exposed runway and a dark and walled runway that intersect in the middle. The animal is usually placed at the intersection, facing an open arm. It is then freely allowed to seek the relative safety of one of the closed arms or venture out onto the open arms. An “anxious” animal will spend less time in the open arms and visit the open arms a lower percentage of time relative to the total number of visits it makes to both the open and closed arms. A rodent’s behavior on the elevated plus maze is very sensitive to stress, drug withdrawal, and treatments that produce disinhibition, such as sedative/hypnotic drugs or alcohol.

FIGURE 3.9 (A) Mean intracranial self-stimulation (ICSS) reward thresholds in rats during amphetamine withdrawal (10 mg/kg/day for 6 days). The data are expressed as a percentage of the mean of the last five baseline values prior to drug treatment. ∗p < 0.05, significant differences from the saline control group. (B) Mean ICSS thresholds in rats during ethanol withdrawal (blood alcohol levels reached 197.29 mg%). Elevations in thresholds were time-dependent. ∗p < 0.05, significant differences from the control group. (C) Mean ICSS thresholds in rats during cocaine withdrawal 24 h following the cessation of cocaine self-administration. ∗p < 0.05, significant differences from the control group. (D) Mean ICSS thresholds in rats during naloxone-precipitated morphine withdrawal. The minimum dose of naloxone that elevated ICSS thresholds in the morphine group was 0.01 mg/kg. ∗p < 0.05, significant differences from the control group. (E) Mean ICSS thresholds in rats during spontaneous nicotine withdrawal following surgical removal of osmotic minipumps that delivered nicotine hydrogen tartrate (9 mg/kg/day) or saline. ∗p < 0.05, significant differences from the control group. (F) Mean ICSS thresholds in rats during withdrawal from an acute 1.0 mg/kg dose of Δ9-tetrahydrocannabinol (THC). Withdrawal significantly shifted the reward function to the right (indicating diminished reward). Note that because different equipment systems and threshold procedures were used in the collection of the above data, direct comparisons among the magnitude of effects induced by these drugs cannot be made.

[Panel A. Taken with permission from Paterson NE, Myers C, Markou A. Effects of repeated withdrawal from continuous amphetamine administration on brain reward function in rats. Psychopharmacology, 2000, (152) 440–446.]

[Panel B. Taken with permission from Schulteis G, Markou A, Cole M, Koob G. Decreased brain reward produced by ethanol withdrawal. Proceedings of the National Academy of Sciences USA, 1995, (92) 5880–5884.]

[Panel C. Taken with permission from Markou A, Koob GF. Post-cocaine anhedonia: an animal model of cocaine withdrawal. Neuropsychopharmacology, 1991, (4) 17–26.]

[Panel D. Taken with permission from Schulteis G, Markou A, Gold LH, Stinus L, Koob GF. Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis. Journal of Pharmacology and Experimental Therapeutics, 1994, (271) 1391–1398.]

[Panel E. Data adapted with permission from Epping-Jordan MP, Watkins SS, Koob GF, Markou A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature, 1998, (393) 76–79.]

[Panel F. Taken with permission from Gardner EL, Vorel SR. Cannabinoid transmission and reward-related events. Neurobiology of Disease, 1998, (5) 502–533.]

FIGURE 3.10 Place conditioning with naloxone (15 μg/kg, s.c.) in morphine-dependent rats. D0 indicates the time spent in the naloxone-paired compartment before conditioning. The rats were then evaluated 1 day and 1, 2, 4, 8, and 16 weeks later. The data are expressed as the mean ± SEM time spent in the naloxone compartment after conditioning minus the time spent in the naloxone compartment before conditioning. [Data from Stinus L, Caille S, Koob GF. Opiate withdrawal-induced place aversion lasts for up to 16 weeks. Psychopharmacology, 2000, (149), 115–120.]

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