Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake

Abstract

The impact of ostensibly aversive social stresses on triggering, amplifying and prolonging intensely rewarding drug taking is an apparent contradiction in need of resolution. Social stress encompasses various types of significant life events ranging from maternal separation stress, brief episodes of social confrontations in adolescence and adulthood, to continuous subordination stress, each with its own behavioral and physiological profile. The neural circuit comprising the VTA-accumbens-PFC-amygdala is activated by brief episodes of social stress, which is critical for the DA-mediated behavioral sensitization and increased stimulant consumption. A second neural circuit comprising the raphe-PFC-hippocampus is activated by continuous subordination stress and other types of uncontrollable stress. In terms of the development of therapeutics, brief maternal separation stress has proven useful in characterizing compounds acting on subtypes of GABA, glutamate, serotonin and opioid receptors with anxiolytic potential. While large increases in alcohol and cocaine intake during adulthood have been seen after prolonged maternal separation experiences during the first two weeks of rodent life, these effects may be modulated by additional yet to be identified factors. Brief episodes of defeat stress can engender behavioral sensitization that is relevant to escalated and prolonged self-administration of stimulants and possibly opioids, whereas continuous subordination stress leads to anhedonia-like effects. Understanding the intracellular cascade of events for the transition from episodic to continuous social stress in infancy and adulthood may provide insight into the modulation of basic reward processes that are critical for addictive and affective disorders.

Fig. 1

Changes in behavioral performance as a function of stress level, as originally proposed by Yerkes and Dodson (1908).

Fig. 2

(A) Display of an upright defeat posture by a mouse and (B) display of submissive supine posture by a defeated male rat of the Long–Evans strain. (From Miczek et al., 1982, 2004).

Fig. 3

Social conflict in Tupaia belangeri (from von Holst).

Fig. 4

The effects of paroxetine (7 mg/kg/day) or 20% polyethelyne glycol vehicle on average intake over three 24-h periods of 8% ethanol in 2.5% sucrose by adult rats reared in the animal facility (AFR; white bars), those handled and separated from the mother for 15 min (HMS 15; gray bars) and those handled and separated from the mother for 180 min (HMS 180; black bars). Bars are means ± SEM, ** p <0.01 compared with AFR and HMS 15 groups, ‡p <0.01 compared to vehicle-treated HMS 180. (From Huot et al., 2001).

Fig. 5

10% ethanol intake by AFR (white bars) and MS (gray bars) mice using a 3-bottle choice procedure and during a 60-min session with unlimited dosage, using operant self-administration panels inserted into the home cage. Alcohol solutions were diluted in 0.05% (w/v) saccharin. Alcohol intake (g/kg) is presented as group averages (±SEM) over 10 days during the bottle choice procedure and as data from a single 60-min self-administration session. *p < 0.05. (From Cruz et al., 2008).

Fig. 6

Neural circuits for brief social defeat stress and continuous subordination stress. The ascending DA pathway originating in the ventral tegmental area (VTA) and projecting to themedial prefrontal cortex is inhibited by GABA interneurons which in turn receive input from opioid peptides and CRH, among others. The glutamatergic feedback from PFC and amygdala modulates the DA pathway either directly or by acting on the GABA interneurons. This pathway may be rendered hyperactive as a result of brief social defeat episodes. By contrast, continuous uncontrollable subordination stress activates the serotonergic DRN cells that project to the forebrain, including the PFC. Glutamatergic feedback fromPFC and limbic forebrain modulates the ascending 5-HT projections and it has been proposed that this feedback prevents dysregulation of the 5-HT system.

Fig. 7

Extracellular DA in prefrontal cortex, n. accumbens or dorsal striatum of (A) socially-defeated rats, before, during and after threat of social defeat, and (B) non-defeated rats, before, during and after being placed in a novel cage. Dopamine concentrations are expressed as percent of baseline (home cage). (From Tidey and Miczek, 1996).

Fig. 8

Firing rates of the dorsal raphe neurons during 13 defensive encounters of a male tree shrew with a conspecific resident. The numbers 2.1 and 2.3 correspond to the experimental animal at rest before and after the encounter, while 2.2 corresponds to the animal showing a defensive posture after being approached by the resident. (From Walletschek and Raab, 1982).

Fig. 9

Schematic presentation of the sagittal rodent brain depicting cellular activation by c-fos in mice, hamsters and rats that were attacked by a resident in an aggressive episode (data from Martinez et al., 1998; Nikulina et al., 1998; Kollack-Walker et al., 1999).

Fig. 10

Cumulative histogram showing rates of acquisition of cocaine self-administration for previously defeated (solid bars) and non-defeated (open bars) rats. Rate data for each group were parsed into 12-h bins. (From Tidey and Miczek, 1997).

Fig. 11

The effect of a cocaine or amphetamine challenge on the frequency of walking behavior for defeat-stressed rats (gray bars) and unstressed controls (open bars). Baseline (BL) measurements of walking behavior were obtained after a saline injection before the first stress exposure. Stressed rats received episodes of social defeat on days 1, 4, 7, and 10. One cohort was challenged with 10.0 mg/kg cocaine on day 20 (top) for the expression of behavioral sensitization. Two additional cohorts were challenged with 1.0 mg/kg amphetamine either on days 20, 40, 60, and 70 (middle) or only on day 70 (bottom). Bars represent averages ±SEM for the sum of walking frequency over 5–10 and 25–30 min postinjection for each group. *Indicates stressed vs. control rats were significantly different from each other (p < 0.05) on that day. (From Miczek et al., 2004).

Fig. 12

Total self-administered intake during a 24 h cocaine binge in intermittently defeated and non-defeated rats that were “pharmacologically protected” with infusions of the NMDA receptor antagonist AP-5 into the VTA prior to each stress episode. The mean (±SEM) total amount of cocaine (mg/kg) self-administered during the 24-hour bringe is shown for non-stressed (open bar) and episodically defeated (filled bars) rats. The open and dark gray bars represent rats that were infused with artificial cerebrospinal fluid (aCSF) and the light gray bar represents rats that were infused with the NMDA receptor antagonist AP-5 (5 nmol). (From Covington et al., 2008).

Fig. 13

The effect of social defeat or offensive aggression on cocaine self-administration behavior during a 24-h cocaine binge (0.3 mg/kg/infusion). Individual cumulative records of cocaine intake across each hour of the binge in (A) previously defeated intruder rats, (B) contemporary handled control rats, and (C) resident rats with a history of offensive aggression. (D) Average total cocaine intake (mg/kg) during the 24-h binge in groups of intruder, resident, and control rats. *Indicates that intruders accumulated significantly more cocaine than controls and residents (p < 0.05). (E) The percentage of intruder, resident, and control rats that continued to respond after hour 16 of the 24-h binge. The difference between groups was statistically significant (p = 0.001) (From Covington and Miczek, 2005).

Fig. 14

Hourly cocaine intake during a 24-h cocaine binge. Circadian-like cocaine self-administration behavior was maintained in control rats (open circles), whereas stressed rats (filled circles) self-administered cocaine intensely for 24 h, effectively abolishing the circadian pattern of intake (p <0.01). (From Covington et al., 2005).

Fig. 15

Effect of 36 days of chronic subordination or intermittent social defeat stress episodes on BDNF protein levels in the VTA. Continuous subordination stress leads to significantly decreased levels of BDNF protein in the VTA compared to control levels, whereas 4 acute defeats over 10 days result in increased BDNF protein levels. Bars represent average number of BDNF-labeled cells in the VTA. *Indicates stressed vs. control rats were significantly different from each other (p < 0.05). (From Miczek et al., in preparation).

Fig. 16

Long-term voluntary alcohol intake of Crhr1^−/− (black bar; n = 9) and wild-type (white bar; n = 11) mice. The animals were offered water and an ethanol solution (8% v/v) in a two-bottle free-choice paradigm. The data represent mean ethanol intake per month. Stress events are indicated by arrows. *Indicates Crhr1^−/− is significantly different from wild type (p < 0.01). (From Sillaber et al., 2002).