Prevention of social stress-escalated cocaine self-administration by CRF-R1 antagonist in the rat VTA

Abstract

Rationale Intermittent exposure to social defeat stress can induce long-term neural plasticity that may influence escalated cocaine-taking behavior. Stressful encounters can lead to activation of dopamine neurons in the ventral tegmental area (VTA), which are modulated by corticotropin releasing factor (CRF) neurons. Objective The study aims to prevent the effects of intermittently scheduled, brief social defeat stress on subsequent intravenous (IV) cocaine self-administration by pretreatment with a CRF receptor subtype 1 (CRF-R1) antagonist. Materials and methods Long–Evans rats were submitted to four intermittent social defeat experiences separated by 72 h over 10 days. Two experiments examined systemic or intra-VTA antagonism of CRF-R1 subtype during stress on the later expression of locomotor sensitization and cocaine self-administration during fixed (0.75 mg/kg/infusion) and progressive ratio schedules of reinforcement (0.3 mg/kg/infusion), including a continuous 24-h “binge” (0.3 mg/kg/infusion). Results Pretreatment with a CRF-R1 antagonist, CP 154,526, (20 mg/kg i.p.) prior to each social defeat episode prevented the development of stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h “binge” In addition, pretreatment with a CRF-R1 antagonist (0.3 μg/0.5 μl/side) into the VTA prior to each social defeat episode prevented stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h “binge”. Conclusions The current results suggest that CRF-R1 subtype in the VTA is critically involved in the development of stress-induced locomotor sensitization which may contribute to escalated cocaine self-administration during continuous access in a 24-h “binge”.

Individual Differences and Social Influences on the Neurobehavioral Pharmacology of Abused Drugs

“…An increase in cocaine intake as a result of SD is observed consistently in animals given binge access (i.e., 24 h) to cocaine Miczek, 2001, 2005;Quadros and Miczek, 2009;Boyson et al, 2011;Miczek et al, 2011b). This effect reflects a shortened inter-reinforcer interval at high doses of cocaine (.0.25 mg/kg per infusion) earned during the late portion of the binge, as well as a longer persistence of responding before stopping the binge.…”

“…In animals that have acquired cocaine selfadministration, SD increases cocaine intake during maintenance of self-administration (Boyson et al, 2011), and this effect is greater when low doses of cocaine (0.03-0.125 mg/kg per infusion) are available (Miczek and Mutschler, 1996). An increase in cocaine intake as a result of SD is observed consistently in animals given binge access (i.e., 24 h) to cocaine Miczek, 2001, 2005;Quadros and Miczek, 2009;Boyson et al, 2011;Miczek et al, 2011b).…”

“…For instance, acute or repeated SD typically cross sensitizes animals to cocaine-and amphetamine-induced locomotion (Nikulina et al, 1998;Marrow et al, 1999;Miczek et al, 1999b;Covington and Miczek, 2001;Nikulina et al, 2004;Boyson et al, 2011;de Jong et al, 2005;Yap et al, 2005;Yap and Miczek, 2007;Dietz et al, 2008;Quadros and Miczek, 2009). In rats bred for low responsivity to amphetamine-induced locomotion, SD cross-sensitizes these animals to acute amphetamineinduced hyperactivity such that these rats do not differ from rats bred for high responsivity to amphetamine (Dietz et al, 2008).…”

“…With repeated exposures to SD, corticosterone release does not habituate, unlike that typically observed with nonsocial stressors . Enhanced activation of the HPA axis also is involved in SDinduced increases in cocaine self-administration, and this increase is blocked by a CRH1 receptor antagonist administered either systemically or into the ventral tegmental area (Boyson et al, 2011). By contrast, a blunted response of the HPA axis is observed in rats that experience SD during adolescence and then are tested for amphetamine-induced elevation in corticosterone as adults (Burke et al, 2010), suggesting that SD produces differential effects on the HPA axis across the life span.…”

The Role of the Amygdala in Anxiety Disorders

“…Combined, these findings suggest that CRF2 receptor modulation of 5-HT activity in the amygdala may play an important role in heightened anxiety. While similar studies have not been performed to elucidate the role of CRF receptors in the LC and VTA in mediating NE and DA activity in the amygdala and anxiety states, some indirect evidence suggests an important role for CRF receptors in the LC and VTA stress responses [136,138,144]. Overall, it is clear that further investigations are needed to ascertain the role of CRF receptors in mediating NE and DA activity in the amygdala and how CRF modulation of this activity could relate to fear or anxiety.…”