Progress in Neuro-Psychopharmacology and Biological Psychiatry
Interactions between endocannabinoids and stress-induced decreased sensitivity to natural reward
Introduction
Several endocannabinoids have been identified, including N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG) that activate the central cannabinoid receptor (CB1) (Devane et al., 1992, Mechoulam et al., 1995, Sugiura et al., 1995). Endocannabinoids serve as activity-dependent, retrograde inhibitors of neurotransmitter release (Alger, 2002, Brown et al., 2003, Wilson and Nicoll, 2001) and are involved in the mechanisms that underlie synaptic plasticity, including depolarization-induced suppression of inhibition and excitation (Ohno-Shosaku et al., 2002, Wilson et al., 2001).
The literature is mixed regarding the role that endocannabinoids play in the processing of reward. Although several groups have reported that cannabinoids produce a robust conditioned place preference (Braida et al., 2001a, Lepore et al., 1995, Valjent and Maldonado, 2000) others have reported that cannabinoids produce a conditioned place aversion (Parker and Gillies, 1995, McGregor et al., 1996, Sañudo-Peña et al., 1997). Although it has been reported that both the cannabinoid receptor agonists, WIN 55212-2 and CP55940, are self-administered by mice, an effect that is blocked by pretreatment with a CB1 receptor antagonist rimonabant (Braida et al., 2001b, Ledent et al., 1999, Martellotta et al., 1998), there are several instances in which a failure of cannabinoid self-administration has been reported (Mansbach et al., 1994, Takahashi and Singer, 1981). Cannabinoid receptor agonists, at low and pharmacologically meaningful doses, enhance electrical brain stimulation reward (Gardner et al., 1988). CB1 receptor activation increases extracellular dopamine overflow in terminal regions of the reward circuit, an effect reversed by CB1 receptor blockade (Cheer et al., 2004, Tanda et al., 1997). In addition, genetic deletion of the CB1 receptor results in a reduction in the sensitivity to the rewarding effects of sucrose (Sanchis-Segura et al., 2004). CB1 receptor activation accentuates whereas CB1 receptor blockade attenuates the rewarding effects of sweet and palatable foods (Ward and Dykstra, 2005).
The effects of CB1 receptor activity in the regulation of stress are complex (Carrier et al., 2005). However, evidence is accumulating that tonic activation of CB1 receptors exerts a stress-inhibitory effect. For example, blockade of endogenous CB1 receptor activity with rimonabant increases adrenocorticotropin hormone and corticosterone plasma concentrations (Manzanares et al., 1999). Similarly, basal adrenocorticotropin hormone concentrations are increased in CB1 receptor null mice (Haller et al., 2004). On the other hand, inhibition of fatty acid amide hydrolase (FAAH) activity during stress inhibits activation of the hypothalamic-pituitary–adrenal axis (Patel et al., 2004). FAAH catalyzes the hydrolysis of AEA (Deutsch and Chin, 1993) and 2-AG (Goparaju et al., 1998) in vitro. However, AEA but not 2-AG concentrations in brain are elevated in FAAH null mice (Lichtman et al., 2002, Patel et al., 2005a). Moreover, CB1 receptor activation decreases stress-related behaviors. For example, CB1 receptor activation by endocannabinoids reduces the expression of active escape behaviors during an acute stress episode (Patel et al., 2005b).
The purpose of the present study was to assess the contribution of changes in endocannabinoid signaling to the reduction of sucrose consumption that accompanies subchronic stress exposure. Our hypothesis is that subchronic stress recruits endocannabinoid signaling, and that enhanced endocannabinoid signaling opposes the anhedonic effects of stress. We have tested this hypothesis using sucrose consumption to assess reward processing and restraint as a stressor.
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Animals
Male ICR mice (21–24 g, N = 713) were used in these experiments (Harlan, Madison, WI). All animals were housed, five per cage, on a 12 h light/dark cycle with lights on at 0600 h. All studies were carried out in accordance with the Declaration of Helsinki and with the Guide for the Care and Use of Laboratory Animals and were approved by the Medical College of Wisconsin Institutional Animal Care and Use Committee. All efforts were made to minimize the number of mice used and their suffering.
Materials
Restraint stress effects on sucrose preference
Mice habituated to the fluid consumption procedure drank approximately 3.75 g (140 g/kg body weight) of 10% sucrose solution and approximately 0.25 g (10 g/kg body weight) of water during a 60 min fluid consumption period. Mice exposed to a 30 min restraint episode immediately prior to the fluid consumption test drank approximately 2.40 g (90 g/kg body weight) of 10% sucrose solution and approximately 0.25 g (10 g/kg body weight) of water. A two-way ANOVA of the effect of restraint stress on
Discussion
Earlier reports had indicated that exposure to a series of unpredictable mild (Monleon et al., 1995, Willner et al., 1987), relatively intense (Katz, 1982), or uncontrollable stressors (Griffiths et al., 1992) results in persistent reductions in the consumption of sweet solutions. Likewise, we find that restraint stress causes a persistent decrease in sucrose preference that does not vary across days of restraint, suggesting that behavioral adaptation to repeated exposure to restraint stress
Conclusions
In conclusion, restraint stress decreases sensitivity to natural reward regardless of caloric value. The effect of restraint to decrease sensitivity to natural reward is regulated by activity at the CB1 receptor such that CB1 receptor activity opposes the effects of stress. The endocannabinoids most likely modulate the decreased sensitivity to natural reward induced by acute and subchronic restraint stress by regulating the central stress response. Furthermore, when the stress is repeated for
Acknowledgements
These studies were funded by grants from the National Institute on Drug Abuse (R01 DA16967 and F32 DA16510).
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