Distinct Profiles of Anxiety and Dysphoria during Spontaneous Withdrawal from Acute Morphine Exposure

Abstract

The negative motivational aspects of withdrawal include symptoms of both anxiety and depression, and emerge following termination of chronic drug use as well as after acute drug exposure. States of acute withdrawal are an inherent part of intermittent drug use in humans, but the contribution of acute withdrawal to the development of addiction has received limited systematic investigation, due to a lack of preclinical models for withdrawal states that emerge spontaneously after acute drug exposure. Here, we have characterized a spontaneous increase in the magnitude of the acoustic startle reflex (i.e., spontaneous withdrawal-potentiated startle) that emerges following acute morphine administration in rats, and compared the time course of startle potentiation and place conditioning. We find that startle potentiation appears related to a decrease in opiate receptor occupancy and reflects an anxiety-like state with a pharmacological profile similar to other signs of opiate withdrawal. Spontaneous startle potentiation emerges before the rewarding effects of morphine have subsided, even though naloxone administration after a single morphine exposure causes both startle potentiation and conditioned place aversion (CPA). These results demonstrate that negative emotional signs of withdrawal develop following just one exposure to morphine, and are likely a recurrent aspect of intermittent drug use that may contribute to the earliest adaptations underlying the development of addiction. Furthermore, the dissociation between spontaneous startle potentiation and CPA suggests anxiogenic and dysphoric manifestations of opiate withdrawal may be mediated by distinct neural mechanisms that are progressively engaged as withdrawal unfolds.

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

“…Decreased dopaminergic activity has been shown to contribute to the production of negative emotional states (Stinus et al, 1990;Liu et al, 2008;Nestler and Carlezon, 2006) and manipulation of dopaminergic signaling attenuates conditioned place aversion (Bechara et al, 1995;Laviolette et al, 2002;Chartoff et al, 2006;but see Caillé et al, 2003) and other signs of opiate withdrawal (Harris and Aston-Jones, 1994;Rodríguez-Arias et al, 1999). Importantly, the initial increase in NAc dopamine release following acute exposure to 10 mg/kg of morphine would have largely dissipated at the time at which spontaneous withdrawal-potentiated startle is observed (Di Chiara and Imperato, 1988;Rothwell et al, 2009). The current finding that apomorphine infusion into the NAc shell prevents the expression of withdrawal-induced anxiety also agrees with the idea that reduced activity within the VTA-to-NAc dopamine projection contributes to negative emotional signs of withdrawal (Diana et al, 1995(Diana et al, , 1999.…”

“…To determine whether activation of dopamine receptors can relieve another negative affective sign of opiate withdrawal, rats were administered apomorphine (0 or 100 mg/kg) during a 2-day, naloxone-precipitated place conditioning paradigm (Rothwell et al, 2009). One vehicle and one drug conditioning session were conducted over 2 days.…”

“…Increases in startle following drug exposure likely represent the anxiety-like component of the withdrawal state. For example, potentiated startle during withdrawal is relieved by a second drug exposure or administration of anxiolytic compounds (Harris and Gewirtz, 2004;Rothwell et al, 2009;Engelmann et al, 2009, Radke et al, 2011. The timing of the withdrawal-potentiated startle effect following morphine also coincides with the decrease in drug levels in the brain (Barjavel et al, 1995;Hipps et al, 1976).…”

“…To better understand how drug-induced changes in dopaminergic signaling contribute to withdrawal behaviors, we evaluated the effects of intracerebrally infused dopamine receptor agonists on potentiation of the acoustic startle reflex ('withdrawal-potentiated startle') during opiate withdrawal (Harris and Gewirtz, 2004;Rothwell et al, 2009;Cabral et al, 2009). Increases in startle following drug exposure likely represent the anxiety-like component of the withdrawal state.…”

Episodic Withdrawal Promotes Psychomotor Sensitization to Morphine

“…Although the onset of drug action is associated with rewarding effects, the offset of drug action generates a negative emotional state of withdrawal that includes symptoms of anxiety, irritability, and dysphoria (Koob and Volkow, 2010). Withdrawal is often associated with the termination of chronic drug exposure, but spontaneous signs of withdrawal can be detected after a single drug exposure in humans (Breiter et al, 1997;Kirby and Stitzer, 1993;Van Dyke and Byck, 1982) and rodents (Laulin et al, 1998;Rothwell et al, 2009). These episodes of 'acute withdrawal' represent an intrinsic feature of intermittent drug abuse (Baker et al, 2004;Dole et al, 1966) that contribute to some unique effects of intermittent drug exposure (Breese et al, 2005a, b;Houshyar et al, 2003Houshyar et al, , 2004.…”