An Anatomical Basis for Opponent Process Mechanisms of Opiate Withdrawal

Abstract

Opponent process theory predicts that the first step in the induction of drug withdrawal is the activation of reward-related circuitry. Using the acoustic startle reflex as a model of anxiety-like behavior in rats, we show the emergence of a negative affective state during withdrawal after direct infusion of morphine into the ventral tegmental area (VTA), the origin of the mesolimbic dopamine system. Potentiation of startle during withdrawal from systemic morphine exposure requires a decrease in opiate receptor stimulation in the VTA and can be relieved by administration of the dopamine receptor agonist apomorphine. Together, our results suggest that the emergence of anxiety during withdrawal from acute opiate exposure begins with activation of VTA mesolimbic dopamine circuitry, providing a mechanism for the opponent process view of withdrawal.

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

“…Previous work from our laboratory and others (Harris and Aston-Jones, 1994;Chartoff et al, 2006;Chartoff et al, 2009;Radke et al, 2011) has demonstrated that dopamine receptor agonists attenuate withdrawal behaviors. The current experiments used two subtype-specific dopamine receptor agonists, SKF82958 and quinpirole, to examine the individual contributions of D1-and D2-like dopamine receptors, respectively, to this effect.…”

“…Recent work in our laboratory (Radke et al, 2011) supported this prediction by demonstrating that targeted infusion of morphine in the ventral tegmental area (VTA) was sufficient to induce anxiety-like withdrawal behaviors. In the same study, we also found that systemic injection of the general dopamine receptor agonist apomorphine relieved withdrawal-induced anxiety (Radke et al, 2011). Taken together, this evidence led us to hypothesize that negative affective withdrawal behaviors are triggered by declining levels of dopamine in structures downstream of the VTA.…”

“…To determine whether the effect of apomorphine seen in our previous experiments (Radke et al, 2011) was mediated by D1-or D2-like dopamine receptors, rats were injected systemically with the D1-like receptor agonist SKF82958 or the D2-like receptor agonist quinpirole (0, 10, or 50 mg/kg) during spontaneous withdrawal from morphine, and startle was tested 10-30 min later (Figure 1a). Repeated measures ANOVA revealed a significant main effect of morphine (F 1,42 ¼ 22.904, p o0.001) and a significant main effect of the dopamine receptor agonists (F 4,42 ¼ 3.562, p ¼ 0.014).…”

“…Treatments that attenuate withdrawal behaviors have been shown to reverse this decrease in dopaminergic signaling, while treatments that exacerbate withdrawal potentiate it (Spanagel et al, 1994;Georges and Aston-Jones, 2003). Finally, studies examining the role dopamine plays in opiate withdrawal behaviors (Bechara et al, 1995;Laviolette et al, 2002;Chartoff et al, 2006Chartoff et al, , 2009Radke et al, 2011) have found that dopaminergic signaling contributes to increased aversion, aggression, and anxiety during withdrawal (but see, Caillé et al, 2003).…”

“…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).…”