Opiate Withdrawal-Induced Fos Immunoreactivity in the Rat Extended Amygdala Parallels the Development of Conditioned Place Aversion

Abstract

Low doses of naloxone have been shown to affect the motivational aspects of opiate withdrawal in morphinedependent rats. Conditioned place aversion to opiate withdrawal is one of the most sensitive of motivational indices of opiate withdrawal and is thought to be mediated by the basal forebrain. Expression of the transcription factor Fos is known to increase during opiate withdrawal, but its presence during low-dose antagonist-precipitated withdrawal has not previously been established. In order to determine if there is a relationship between withdrawal-induced neuronal activity and conditioned place aversion, immunocytochemical localization of Fos was examined in the basal forebrain of opiate-dependent animals receiving one of several doses of naloxone (0, 3.25, 7.5, 15, 30, or 1000 g/kgChronic opiate use is partially characterized by the emergence of withdrawal symptoms upon cessation of drug administration. These symptoms include a wellcharacterized group of both physical and affective changes. In humans, affective symptoms often involve feelings of anxiety, restlessness, tension, irritability, and dysphoria (Haertzen and Hooks 1969;Henningfield et al. 1987;Jaffe 1990). Animal models of withdrawal include a number of characteristic somatic signs (Blasig et al. 1973;Gellert and Sparber 1977;Martin et al. 1963;Wei et al. 1975), as well as behavioral changes which are thought to reflect the affective symptoms associated with opiate withdrawal (Koob et al. 1993;Koob et al. 1989).In opiate-dependent rats, affective or motivational signs of withdrawal are apparent at low doses of opiate antagonists at which physical signs of withdrawal are not seen (Higgins and Sellers 1994). Animals experiencing low-dose antagonist-precipitated opiate withdrawal show suppressed locomotor activity (Brady and Holtzman 1981) and operant responding for food (Gellert and Sparber 1977;Higgins and Sellers 1994;Koob et al. 1989), increased intracranial self-stimulation (ICSS) thresholds (Schaefer and Michael 1986), and aversion to the environment associated with withdrawal (Hand et al. 1988;Mucha 1987;Schulteis et al. 1994;Stinus et al. 1990). Conditioned place aversion is one of the most sensitive of these indices and can be shown in dependent animals administered doses of opiate antagonists well below those able to induce physical signs of withdrawal (Schulteis et al. 1994).Many of the behaviors associated with the motivational aspects of opiate withdrawal have been shown to be modulated by certain structures of the basal forebrain known to be a part of the extended amygdala (Heinrichs et al. 1995;Koob et al. 1989;Stinus et al. 1990), notably the nucleus accumbens (Acb) and the central nucleus (ACe) of the amygdala (Alheid and Heimer 1988). Studies by Stinus et al. (1990) showed that both regions are involved in opiate withdrawalinduced conditioned place aversion.The transcription factor c-fos is commonly used as a marker of neuronal activity. Several studies have shown that opiate withdrawal increases the expression of the c-fos protei...

Behavioral and Molecular Effects of Dopamine D1 Receptor Stimulation during Naloxone-Precipitated Morphine Withdrawal

“…Thus, naloxone-induced P-CREB in morphine-dependent rats might reflect synergism between signaling from withdrawal-induced glutamate release (Sepulveda et al, 1998) and increased cAMP. Other studies have shown that low doses of naloxone induce c-fos and Fos-related antigens (FRAs) in the NAc of morphinedependent rats (Walters et al, 2000;Gracy et al, 2001). Fos can be activated by Ca 2ϩ -mediated signaling and is not necessarily reliant on P-CREB (Lerea and McNamara, 1993), suggesting different sensitivities and functions for these various proteins.…”

“…Considering that morphine withdrawal increases the function of downstream targets of cAMP signaling in the striatum and NAc (Nye and Nestler, 1996;Gracy et al, 2001;Shaw-Lutchman et al, 2002) and triggers aversive withdrawal signs, we examined whether precipitated morphine withdrawal would activate CREB and GluR1 within the NAc. We also examined whether D 1 agonist-induced stimulation of cAMP signaling during precipitated morphine withdrawal would further increase CREB and GluR1, thereby exacerbating withdrawal signs.…”

Conditional deletion of the NMDA-NR1 receptor subunit gene in the central nucleus of the amygdala inhibits naloxone-induced conditioned place aversion in morphine-dependent mice

“…NMDA receptors are present in extensive areas of the central nervous system, including limbic brain areas that are strongly implicated in opioid plasticity (Gracy et al, 2001), particularly the central nucleus of the amygdala (CeA). Electron microscopic immunohistochemical studies indicate that NMDA receptors have a heterogeneous cellular localization in the extended amygdala and other brain areas implicated in opioid dependence.…”

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

“…Importantly, the increase in the aversive effect of naloxone has been shown to persist for 48 h after morphine administration (Parker et al, 2002), by which time very little morphine should remain in the system (Iwamoto and Klaassen, 1977). Such enhanced aversion is thought to reflect the negative motivational and affective state associated with morphine withdrawal (Gracy et al, 2001;Mucha and Walker, 1987) and may be a product of the counteradaptive processes that lead to dysregulation of hedonic homeostasis (Kreek and Koob, 1998). As important as this may be to compulsive drug seeking and addiction (Kreek and Koob, 1998), the mechanisms underlying the increase in naloxone CPA after morphine pretreatment are unknown.…”