Autonomic areas of rat brain exhibit increased Fos-like immunoreactivity during opiate withdrawal in rats

Stornetta, Ruth L.; Norton, Frederick E.

doi:10.1016/0006-8993(93)90055-r

Cited by 118 publications

(78 citation statements)

References 68 publications

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“…Outside the extended amygdala, opiate withdrawal-induced Fos immunoreactivity was observed in the septum, suggesting that this structure may also be involved in motivational responses to opiate withdrawal. In contrast, none of the regions of the forebrain known to show increased Fos levels in response to high-dose opiate withdrawal (Stornetta et al 1993) contained Fos labeling at these low doses. Only the paraventricular nucleus of the hypothalamus showed faint labeling in this study and only at the highest dose of naloxone (1000 g/kg).…”

Section: Discussionmentioning

confidence: 75%

“…Immunohistochemical localization of Fos protein in tissue from opiate withdrawn animals has been previously described in the amygdala (Stornetta et al 1993) and the BNST (Aston-Jones et al 1999;Delfs et al 2000). The doses of opiate antagonist (1-100 mg/kg naltrexone) used in these studies, however, produced physical signs of withdrawal.…”

Section: Discussionmentioning

confidence: 87%

“…Several studies have shown that opiate withdrawal increases the expression of the c-fos protein (Fos) both in brain regions associated with the physical (Beckmann et al 1995;Chieng et al 1995;Hayward et al 1990;Rohde et al 1996;Stornetta et al 1993) and motivational aspects of opiate dependence (Rasmussen et al 1995;Stornetta et al 1993). While the Acb and amygdala have been shown to have increased Fos levels during opiate withdrawal (Hayward et al 1990;Rasmussen et al 1995;Stornetta et al 1993), these studies used doses of opiate antagonists that produce dramatic physical withdrawal signs. The induction of Fos in response to naloxone doses associated only with motivational signs of withdrawal has not previously been assessed.…”

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confidence: 99%

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

Gracy

Dankiewicz

Koob

2001

Neuropsychopharmacology

118

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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...

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

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

Gracy

Dankiewicz

Koob

2001

Neuropsychopharmacology

118

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“…Recent evidence suggests that the caudal shell of the NAc is substantially innervated by NA fibers from caudal brainstem nuclei (A1 and A2 cell groups), whereas the core and rostral pole subregions are devoid of such inputs (Berridge et al 1997;Delfs et al 1998). Opiate withdrawal potently activates NA cells in the caudal medullary cell groups, and increases NA release in the NAc (Stornetta et al 1993;Baraban et al 1995;Zhu et al 1997;McKittrick et al 1999). Stimulation of NA receptors has been found to increase FRA expression in several brain areas (Stone et al 1991(Stone et al , 1995Bing et al 1992), and a greater activation of NA receptors in the caudal shell may contribute to the neuronal activation in this subregion observed during opiate withdrawal.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of Fos-related antigen (FRA) in cell nuclei can be detected immunohistochemically to identify cells that have been influenced by specific experimental treatments (Dragunow and Faull 1989;Morgan and Curran 1991;Sagar et al 1988). Several studies have used this technique successfully to identify CNS regions influenced by specific pharmacological or behavioral manipulations (Brown et al 1992;DiNardo and Travers 1997;Pfaus et al 1996), including opiate withdrawal (Stornetta et al 1993). Our studies employed FRA immunohistochemistry to examine withdrawal-related neuronal activity within specific subregions of the NAc, and to determine whether stimulation of D2 receptors could interfere with this activity.…”

Section: Previous Studies From This Laboratory Indicated That D2 Dopamentioning

confidence: 99%

Expression of Fos-related Antigens in the Nucleus Accumbens during Opiate Withdrawal and Their Attenuation by a D2 Dopamine Receptor Agonist

Walters

Aston‐Jones

Druhan

2000

Neuropsychopharmacology

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Previous studies from this laboratory indicated that D2 dopamine (DA) receptors within the nucleus accumbens (NAc) are important for regulating somatic signs of opiate withdrawal. The present study measured the expression of Fos-related antigens (FRAs) The abrupt cessation of chronic opiate use results in a well-characterized withdrawal syndrome that includes symptoms of nausea, dysphoria, and anxiety. This syndrome is sufficiently adverse that opiate abusers will continue to use drugs to relieve the symptoms of withdrawal. In fact, the need to self-medicate has been identified as an important factor contributing to the maintenance of opiate use, and a major impediment to successful drug detoxification and rehabilitation (Schulteis and Koob 1996).Studies of the neurobiological basis for opiate withdrawal have identified a potential role for dopaminergic processes within the nucleus accumbens (NAc) in the expression of opiate withdrawal symptoms. This involvement of the NAc in opiate withdrawal was first suggested by findings that intra-NAc infusions of the quaternary opiate antagonist methylnaloxinium could disrupt operant responding for food and induce conditioned aversions for environments associated with the central infusion (Koob et al. 1989;Stinus et al. 1990). Subsequent in vivo microdialysis studies revealed that extracellular dopamine (DA) levels within the NAc were reduced during both naloxone-precipitated and abstinence-induced opiate withdrawal, thus implicating DA processes within the NAc in the expression of NO . 3 withdrawal symptoms (Acquas et al. 1991;Crippens and Robinson 1994;Rossetti et al. 1992;Shaham et al. 1996). Studies in our laboratory have shown that somatic signs of opiate withdrawal can be elicited by infusions of a D2 DA antagonist, whereas somatic signs precipitated by systemic naloxone injections can be abolished by intra-NAc infusions of a D2 receptor agonist (Harris and Aston-Jones 1994).The present study further examined the role of NAc processes in opiate withdrawal by assessing whether opiate withdrawal states were associated with changes in neuronal activity within the NAc, and whether any measured changes could be reversed when somatic signs of opiate withdrawal were alleviated by systemic injections of the D2 agonist propylnorapomorphine (NPA). To accomplish this, we measured withdrawalinduced changes in the expression of immediate early gene (IEG) products within NAc cells. Changes in neuronal activity often result in the induction of IEGs that, in turn, promote the synthesis of various intracellular constituents including Fos or Fos-related proteins. The presence of Fos-related antigen (FRA) in cell nuclei can be detected immunohistochemically to identify cells that have been influenced by specific experimental treatments (Dragunow and Faull 1989;Morgan and Curran 1991;Sagar et al. 1988). Several studies have used this technique successfully to identify CNS regions influenced by specific pharmacological or behavioral manipulations (Brown et al. 1992;DiNardo and Trave...

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Activation of neuropeptide FF neurons in the brainstem nucleus tractus solitarius following cardiovascular challenge and opiate withdrawal

et al. 1998

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Neuropeptide FF (NPFF), a morphine modulatory peptide, is localized within discrete autonomic regions including the brainstem nucleus tractus solitarius (NTS) and the parabrachial nucleus (PBN). We investigated the activation of NPFF neurons in the NTS of rats induced by cardiovascular challenge and centrally generated opiate withdrawal. For hypotensive stimulation, we used systemic infusions of sodium nitroprusside (NP) or hemorrhage (HEM), and hypertension was achieved by intravenous phenylephrine (PHENYL) or angiotensin II (AII). In rats that received continuous intracerebroventricular injections of morphine, intraperitoneal injections of naloxone precipitated behavioural signs of opioid withdrawal. Activated NTS neurons were identified by using a combined immunohistochemistry for Fos and NPFF, and neurons projecting to the PBN were determined with a retrograde tracer. HEM, administration of vasoactive drugs, and opiate withdrawal produced a very robust activation of NTS neurons. In NP and HEM groups, 25.6+/-3.2% and 7.6+/-1.3% of NPFF neurons were activated, respectively. Lesser numbers of NPFF neurons were activated in the PHENYL (4.6+/-1.6%) and AII (2.4+/-0.8%) groups. However, following opiate withdrawal, virtually no Fos expression was observed in NPFF neurons. NPFF neurons activated during NP infusion constituted the largest number of cells projecting to the PBN. This study shows that NPFF neurons in NTS that project to the PBN respond selectively to NP as opposed to other cardiovascular challenges or opiate withdrawal. These data support an emerging and important role for NPFF in the context of central cardiovascular regulation.

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Autonomic areas of rat brain exhibit increased Fos-like immunoreactivity during opiate withdrawal in rats

Cited by 118 publications

References 68 publications

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

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

Expression of Fos-related Antigens in the Nucleus Accumbens during Opiate Withdrawal and Their Attenuation by a D2 Dopamine Receptor Agonist

Activation of neuropeptide FF neurons in the brainstem nucleus tractus solitarius following cardiovascular challenge and opiate withdrawal

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