Research reportLocomotor sensitization to cocaine is associated with increased Fos expression in the accumbens, but not in the caudate
Introduction
Repeated administrations of psychostimulant drugs, such as cocaine or amphetamine, produce a progressive and persistent increase or sensitization of their psychomotor activating effects (for review see [29]). The rewarding effects of these drugs also sensitize as indicated by the facilitation of drug self-administration and conditioned place preference [14], [28]. Therefore, sensitization-related alterations in neuronal function are thought to contribute to the transition from ‘casual’ drug taking to the compulsive drug seeking and drug taking behaviors that characterize addiction [30].
Research on the neurobiology of sensitization has focused on the caudate and accumbens because these brain regions play important roles in psychomotor activation and reward-related processes. Histochemical detection of c-fos mRNA or Fos-protein [8], [12], [31], [35], [41] has often been used because these methodologies have the advantage of detecting changes in neural activity in large populations of neurons at the single cell level. Although potentiation of drug-induced c-fos or Fos has been observed following repeated treatments with amphetamine or cocaine [6], [22], most researchers have either failed to find changes [9], [23], [37] or have reported marked tolerance [4], [7], [15], [20], [26], [31], [35]. This is surprising in light of the evidence for sensitization-related increases in both dopamine and glutamate neurotransmission in the striatum (for recent review see [40]) and the established role of these neurotransmitter systems in regulating c-fos expression [19].
There are a number of reasons why evidence for psychomotor stimulant induced sensitization of c-fos or Fos regulation is fragmented. First, in the majority of published reports [7], [15], [20], [26], [31], [35], rats were tested within 24 h following the final drug treatment (except [4], [9], [23]). In contrast, robust behavioral and neurochemical sensitization are typically seen only after an extended drug-free period [24]. Second, the effects of past drug experience may be dose-dependent and in all previous studies, the regulation of Fos was assessed only following a single challenge dose of the drug. Third, and more important, most studies have focused on the caudate nucleus (except [6], [9], [12], [33], [34]) even though a number of alterations have been reported to be restricted to the accumbens [3], [36]. Thus, in the present experiment, we examined the regulation of Fos induction in both the caudate and accumbens following a treatment regimen shown to produce robust and persistent sensitization.
Section snippets
Subjects
Male Sprague Dawley rats (Charles River, Raleigh, NC) weighing 200–225g at arrival were housed individually in standard plastic cages in a temperature and humidity controlled room. Rats were maintained on a 12:12 h light/dark cycle (lights on at 8:00 PM) and were allowed ad libitum access to food and water. Rats were acclimatized to these housing conditions for a minimum of 7 days prior to any experimental manipulation.
Behavioral testing procedures
During the pretreatment phase of the experiment, rats were removed each day
Results
Behavioral data were obtained from a total of 168 rats. Because of a freezer malfunction, the brain tissue from only approximately half of the rats were assayed for Fos immunohistochemistry (n=5–6 for each group). Thus, the group sizes for Fos-immunohistochemical analyses were less than that for behavioral analyses.
Discussion
The first injection of cocaine (i.e., saline pretreated rats receiving cocaine on the challenge test) produced marked dose-dependent increases in the number of Fos-positive nuclei in the caudate, but not in the accumbens. This result is consistent with previous reports showing that the ability of cocaine to induce Fos and c-fos mRNA is much weaker in the accumbens compared to that in the dorsal portion of the striatum [6], [35]. Repeated injections of cocaine (7 daily injections of 15mg/kg
Acknowledgements
This research was supported by funding from the National Institute on Drug Abuse (NIDA) Intramural Research Program to B.T.H.
References (41)
- et al.
Subchronic cocaine treatment enhances cocaine-induced dopamine efflux, studied by in vivo intracerebral dialysis
Brain Res.
(1989) - et al.
Persistent reduction of immediate early gene mRNA in rat forebrain following single or multiple doses of cocaine
Mol. Brain Res.
(1994) - et al.
Amphetamine sensitization augments amphetamine-induced Fos expression in the lateral habenula
Brain Res.
(1997) - et al.
Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments
Neuron
(1994) - et al.
Preexposure sensitizes rats to the rewarding effects of cocaine
Pharmacol. Biochem. Behav.
(1990) - et al.
Acute and chronic amphetamine treatments differently regulate neuropeptide messenger RNA levels and Fos immunoreactivity in rat striatal neurons
Neuroscience
(1995) - et al.
Network-level changes in expression of inducible Fos-Jun proteins in the striatum during chronic cocaine treatment and withdrawal
Neuron
(1996) - et al.
Sensitization of c-fos expression in rat striatum following multiple challenges with D-amphetamine
Brain Res.
(1993) - et al.
Brain transcription factor expression: effects of acute and chronic amphetamine and injection stress
Mol. Brain Res.
(1993) - et al.
Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis
Brain Res.
(1986)
The neural basis of drug craving: an incentive-sensitization theory of addiction
Brain Res. Rev.
Differential induction of Fos protein and a Fos-related antigen following acute and repeated cocaine administration
Mol. Brain Res.
Nicotine-induced behavioral sensitization is associated with extracellular dopamine release and expression of c-Fos in the striatum and nucleus accumbens of the rat
Behav. Brain Res.
Repeated amphetamine administration induces a prolonged augmentation of phosphorylated cyclase response element-binding protein and Fos-related antigen immunoreactivity in rat striatum
Neuroscience
A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function
Brain Res.
Behavioral sensitization to amphetamine is not accompanied by a decrease in the number of c-Fos containing cells in the striatum
Brain Res.
Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization
Brain Res.
Morphine and cocaine exert common chronic actions on tyrosine hydroxylase in dopaminergic brain reward regions
J. Neurochem.
A measure of striatal function predicts motor stereotypy
Nat. Neurosci.
Cited by (68)
Drug-activated cells: From immediate early genes to neuronal ensembles in addiction
2021, Advances in PharmacologyCitation Excerpt :Several IEGs, including Fos, Arc and Zif268, are induced by drugs of abuse in a variety of drug exposure paradigms and across multiple regions of the reward circuitry (Table 1). Fos is induced in the nucleus accumbens (NAc), dorsal striatum and prefrontal cortex (PFC) following treatment with cocaine, amphetamine or methamphetamine (Crombag et al., 2002; Graybiel et al., 1990; Hope et al., 1992; Moratalla et al., 1993; Norman et al., 1993; Robertson, Paul, Moratalla, & Graybiel, 1991; Rosen et al., 1994; Torres et al., 2015; Young et al., 1991). Like Fos, Arc expression is increased in the same three brain regions after both acute and chronic cocaine (Fosnaugh et al., 1995; Freeman et al., 2010; Fumagalli et al., 2006; Salery et al., 2017; Tan et al., 2000; Yuferov et al., 2003), methamphetamine (Fujiyama et al., 2003; Kodama et al., 1998) and amphetamine (Tan et al., 2000).
Within-animal comparisons of novelty and cocaine neuronal ensemble overlap in the nucleus accumbens and prefrontal cortex
2020, Behavioural Brain ResearchAmygdaloid involvement in the defensive behavior of mice exposed to the open elevated plus-maze
2018, Behavioural Brain ResearchUsing c-fos to study neuronal ensembles in corticostriatal circuitry of addiction
2015, Brain ResearchCitation Excerpt :These IEGs are rapidly induced within activated neurons (Cohen and Greenberg, 2008; Herdegen and Leah, 1998; Morgan and Curran, 1991) and their mRNA or protein products have long been used as markers of behaviorally activated neurons. C-fos mRNA and its protein product Fos have been the most commonly used IEG markers of neuronal activity in addiction research (Brenhouse and Stellar, 2006; Crombag et al., 2002; Graybiel et al., 1990; Hope et al., 1992; Konradi et al., 1994; Moratalla et al., 1993; Persico et al., 1993; Steiner and Gerfen, 1993; Young et al., 1991), with the first paper published in 1989 (Robertson et al., 1989). Immunohistochemical assays indicated that Fos expression is increased during cocaine or heroin self-administration throughout the corticostriatal circuitry, including medial prefrontal and orbitofrontal cortex, nucleus accumbens core and shell subregions, and the dorsal striatum (Ben-Shahar et al., 2004; Larson et al., 2010; Madsen et al., 2012; Martin-Garcia et al., 2014; Pich et al., 1997; Thiel et al., 2010; Zahm et al., 2010).
Brain regions associated with inverse incentive learning: c-Fos immunohistochemistry after haloperidol sensitization on the bar test in rats
2015, Behavioural Brain ResearchCitation Excerpt :Many studies have linked catalepsy to the dorsal and ventromedial striatum, and nucleus accumbens (NAc) [27,43]; these areas may also be involved in inverse incentive learning measured with the bar test. Areas linked to these striatal regions have been implicated in context-dependent incentive learning [2,10,15,23,26,28,40,41]. They may also be involved in inverse incentive learning; thus we evaluated striatal input regions including the cerebral cortex, ventral hippocampus (vHipp), substantia nigra, and ventral tegmental area (VTA), and output regions including the globus pallidus and ventral pallidum (VP) for c-Fos expression.