Involvement of the Nucleus Accumbens and Medial Prefrontal Cortex in the Expression of Conditioned Hyperactivity to a Cocaine-Associated Environment in Rats

Abstract

This study examined the roles of the nucleus accumbens (NAc), medial prefrontal cortex, basolateral amygdala, and ventral subiculum of the hippocampus in the expression of Pavlovian conditioned hyperactivity responses to cocainerelated stimuli. This was accomplished by pharmacologically inhibiting these regions prior to drug-free tests for conditioned hyperactivity in an environment previously associated with cocaine. The results indicate that conditioned hyperactivity could be disrupted by infusions of the baclofen (0.2 nmol/0.5 l/side) Environmental stimuli associated with cocaine use can elicit a variety of conditioned physiological and subjective responses in abstinent cocaine addicts (Childress et al. 1999;Newlin 1992). These Pavlovian conditioned responses may contribute to the maintenance of drug-taking habits in active cocaine users, and promote relapse in detoxified addicts. In rats, environments associated with cocaine evoke conditioned locomotor activation in the absence of the drug (Barr et al. 1983;Cervo and Samanin 1996;DiCiano et al. 1998a;Stewart et al. 1984). This Pavlovian conditioned behavioral activation may be analogous to some of the conditioned subjective and physiological responses elicited by cocaine-related stimuli in human drug addicts (Pert 1994). Accordingly, studies of the neurobiological mechanisms underlying conditioned behavioral activation in rats may provide valuable information that could facilitate the development of pharmacological treatments for cocaine addiction.Several lines of evidence suggest that the nucleus accumbens (NAc) may regulate the expression of conditioned responses to stimuli associated with cocaine or other psychostimulants. For example, 6-OHDA lesions of mesoaccumbens dopamine terminals post-conditioning can interfere with conditioned hyperactivity elicited NO . 6 by an environment repeatedly paired with amphetamine (Gold et al. 1988). Moreover, exposure to cocaine-or amphetamine-related cues increases dopamine release within the NAc (DiCiano et al. 1998a,b;Fontana et al. 1993;Gratton and Wise 1994), alters NAc cell firing (Bowman et al. 1996;Giampoala et al. 1999), and induces conditioned increases in Fos-related protein within the caudal NAc (Franklin and Druhan 2000;Neisewander et al. 2000; although see Brown and Fibiger 1992). Together, these studies suggest that the NAc may be important for the expression of conditioned hyperactivity responses to psychostimulantpaired stimuli.Cortical and limbic regions that project to the NAc also may regulate conditioned responses to psychostimulant-related cues. Indeed, lesions or pharmacological manipulations of the medial prefrontal cortex (mPFC), the basolateral amygdala (Bl), and the ventral subiculum of the hippocampus (vSub) disrupt the stimulus control of operant drug-seeking responses measured in place-preference, conditioned reinforcement, or self-administration procedures (Brown and Fibiger 1993; Hiroi and White 1991; Phillips 1997, 1998;Isaac et al. 1989;Tzschentke and Schmidt 1998;Whitelaw et al...

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

“…Mice were tested, in the absence of drug, for conditioned locomotor activity to their previously drug-paired environment, a behavior which depends on mPFC function (Franklin and Druhan, 2000). Adult mice that were exposed to AMPH during adolescence show significantly greater locomotor activity (95%) than their saline-treated littermates when re-exposed to the pretreatment environment (Figure 5a:…”

“…Conditioned locomotor activity is a measure of contextual salience attribution and depends on mPFC function (Stewart et al, 1984;Cervo and Samanin, 1996;Di Ciano et al, 1998;Franklin and Druhan, 2000;Hall et al, 2008;Berridge, 1993, 2008). Whereas the amphetamine regimen used in this experiment produced exaggerated salience attribution when administered in adolescence, it failed to induce salience attribution when administered in adulthood.…”

Glutamatergic mechanisms in addiction

“…Locomotion produced by a cocaine-associated environment was blocked selectively by pharmacological inactivation of the NAS and the medial PFC. 98 Conditioned locomotion in a cocaine-paired environment was not associated with increased levels of extracellular dopamine in the NAS 99 (but see, eg Ito et al 100 ), but exposure to discrete contextual stimuli repeatedly paired with cocaine significantly increased extracellular levels of glutamate in the NAS. 50 In view of the above discussion, this cue-induced glutamate release in the NAS might be a trigger for relapse.…”

The GABAB Receptor Agonist Baclofen Attenuates Cocaine- and Heroin-Seeking Behavior by Rats

“…Thus, baclofen may attenuate both cocaine and heroin incentive motivational processes through its ability to decrease nucleus accumbens DA release via effects in the VTA. However, other sites of action of the systemically administered drug are also likely, since infusion of GABA receptor agonists into the prefrontal cortex and nucleus accumbens, but not the basolateral amygdala, abolished conditioned activity expressed following exposure to a drug-paired environment (Franklin and Druhan, 2000). Thus, baclofen may disrupt conditioned influences on behaviour also via its action in limbic-cortical sites.…”

“…Baclofen is a GABA B receptor agonist that has been shown to attenuate behavior induced by conditioned stimuli when infused directly into the mesolimbic DA terminal area, the nucleus accumbens (Franklin and Druhan, 2000). Preclinical evidence that baclofen may be effective as a treatment for cocaine addiction was provided by the finding that the GABA B receptor agonist baclofen decreased the selfadministration of both cocaine (Brebner et al, 2000a, b;Roberts and Andrews, 1997) and heroin (Xi and Stein, 1999).…”