Although many studies have shown Pavlovian conditioned approach to cues paired with natural reinforcers, it has been quite difficult to induce such behavior with drug reinforcers.
This experiment tested a novel Pavlovian procedure for inducing approach to a conditioned stimulus (CS) paired with ethanol.
Mice (NZB/B1NJ, DBA/2J) received intraperitoneal injections of ethanol (2 g/kg) immediately before 10-min exposure to a rectangular chamber that contained a distinctive visual cue (star) at one end (Paired group, CS+ trials). On alternate days, saline injection preceded apparatus exposure with no distinctive cues (CS- trials). Unpaired control mice received ethanol in the home cage 60-75 min after each CS+ trial.
NZB/B1NJ Paired group mice spent increasing amounts of time (>85% of the session) in proximity to the star, whereas Unpaired group mice did not. DBA/2J Paired group mice spent slightly more time on the star side than Unpaired group mice but did not show an acquisition curve. Postconditioning tests showed a strong preference for the star side in Paired groups from both strains after saline injection. However, only NZB/B1NJ mice showed a preference after ethanol.
This study provides the first unambiguous demonstration of Pavlovian conditioned approach to an ethanol-paired visual stimulus in the absence of any contingency between the animal's behavior and drug exposure. This effect, which is remarkable both in terms of its magnitude and the rapidity with which it was produced (within 2-3 trials), may be related to the cue-associated craving that accompanies alcohol and drug addiction.
"In the current study, we used a previously established CPP paradigm (Liu et al., 2010; Young et al., 2011b) to investigate the effects of pair bonding experience on the rewarding properties of AMPH. We use the ambiguous term 'rewarding properties' to describe the impact of AMPH on place conditioning because it allows us to simultaneously address the individual components of reward—including hedonics, associative learning, and incentive motivation (Berridge and Robinson, 2003)—that have been implicated in processes underlying place conditioning (Hnasko et al., 2005; White et al., 2005; Cunningham and Patel, 2007), without distinguishing between them. Our results demonstrate that AMPH conditioning induced a CPP in SN, but not PB, male voles, and as such, offer the first empirical evidence that pair bonding experience decreases the rewarding properties of AMPH. "
[Show abstract][Hide abstract] ABSTRACT: Although the protective effects of social bonds on drug use/abuse have been well documented, we know little about the underlying neural mechanisms. Using the prairie vole (Microtus ochrogaster)--a socially monogamous rodent that forms long-term pair bonds after mating--we demonstrate that amphetamine (AMPH) conditioning induced a conditioned place preference (CPP) in sexually naive (SN), but not pair-bonded (PB), males. Although AMPH treatment induced a similar magnitude of dopamine release in the nucleus accumbens (NAcc) of SN and PB males, it had differential effects on NAcc D1 receptor (D1R) binding. Specifically, AMPH treatment increased D1R binding in SN, but decreased D1R binding in PB males. NAcc D1R, but not D2 receptor, antagonism blocked AMPH-induced CPP in SN males and NAcc D1R activation before AMPH conditioning enabled AMPH-induced CPP in PB males. Together, our data demonstrate that pair-bonding experience decreases the rewarding properties of AMPH through a D1R-mediated mechanism.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2011; 31(22):7960-6. DOI:10.1523/JNEUROSCI.1006-11.2011 · 6.34 Impact Factor
"These two aspects of cue–reward association appear to be mediated by different neural systems (Parkinson et al., 2000). In a modified version of the CPP task, Cunningham and Patel (2007) demonstrated that mice will show Pavlovian approach, seen as approach to a discrete cue associated with alcohol administration. Additionally, we have recently demonstrated that binge exposure to ethanol enhances sign-tracking behaviour for a sucrose reward in C57BL/6J mice (Ripley, unpubl. "
[Show abstract][Hide abstract] ABSTRACT: Despite years of neurobiological research that have helped to identify potential therapeutic targets, we do not have a reliable pharmacological treatment for alcoholism. There are a range of possible explanations for this failure, including arguments that alcoholism is a spectrum disorder and that different population subtypes may respond to different treatments. This view is supported by categorisations such as early- and late-onset alcoholism, whilst multifactorial genetic factors may also alter responsivity to pharmacological agents. Furthermore, experience of alcohol withdrawal may play a role in future drinking in a way that may distinguish alcoholism from other forms of addiction. Additionally, our neurobiological models, based largely upon results from rodent studies, may not mimic specific aspects of the human condition and may reflect different underlying phenomena and biological processes from the clinical pattern. As a result, potential treatments may be targeting inappropriate aspects of alcohol-related behaviours. Instead, we suggest a more profitable approach is (a) to identify well-defined intermediate behavioural phenotypes in human experimental models that reflect defined aspects of the human clinical disorder and (b) to develop animal models that are homologous with those phenotypes in terms of psychological processes and underlying neurobiological mechanisms. This review describes an array of animal models currently used in the addiction field and what they tell us about alcoholism. We will then examine how established pharmacological agents have been developed using only a limited number of these models, before describing some alternative novel approaches to achieving homology between animal and human experimental measures.
British Journal of Pharmacology 04/2011; 164(4):1335-56. DOI:10.1111/j.1476-5381.2011.01406.x · 4.84 Impact Factor
"Since recent data have demonstrated a negative correlation between test activity levels and magnitude of preference (Gremel & Cunningham, 2007), it could be that increased activity levels during testing disrupted CPP. However, even though AP-5 treated mice were slightly more active during testing (see Table 3), we previously reported that a similar level of test activity expressed in a different set of mice was insufficient to disrupt expression of ethanol CPP (Gremel & Cunningham, 2007). This suggests that the lack of preference expressed following unilateral AP-5 infusions cannot solely be attributed to activity influences on CPP behavior. "
[Show abstract][Hide abstract] ABSTRACT: There is a strong interest in harnessing the genetic manipulations that are possible in mice to investigate the functional neural mechanisms modulating the associative processes that control drug-seeking behavior. However, it is unknown whether intracranial techniques, such as the disconnection procedure commonly used in rats to examine serial connectivity between implicated areas, can be successfully applied to mice. We have previously demonstrated that the expression of ethanol-seeking behavior in mice is dependent upon amygdala (Amy) dopamine and nucleus accumbens (Acb) N-methyl-d-aspartate (NMDA) receptor activation (Gremel & Cunningham, 2009). Here, we used a neuropharmacological disconnection procedure to investigate whether dopamine activation of the Amy directly leading to increases in Acb glutamate release and binding of NMDA receptors modulates the expression of ethanol-seeking behavior. Immediately before testing the expression of an ethanol-induced conditioned place preference, mice were given an Amy infusion of flupenthixol and either an ipsilateral or contralateral Acb infusion of AP-5. Although both ipsilateral and contralateral manipulations reduced the expression of ethanol conditioned place preference, in a separate experiment we demonstrated that a unilateral Acb infusion of AP-5, but not Amy flupenthixol, is sufficient to disrupt preference. The finding of a significant blockade by unilateral AP-5 into the Acb precludes any conclusions about a unique role for the Amy/Acb neuroanatomical connection in this model of ethanol-seeking behavior. Further, the current results suggest potential limitations in transferring techniques from rats to mice in order to study serial interactions between neural areas underlying motivated behaviors. Nevertheless, these findings provide evidence showing that Acb NMDA receptors play an important role in the expression of ethanol-conditioned behavior.
European Journal of Neuroscience 01/2010; 31(1):148-55. DOI:10.1111/j.1460-9568.2009.07044.x · 3.18 Impact Factor
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