Music and methamphetamine: Conditioned cue-induced increases in locomotor activity and dopamine release in rats

Abstract

Associations between drugs of abuse and cues facilitate the acquisition and maintenance of addictive behaviors. Although significant research has been done to elucidate the role that simple discriminative or discrete conditioned stimuli (e.g., a tone or a light) play in addiction, less is known about complex environmental cues. The purpose of the present study was to examine the role of a musical conditioned stimulus by assessing locomotor activity and in vivo microdialysis. Two groups of rats were given non-contingent injections of methamphetamine (1.0 mg/kg) or vehicle and placed in standard conditioning chambers. During these conditioning sessions both groups were exposed to a continuous conditioned stimulus, in the form of a musical selection (“Four” by Miles Davis) played repeatedly for 90 min. After seven consecutive conditioning days subjects were given one day of rest, and subsequently tested for locomotor activity or dopamine release in the absence of drugs while the musical conditioned stimulus was continually present. The brain regions examined included the basolateral amygdala, nucleus accumbens, and prefrontal cortex. The results show that music is an effective contextual conditioned stimulus, significantly increasing locomotor activity after repeated association with methamphetamine. Furthermore, this musical conditioned stimulus significantly increased extracellular dopamine levels in the basolateral amygdala and nucleus accumbens. These findings support other evidence showing the importance of these brain regions in conditioned learning paradigms, and demonstrate that music is an effective conditioned stimulus warranting further investigation.

Introduction

Drug addiction is a chronic relapsing disease characterized by neurobiological changes that lead to compulsive drug taking (Koob, 2000). Exposure to cues previously paired with drug reward have been shown to elicit craving and cause drug seeking behavior in both human and animal models of relapse (Childress et al., 1999, Di Ciano and Everitt, 2003, Fuchs et al., 2008, O'Brien et al., 1998). These drug-paired conditioned stimuli (CS) ostensibly hijack normal learning and memory processes, allowing maladaptive addictive behaviors to acquire increased salience. It is therefore of great importance to elucidate the behavioral and biochemical mechanisms through which drug-associated stimuli exert their effects.

The basolateral amygdala (BLA) encodes the motivating and reinforcing properties of CS via populations of cue-responsive neurons. This neuronal activation supplies cognitive systems with information regarding the motivational and reinforcing qualities of an associated cue that help determine, plan, and execute the appropriate behavioral response (Tye and Janak, 2007). Alterations of the cortico-limbic-striatal circuitry may influence associative learning mediated by the BLA, the brain area ultimately responsible for cue-induced reinstatement of drug-seeking behavior (McLaughlin and Floresco, 2007). Repeated psychostimulant exposure may affect reciprocal, functional connections between the BLA and other reward-related structures, signaling changes in incentive salience and influencing behavioral and neurochemical responses.

The functional relationship between the BLA and the nucleus accumbens (NAcc) promotes goal-directed behavior based on learned associations related to reward. Exposure to reward predictive stimuli has been shown to increase dopamine (DA) efflux in the NAcc and BLA (Weiss et al., 2000). Furthermore, several studies using conditioning paradigms have documented the complex role of the NAcc with regard to psychostimulant seeking and goal directed behavior (Bossert et al., 2005, Everitt and Robbins, 2005, See, 2005). The persistent craving induced by a drug-paired CS has been proposed to be mediated by drug-induced maladaptive encoding of memory via an amygdala–accumbens interaction (Di Ciano and Everitt, 2004).

The involvement of the prefrontal cortex (PFC) in addictive behaviors can be attributed to processes that coordinate sensory and cognitive information, allowing selection of the goal-directed behavior that will likely produce the most advantageous outcome. The BLA provides the PFC with information regarding the motivational significance of the stimuli, and the PFC processes and integrates the affective afferent projections to determine the salient relevance of the stimulus, in order to guide behavior appropriately and purposefully (McLaughlin and See, 2003).

Previous studies that have examined the role of psychostimulant-paired CS in these brain regions have almost all used simple discrete or discriminative CS (e.g., a tone or light). While meeting the criteria of neutrality prior to conditioning, these CS fail to simulate the complexity of contextual cues present in human drug experiences. Conditioned place preference (CPP) paradigms have been used extensively to investigate more complex contextual cues (Bardo et al., 1995, Tzschentke, 2007). However, the effect seen with CPP relies upon CS-reward interactions that take place within the same apparatus. One could seemingly make a stronger case for the influence of a reward-paired contextual CS if the conditioning and test environments were not similar. If a contextual CS was able to influence drug seeking behavior in a different environment, then there would be more certainty that the CS was the determining factor, rather than place serving as a potential confound. The ultimate goal of any animal model is to experimentally replicate conditions present in human pathologies, in order to generalize findings to the human population. Therefore, it would be beneficial if animal models of drug seeking were able to incorporate the same kinds of environmental stimuli that are salient in the human addiction cycle.

Recently, it has been reported that music can enhance MDMA-conditioned reward in rats (Feduccia and Duvauchelle, 2008). This study showed increases in both locomotor behavior and extracellular DA in the NAcc when music was paired with MDMA during operant self-administration. Another recent report demonstrated that rats have the ability to discriminate between music by Bach and Stravinsky, and even transfer this discrimination to novel musical selections by the same artists (Otsuka et al., 2009). Furthermore, both of these studies found that music evoked no primary reinforcing properties by itself. Taken together, these reports indicate that music could serve as an effective contextual conditioned stimulus in rats.

Pleasurable music evokes neurological responses in humans that are similar to the effects induced by drugs of abuse. Specifically, highly enjoyable music has been shown to activate reward-related brain regions such as the striatum, amygdala, and PFC (Blood and Zatorre, 2001). Music has also been shown to increase dopaminergic neurotransmission (Sutoo and Akiyama, 2004). More advanced techniques such as functional magnetic resonance imaging (fMRI) have shown that pleasurable music is strongly correlated with activation in reward-related brain regions such as the NAcc and ventral tegmental area (VTA); enhanced functional connectivity between brain regions that mediate reward may help explain why listening to music is regarded as a highly pleasurable human experience (Menon and Levitin, 2005). Recent clinical reports also indicate that music can be an effective treatment for a multitude of disorders. Music therapy has shown promising results in treating anxiety, chronic stress, pain, sleep disorders, autism, depression, psychosis, post-traumatic stress disorder, respiratory disease, and as an adjunct therapy for addiction. (Bauldoff, 2009, Bradt and Dileo, 2009, de Niet et al., 2009, Gold et al., 2009, Jung and Newton, 2009, Mays et al., 2008, Nilsson, 2008, Rossignol, 2009). However, while musical appreciation is well documented in the human population, there is still significant disagreement in the literature about whether this is confined to the human species or extends to other members of the animal kingdom. Considering the enormous potential that music therapy offers, there is a growing need to develop preclinical models.

The goal of the present study was to address these issues by using a musical CS in a classical conditioning paradigm. To this end, we conditioned rats for one week with a contextual/musical CS (“Four” by Miles Davis) either in the presence or absence of methamphetamine (METH), our unconditioned stimulus (US). The effects of conditioning were then assessed in a non-drug state by measuring locomotor activity and extracellular levels of DA (using in vivo microdialysis); brain regions dialyzed included the BLA, NAcc, and mPFC. Based on previous findings, we postulated that, after conditioning, music alone would increase locomotor activity and increase extracellular DA in the brain regions examined.