Heroin Self-Administration Experience Establishes Control of Ventral Tegmental Glutamate Release by Stress and Environmental Stimuli

Abstract

Heroin and cocaine have very different unconditioned receptor-mediated actions; however, in the brain circuitry of drug-reward and motivation, the two drugs establish common conditioned consequences. A single experience with either drug can change the sensitivity of ventral tegmental area (VTA) dopamine neurons to glutamatergic input. In the case of cocaine, repeated intravenous selfadministration establishes de novo VTA glutamate release and dopaminergic activation in response to conditioned stimuli and mild footshock stress. Here we determined whether repeated self-administration of heroin would establish similar glutamate release and dopaminergic activation. Although self-administration of heroin itself did not cause VTA glutamate release, conditioned glutamate release was seen when rats expecting rewarding heroin were given nonrewarding saline in its place. Mild footshock stress also caused glutamate release in heroin-trained animals. In each case, the VTA glutamate release was accompanied by elevations in VTA dopamine levels, indicative of dopaminergic activation. In each case, infusion of the ionotropic glutamate antagonist kynurenic acid blocked the VTA dopamine release associated with VTA glutamate elevation. Although glutamate levels in the extinction and reinstatement tests were similar to those reported in cocaine studies, the effects of heroin self-administration itself were quite different from what has been seen during cocaine self-administration.

The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research

“…Wang et al (2012) reported that footshock-induced reinstatement of heroin seeking is associated with increased glutamate (and dopamine) release in VTA, and that local blockade of ionotropic glutamate receptors prevents this reinstatement. These data extend previous results with cocaine-trained rats (Wang et al 2005).…”

“…Basolateral amygdala: Food deprivation : heroin (Tobin et al 2013). VTA: Footshock: cocaine (McFarland et al 2004; Wang et al 2005), heroin (Wang et al 2012); Swim stress: (Graziane et al 2013). Median Raphe: Footshock: alcohol (Le et al 2002); y ohimbine: alcohol (Le et al 2012).…”

Opioid-induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons

“…VTA glutamatergic signaling is also associated with conditioned rewarding effects. VTA glutamate levels, measured by microdialysis in rats self-administering intravenous cocaine (You et al, 2007) or heroin (Wang et al, 2012), increase following conditioned cues for the drug, but not following unconditioned drug exposure.…”

Bidirectional Modulation of Cocaine Expectancy by Phasic Glutamate Fluctuations in the Nucleus Accumbens

“…In animals trained to self-administer cocaine or heroin, response-contingent presentations of drug availability cues cause release of the neurotransmitter glutamate in the ventral tegmental area (You et al, 2007a; Wise et al, 2008; Wang et al, 2012) and in the nucleus accumbens (NAS) (LaLumiere and Kalivas, 2008; Suto et al, 2010: also see Hotsenpiller et al, 2001); glutamatergic input to each of these brain regions can cause renewal of responding after apparent extinction of the response tendency (Cornish et al, 1999; Suto et al, 2004; Wang et al, 2005; Wang et al, 2012). …”