d-Amphetamine-induced behavioral sensitization: implication of a glutamatergic medial prefrontal cortex–ventral tegmental area innervation

Previous Exposure to VTA Amphetamine Enhances Cocaine Self-Administration under a Progressive Ratio Schedule in an NMDA, AMPA/Kainate, and Metabotropic Glutamate Receptor-Dependent Manner

“…The dose of AMPH was selected based on the findings of Vezina (1996), Kim and Vezina (1998), Cador et al (1999), Vezina et al (2002), and Suto et al (2002) firmly establishing a critical role for actions of AMPH in the VTA in the induction of sensitization. In these studies, this dose of AMPH was sufficient to induce not only sensitization of its locomotor activating effects and its ability to increase extracellular levels of DA in the NAcc, but also enhanced self-administration of AMPH and cocaine.…”

“…Indeed, induction of locomotor sensitization by AMPH has been shown to be dependent on activation of Nmethyl-D-aspartate (NMDA: Cador et al, 1999;Vezina and Queen, 2000) and metabotropic glutamate (mGlu: Kim and Vezina, 1998) receptors in the VTA. Systemic administration of NMDA (Karler et al, 1989;Wolf et al, 1995) or a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor antagonists (Karler et al, 1991a;Li et al, 1997) also prevents the development of locomotor sensitization by systemic AMPH.…”

“…Systemic administration of NMDA (Karler et al, 1989;Wolf et al, 1995) or a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor antagonists (Karler et al, 1991a;Li et al, 1997) also prevents the development of locomotor sensitization by systemic AMPH. Moreover, induction of locomotor sensitization by AMPH is blocked by lesions of the PFC, which provides major glutamatergic afferentation to the VTA Cador et al, 1999).…”

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…Acamprosate, a mixed antagonist at the NMDA ionotropic glutamate receptor (iGluR) and the mGluR5 subtype of the Group1 metabotropic glutamate receptor (mGluR) [71,72], is clinically effective at treating alcoholism [73,74] and may prove to be effective for treating psychomotor stimulant and opiate addiction [75,76]. Moreover, direct pharmacological manipulation of glutamate receptors within the PFC or the NAC result in reduced behavioral responsiveness to various drugs of abuse, including cocaine [48,50,53,[77][78][79]; but see 80], alcohol [e.g., 44, 81,82], amphetamines [e.g., [83][84][85][86][87][88][89] and opiates [90-92, but see 79], and systemic administration of antagonists of glutamate receptors blocks several aspects of nicotine reward in laboratory animals [e.g., 93-100, but see 101]. Taken together, these data pose cellular factors regulating pre-and postsynaptic aspects of corticoaccumbens glutamatergic transmission as likely molecular candidates contributing to an addicted phenotype.…”

Rapid Synaptic Plasticity of Glutamatergic Synapses on Dopamine Neurons in the Ventral Tegmental Area in Response to Acute Amphetamine Injection

“…Thus, considerable effort has been directed at studying the mechanisms responsible for behavioral sensitization. Local effects of drugs of abuse on VTA neurons appear to be necessary and sufficient to trigger sensitization, because repeated local microinjections of amphetamine or morphine into the VTA elicit behavioral sensitization (Kalivas and Duffy, 1987;Kalivas and Weber, 1988;Druhan et al, 1993;Vezina, 1993;Cador et al, 1995) and microinjections of specific DA or glutamate receptor antagonists into the VTA prevent sensitization (Vezina and Stewart, 1989;Kalivas and Alesdatter, 1993;Bjijou et al, 1996;Kim and Vezina, 1998;Cador et al, 1999;Vezina and Queen, 2000). Several lines of evidence support the idea that synaptic plasticity at glutamate synapses in the VTA plays a key role in triggering sensitization and other neuroadaptations that may contribute to the development of addiction (Schenk and Snow, 1994;White, 1996;Carlezon et al, 1997;Ungless et al, 2001;Hyman and Malenka, 2001;Kauer, 2004).…”