Cocaine-induced potentiation of synaptic strength in dopamine neurons: Behavioral correlates in GluRA(–/–) mice

Abstract

Synaptic plasticity in the mesolimbic dopamine (DA) system is thought to contribute to the neural adaptations that mediate behavioral sensitization, a model for core aspects of addiction. Recently, it has been demonstrated that multiple classes of drugs of abuse, as well as acute stress, enhance strength at excitatory synapses on midbrain DA neurons. Here, we show that both the cocaine-and stress-induced synaptic enhancement involves an up-regulation of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This enhancement requires the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluRA as evidenced by its absence in mice lacking this subunit. The cocaine-elicited, but not the stress-elicited, synaptic potentiation in DA neurons was blocked by a D1-like receptor antagonist, indicating that the in vivo triggering mechanisms differ for these forms of experience-dependent synaptic modification. Surprisingly, behavioral sensitization to cocaine was elicited in GluRA(؊͞؊) mice, indicating that potentiation of excitatory synaptic transmission in DA neurons is not necessary for this form of behavioral plasticity. However, GluRA(؊͞؊) mice did not exhibit a conditioned locomotor response when placed in a context previously paired with cocaine, nor did they exhibit conditioned place preference in response to cocaine. We suggest that the drug-induced enhancement of excitatory synaptic transmission in midbrain DA neurons, although not required for behavioral sensitization per se, may contribute to the attribution of incentive value to drug-associated cues.

Cocaine Enhances NMDA Receptor-Mediated Currents in Ventral Tegmental Area Cells via Dopamine D5Receptor-Dependent Redistribution of NMDA Receptors

“…Recent evidence has shown that blockade of D 1 /D 5 receptor inhibits the AMPAR/NMDAR ratio increase on VTA neurons produced by in vivo cocaine exposure (Dong et al, 2004), supporting our hypothesis for a role of a D 5 -dependent potentiation of NMDARs as a possible mechanism in mediating VTA long-term plasticity produced by cocaine.…”

Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors

“…[24][25][26][27][28][29] Previous studies have demonstrated that GluR1 knockout mice (KO) 30 exhibit behavioral abnormalities on tests for cognition, motor function and responses to drugs of abuse. [30][31][32][33][34][35][36][37] In the present study, we sought to extend these data by assessing these mice for a variety of 'schizophrenia-related' phenotypes. In addition, given the wealth of evidence implicating dysfunction of dopamine (DA) neurotransmission in schizophrenia 2 and the major interaction between the dopamine and glutamate systems, 2,38 we evaluated regulation of extracellular striatal DA in GluR1 KO in vivo using high-speed chronoamperometry.…”

Dopamine Receptor Stimulation Modulates AMPA Receptor Synaptic Insertion in Prefrontal Cortex Neurons

“…Therefore, effects of addictive drugs on long-term potentiation (LTP) and long-term depression (LTD) have become a focus of addiction research (Kauer, 2004;Wolf et al, 2004). Dopamine (DA) receptors modulate LTP and LTD in many brain regions important for addiction (Centonze et al, 2003;Jay, 2003;Lovinger et al, 2003), as do DA-releasing psychomotor stimulants such as cocaine (Jones et al, 2000;Thomas et al, 2000Thomas et al, , 2001Ungless et al, 2001;Saal et al, 2003;Dong et al, 2004). However, the mechanisms involved are unclear.…”