Amphetamine-Associated Contextual Learning Is Accompanied by Structural and Functional Plasticity in the Basolateral Amygdala

Abstract

Drug seeking and the vulnerability to relapse occur when individuals are exposed to an environment with sensory cues in which drug taking has occurred. Memory formation is thought to require plasticity in synaptic circuits, and so we examined whether the memory for a drug-paired environment correlates with changes in the synaptic circuits of the basolateral amygdala (BLA), in which emotional learning is a recognized phenomenon. We used amphetamine (AMPH) as the unconditioned stimulus in the conditioned place preference (CPP) paradigm. Rats were conditioned with 1.0 mg/kg AMPH and tested, drug free, 72 h after the last conditioning session. Controls included a saline-conditioned group and a home cage AMPH injection group, whose exposure to the CPP apparatus was delayed by 4 h, long enough to clear the AMPH from the brain. We counted excitatory synapses in the BLA using the electron microscope and the physical disector design (stereology). Rats that expressed AMPH CPP had an increase in excitatory synapses compared with controls. Excitatory synaptic activity was measured using in vivo intracellular recordings from the BLA in anesthetized rats. We found that AMPH CPP, but not drug alone, increased measures of synaptic drive, including the frequency of synaptic events, and the paired-pulse ratio of synaptic inputs to BLA pyramidal neurons. The in vivo findings suggest that the increase in BLA neuronal excitatory drive reflects the change in excitatory synapse number. Thus, context-drug associations are accompanied by structural and functional plasticity in the BLA, findings that have important implications for drug-seeking behavior.

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine

“…In the current study, inactivation of the BLA also prevented the decrease in VTA activity following acute withdrawal. Amphetamine administration alone does not induce changes in synaptic strength in the BLA (Rademacher et al, 2010), although changes in neuronal activity have been described (Wang and Rebec, 1996). This suggests that the drug alone does not induce changes in synaptic plasticity in the BLA.…”

Pleasurable behaviors reduce stress via brain reward pathways

“…Importantly, synaptic remodeling provides an ideal mechanism to produce this type of preferential weighting by previous experiences. BLA plasticity can occur at both excitatory and inhibitory synapses (45)(46)(47) and is linked to altered function (48,49). Moreover, some of the plasticity-related genes affected by sucrose are linked with synaptic remodeling at both excitatory and inhibitory synapses (e.g., NMDA receptor, CamKII) (50,51), suggesting that multiple types of synaptic remodeling may be occurring after palatable food intake.…”

Addiction and Brain Reward and Antireward Pathways

“…In recent decades it has come to be appreciated that two important mechanistic substrates of synaptic remodeling are long-term potentiation (LTP) and long-term depression (LTD) [175]. LTP and LTD have been demonstrated to be produced by addictive drugs in precisely those brain loci implicated in reward and relapse - nucleus accumbens [176–179], amygdala [180,181], and hippocampus [182–184]. As a neuronal trophic factor, BDNF may be involved in - indeed, may be an underlying mechanism for - the synaptic remodeling in the nucleus accumbens, amygdala, and hippocampus that may underlie the incubation of craving phenomenon and, by extension, the development of increased vulnerability to relapse among human addicts.…”