When amphetamine is repeatedly associated with the same environmental context, the environment becomes a powerful stimulus to elicit memories of the drug experience. These memories bring out a strong, physiological response, even in the absence of drug. Such associative learning is maladaptive and contributes to the poor judgment of individuals who crave the drug. However, we know surprisingly little of the synaptic modifications that shape drug-related memories, even though memory retrieval appears critical for the persistence of drug-seeking behavior. Conditioned place preference (CPP) is a model of cue-elicited drug seeking. When amphetamine is repeatedly paired with the same environment, rats learn to associate the rewarding effects of the drug with the cues provided by the environment. Our work has shown that the neural circuitry underlying this behavior could involve synaptic interactions between the hippocampal formation and basolateral amygdala (BLA). We have shown that amphetamine-induced CPP (AM PH CPP) is accompanied by increased synapses and a significant elevation in synaptic drive from the hippocampal formation. We believe that drug-seeking behavior therefore requires both structural and functional plasticity of BLA pyramidal cells to consolidate the learned association of drug and environment. We hypothesize further that this plasticity is mediated by the hippocampal formation. Through experiments outlined herein, we have set 2 specific aims: (1) The first will determine how AMPH CPP rewires BLA pyramidal neurons. The goal is to examine how CPP alters the eXCitatory and inhibitory synaptic complements of pyramidal neurons, using light and electron microscopy, immunocytochemistry and stereology. (2) In the scond, we will determine if AM PH CPP causes enhanced eXCitatory synaptic drive of BLA pyramidal neurons. The goals are to determine, using in vivo intracellular electrophysiological recordings, if BLA pyramidal neurons are subjected to abnormal excitatory drive, and if the hippocampal formation contributes to the excitation. The neuronal structure (dendrites and spines) of recorded BLA neurons will be studied to establish whether morphogenesis (increased spines, dendritic length and branching) is indicative of the strong increases in synaptic drive.
The environment in which humans take elicit drugs evokes memories of the drug experience. These associations are learned and that learning is maladaptive. The proposed studies will identify the structural and functional bases that mediate druginduced learning. Results will fill gaps in our knowledge of the biological basis of drug craving and open avenues to novel therapeutic strategies for its treatment.
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