Drug wanting: behavioral sensitization and relapse to drug-seeking behavior

Abstract

Repeated exposure to drugs of abuse enhances the motor-stimulant response to these drugs, a phenomenon termed behavioral sensitization. Animals that are extinguished from self-administration training readily relapse to drug, conditioned cue, or stress priming. The involvement of sensitization in reinstated drug-seeking behavior remains controversial. This review describes sensitization and reinstated drug seeking as behavioral events, and the neural circuitry, neurochemistry, and neuropharmacology underlying both behavioral models will be described, compared, and contrasted. It seems that although sensitization and reinstatement involve overlapping circuitry and neurotransmitter and receptor systems, the role of sensitization in reinstatement remains ill-defined. Nevertheless, it is argued that sensitization remains a useful model for determining the neural basis of addiction, and an example is provided in which data from sensitization studies led to potential pharmacotherapies that have been tested in animal models of relapse and in human addicts.

Fig 1.

Comparison of the neurocircuitry involved in sensitization and reinstatement behaviors. The nucleus accumbens (NAc) serves as an output to motor circuits. A, in the case of sensitization, the nucleus accumbens is modulated by dopamine input from the VTA that either directly innervates this target or does so indirectly via the PVN and basolateral amygdala (BLA). The nucleus accumbens also receives direct glutamate inputs from the mPFC as well as indirect projections via the LDT/PPT and VTA. Finally, the VTA also receives glutamate input from the hippocampus (Hip). B, the circuitry underlying reinstatement is nearly identical to that of sensitization except that the Hip affects the circuit via the NAc rather than the VTA.

Fig 2.

A, the neurochemistry and neuropharmacology of the sensitization and reinstatement circuits compared with normal circuits. B, sensitization is associated with enhanced dopamine transmission from the VTA to the nucleus accumbens that results from reduced D2 autoreceptor function and enhanced AMPA (A) receptor function. Enhanced glutamate transmission from the mPFC to the nucleus accumbens and VTA is also seen in sensitized animals and is thought to result in part from reduced inhibitory modulation produced by D2 receptors and group II mGluRs (mG2/3). In addition, reduced function of the cystine/glutamate antiporter (X) produces lower basal levels of glutamate in the nucleus accumbens that leads to increased AMPA receptor function in this region. Finally, reduced basal levels of glutamate would produce reduced activation of inhibitory group II mGluRs in the nucleus accumbens that would allow for increased evoked release of glutamate in this region (not illustrated). Like sensitization (C), reinstatement is also associated with reduced basal glutamate levels in the nucleus accumbens and enhanced AMPA receptor function in this region along with enhanced drug-evoked glutamate release. Whether other drug-induced changes seen in sensitization are also apparent during reinstatement is not known.