Amphetamine Activation of Hippocampal Drive of Mesolimbic Dopamine Neurons: A Mechanism of Behavioral Sensitization

Abstract

The repeated administration of psychostimulants induces an enhanced behavioral response to a subsequent drug challenge. This behavioral sensitization is proposed to model the increased drug craving observed in human psychostimulant abusers. Usingin vivoextracellular recordings from identified ventral tegmental area dopamine (DA) neurons, we report that amphetamine-sensitized rats display an activation of ventral hippocampal neuron firing and a significantly greater number of spontaneously active DA neurons compared with saline-treated rats. Moreover, TTX inactivation of the ventral hippocampus restores DA neuron activity to control levels and also blocks the expression of locomotor sensitization. Taken as a whole, we propose that behavioral sensitization to psychostimulant drugs is attributable, at least in part, to persistent activation of the ventral hippocampus–nucleus accumbens pathway, with the resultant increase in tonic DA neuron firing enabling an abnormally higher response to subsequent psychostimulant administration.