The rate of cocaine administration alters gene regulation and behavioral plasticity: implications for addiction

Abstract

The rapid delivery of drugs of abuse to the brain is thought to promote addiction, but why this occurs is unknown. In the present study, we characterized the influence of rate of intravenous cocaine infusion (5-100 sec) on three effects thought to contribute to its addiction liability: its ability to block dopamine (DA) uptake, to activate immediate early gene expression, and to produce psychomotor sensitization. Rapid infusions potentiated the ability of cocaine to block DA reuptake, to induce c-fos and arc mRNA expression, especially in mesocorticolimbic regions, and to produce psychomotor sensitization. Thus, the rate at which cocaine is delivered influences both its neurobiological impact and its ability to induce a form of drug experience-dependent plasticity implicated in addiction. We propose that rapidly delivered cocaine may be more addictive, in part, because this more readily induces forms of neurobehavioral plasticity that lead to the compulsive pursuit of drugs.

Figure 5.

c-fos mRNA density in the CPu as a function of rate of cocaine administration (values are mean ± SEM). Also included are representative densitograms illustrating c-fos mRNA levels in the brains of animals given cocaine over 5, 25, or 100 sec, or vehicle over 5 sec. In a-d, animals in the 5 sec group are represented by filled circles, animals in the 25 sec group are represented by filled triangles, animals in the 100 sec group are represented by filled diamonds, and control animals are represented by open circles.

Figure 1.

Representative histological plates from the DM CPu showing cells double labeled for c-fos mRNA and preproenkephalin mRNA. Top, Bright-field images in which Enk+ cells appear as purple precipitate. Middle, Dark-field images in which c-fos+ cells appear as silver grain clusters. Bottom, Overlay of bright-field and dark-field images. The vertical arrows indicate single-labeled cells (c-fos or Enk+ mRNA), and horizontal arrows indicate double-labeled cells (c-fos/Enk+).

Figure 6.

The effect of the infusion rate on the ability of cocaine to prolong the half-life (an index of reuptake inhibition) of electrically evoked DA release in the Nacc core. For illustrative purposes, a shows typical traces corresponding to the average of three consecutive individual recordings obtained just before an infusion of saline or cocaine (2.0 mg/kg over 5 sec), and 50, 60, and 70 sec after injection, and shows how DA half-life (t_1/2) was determined. b shows the effect of the cocaine infusion rate on DA half-life (values are mean ± SEM). Animals in the 5 sec group are represented by filled circles, animals in the 25 sec group are represented by filled triangles, animals in the 100 sec group are represented by filled diamonds, and control animals are represented by open circles. During the 2 min before and 3 min after the infusion, DA half-life is shown every 20 sec, and thereafter one sample is shown every 2 min for three consecutive data points and every 5 min for all subsequent data points. c shows peak levels of DA uptake inhibition by cocaine as a function of infusion rate (values are mean ± SEM).

Figure 2.

Locomotor activity (quadrant entries) averaged over the first 12 min after an intravenous infusion of 2.0 mg/kg cocaine given over 5, 25, or 100 sec, on 2 consecutive days (values are mean ± SEM).

Figure 3.

The effect of infusion rate on cocaine-induced c-fos and arc mRNA in the medial prefrontal and orbitofrontal cortices (values are mean ± SEM).

Figure 4.

c-fos and arc mRNA expression at three levels of the Nacc core and shell as a function of cocaine infusion rate (values are mean ± SEM). •, Animals in the 5 sec group; ▴, animals in the 25 sec group; ♦, animals in the 100 sec group; ○, control animals.