Cocaine- and morphine-induced synaptic plasticity in the nucleus accumbens

Abstract

The critical brain areas and molecular mechanisms involved in drug abuse and dependence have been extensively studied. Drug-induced persistent behaviors such as sensitization, tolerance, or relapse, however, far outlast any previously reported mechanisms. A challenge in the field of addiction, therefore, has been to identify drug-induced changes in brain circuitry that may subserve long-lasting changes in behavior. This study examined behavioral changes and electron microscopic evidence of altered synaptic connectivity within the nucleus accumbens (NAc) following repeated administration of cocaine or morphine. The unbiased quantitative stereological physical disector method was used to estimate the number of synapses per neuron. Increases in the synapse-to-neuron ratio were found in the NAc shell of cocaine-treated (49.1%) and morphine-treated (55.1%) rats and in the NAc core of cocaine-treated animals (49.1%). This study provides direct ultrastructural evidence of drug-induced synaptic plasticity and identifies synaptic remodeling as a potential neural substrate underlying drug-induced behavioral sensitization.

Figure 1. Coronal Section of the Rat Brain

Schematic representation of a coronal section (Bregma 1.20 mm) of the rat brain atlas (Paxinos and Watson, 1998). The boxes indicate the sample areas where neuron density and synapse density quantifications were obtained from the shell and core compartments of the NAc for each animal.

Figure 2. Non-stereotypic behaviors

The average (±SEM) number of line crosses (A) rears (B) and immobility bouts (C) during the 1-hour testing session, as a function of treatment and day. Significant decreases in line crosses and rears were observed in the cocaine treated animals compared to controls. A significant decrease in those behaviors, were observed in the cocaine group on day 28 compared to day 1. Morphine produced motor immobility and it was significantly higher on day 1 relative to day 28 indicative of motor tolerance. (** indicates statistical significance (p < .05) relative to control group and day 1; * indicates statistical significance (p < .05) relative to day 1).

Figure 3. Stereotypic behaviors

The average (±SEM) number of head bobs (A) seconds spent sniffing (B) and seconds spent chewing/gnawing (C) during the 1-hour testing session, as a function of treatment and day. Sensitization of head bobbing and sniffing was evident in the cocaine group by day 28 relative to controls, whereas the morphine treated animals displayed sensitization of chewing and gnawing behavior by day 28 (** indicates statistical significance (p < .05) relative to control group and day 1; * indicates statistical significance (p < .05) relative to day 1).

Figure 4. Total and asymmetric synaptic quantification in the NAc shell

The average (±SEM) number of total synapses (A) and asymmetric synapses (B), as a function of treatment in the NAc shell. A significant increase in the total number of synapses per neuron and asymmetric synapses per neuron in the NAc were found in the cocaine and morphine treated animals (* indicates statistical significance (p < .05) relative to control group).

Figure 5. Total and asymmetric synaptic quantification in the NAc core

The average (±SEM) number of total synapses (A) and asymmetric synapses (B), as a function of treatment in the NAc core. A significant increase in the total number of synapses per neuron and asymmetric synapses per neuron in the NAc was found in the cocaine group (* indicates statistical significance (p < .05) relative to control group).

Figure 6. Electron micrograph of synapses in the NAc

Electron micrograph (18,000X) taken of asymmetric synapses (arrows) made onto spines in the NAc. A Spine apparatus can be seen in the lower left spine (arrowhead). Scale bar = 500 nm.