Altered neural cholinergic receptor systems in cocaine-addicted subjects

Abstract

Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1- to 6-week abstinent, cocaine- (and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p<0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

Figure 1

Flowchart of physostigmine, scopolamine, and ondansetron infusions. Four sessions, each at least 48 h apart, were conducted over 10 days. In addition to the three infusions noted, a saline infusion was administered on a separate day. Session order was pseudorandomized to assure randomization and to avoid having the two cholinergic probes (physostigmine and scopolamine) administered in consecutive sessions.

Figure 2

Regional cerebral blood flow (rCBF) changes in response to physostigmine relative to saline (p<0.005) in 22 control and 22 cocaine-addicted (middle panel) subjects. In upper and middle panels, yellow areas reveal voxels with increased rCBF after physostigmine relative to saline and blue areas reveal voxels with decreased rCBF after physostigmine relative to saline. Bottom panel displays comparison between cocaine-addicted (physostigmine—saline) and control (physostigmine—saline) subjects. Yellow areas display voxels with greater rCBF response to physostigmine in patients relative to controls; blue areas are voxels with decreased rCBF response in patients relative to controls. MNI coordinates (Z axis) noted at the bottom left of each image. L=left; R=right; DLPFC=dorsolateral prefrontal cortex; ACC=anterior cingulate cortex; amyg=amygdala; hp=hippocampus; ins=insula; MTG=middle temporal gyrus; PCC=posterior cingulate cortex. See Supplement 1 (controls), Supplement 2 (cocaine addicted), and Supplement 3 (comparison images) for all transverse images.

Figure 3

Counts per voxel in the region of the left posterior hippocampus in control and cocaine-addicted subjects after physostigmine infusion relative to saline infusion. Images provide sagittal view (X axis −24) of posterior hippocampus (arrow) and amygdala in patients after physostigmine (^*non-smokers in cocaine-addicted group).

Figure 4

Regional cerebral blood flow (rCBF) changes in response to scopolamine relative to saline (p<0.005) in 20 control (top panel) and 23 cocaine-addicted (middle panel) subjects. In upper and middle panels, yellow areas reveal voxels with increased rCBF after scopolamine relative to saline and blue areas reveal voxels with decreased rCBF after scopolamine relative to saline. Bottom panel displays comparison between cocaine-addicted (scopolamine—saline) and control (scopolamine—saline) subjects. Yellow areas display voxels with greater rCBF to scopolamine in patients relative to controls; blue areas are voxels with decreased rCBF response in patients relative to controls. MNI coordinates (Z axis) noted at the bottom left of each image. L=left; R=right; OFC=orbitofrontal cortex; DLPFC=dorsolateral prefrontal cortex; midbrn=midbrain; hp=hippocampus; ins=insula; PCC=posterior cingulate cortex. See Supplement 4 (controls), Supplement 5 (cocaine addicted), and Supplement 6 (comparison images) for all transverse images.