Treating Substance Abuse: A Step Forward
New discoveries in neuroanatomy are helping clarify what addiction looks like in the brain. Peter Kalivas of the Medical University of South Carolina reported at the 2013 meeting of the Society of Biological Psychiatry that most drugs of abuse alter glutamate levels and the plasticity of synapses in the nucleus accumbens, the reward area of the brain. Glutamate is the main excitatory neurotransmitter in the brain, and compulsive habits may be associated with increased release of glutamate in this brain area.
During chronic cocaine administration, for example, the neurons in the nucleus accumbens lose their adaptive flexibility and their ability to respond to signals from the prefrontal cortex. Normally, low levels of stimulation would induce long-term depression (LTD) while high levels of stimulation would induce long-term potentiation (LTP). These are long-term changes in the strength of a synapse, which allow the brain to change with learning and memory. When long-term potentiation and long-term depression are no longer possible, memory and new learning in response to messages from the prefrontal cortex are diminished.
Given this absence of flexible responding, animals extinguished from cocaine self-administration (when a lever they had pressed to receive cocaine ceases to provide cocaine) are highly susceptible to cocaine reinstatement if a stressor is presented or if a signal appears that suggests the availability of cocaine. This cocaine reinstatement is associated with high levels of glutamate in the nucleus accumbens, so Kalivas reasoned accurately that lowering these levels would be associated with a lesser likelihood of cocaine reinstatement.
The drug N-acetylcysteine (NAC), which is available from health food stores, decreases the amount of glutamate in the nucleus accumbens by inducing a glutamate transporter in glial cells that helps clear excess synaptic glutamate. In Kalivas’ research, NAC prevented cocaine reinstatement, cocaine-induced anatomical changes in spine shape (bigger, stubby spines), and the loss of long-term potentiation and long-term depression in the nucleus accumbens.
The findings on NAC in animal studies led to a series of important small placebo-controlled clinical trials in people with a variety of addictions, and positive results have been found using NAC in people addicted to opiates, cocaine, alcohol, marijuana, and gambling. It also decreases hair-pulling in trichotillomania and reduces stereotypy and irritability in children with autism.
NAC also appears to be effective in the treatment of unipolar and bipolar depressed patients in placebo-controlled trials by Australian researcher Michael Berk. Thus, NAC could be useful for patients with affective disorders who are also having difficulties with comorbid substance use.
Some antibiotics (that are not commonly available) also induce the glutamate transporter and glial cells of the nucleus accumbens, offering a potential new approach to treating some addictions.
