Am J Psychiatry 165:11, November 2008
Images in Neuroscience
Carol A. Tamminga, M.D., Editor
Regulation of Synaptic Connectivity With Chronic Cocaine
In animal models of addiction, repeated exposure to drugs of
abuse, such as cocaine, amphetamines, and nicotine, increases
the number of dendritic spines (panel A) in the nucleus accum-
bens (NAc), a key brain region involved in reward, pleasure, and
motivation. Dendritic spines are the primary anatomical sites of
excitatory synapses. Many scientists deem that this long-lasting
increase in synaptic connectivity in the NAc may underlie the
similarly persistent behaviors of drug taking and drug seeking as-
sociated with drug addiction and relapse. Although this concept
is appealing, the functional relationship between increased syn-
aptic connectivity in the NAc and addiction-related behaviors is
poorly understood. Our recent findings shed some important
light on this issue.
We recently found that cocaine regulates myocyte enhancer
factor 2 (MEF2) transcription factors in the NAc to control the ob-
served increase in synaptic connectivity. During development,
MEF2 sculpts mature brain circuits by promoting activity-depen-
dent synapse elimination. Excitatory synaptic activity and subse-
quent calcium signaling events stimulate MEF2 activity. However,
after chronic cocaine exposure or activation of dopamine recep-
tor signaling, we observed a decrease in MEF2 activity in the stri-
atum and found that decreasing MEF2 activity in the NAc pro-
moted an increase in dendritic spine density. We also found that
chronic cocaine and dopamine signaling reduced MEF2 activity
in the striatum through novel signaling pathways involving the
regulator of calmodulin signaling (RCS), calcineurin (CaN), and
Cdk5 (panel B). Reducing MEF2 is required for cocaine-induced
dendritic spine plasticity in vivo. On the other hand, we observed
that expression of a hyperactive MEF2 in the NAc, the condition
that blocked dendritic spine changes, increased behavioral
responses to repeated cocaine exposure. This suggests that the
increased spine density in the NAc is not required for cocaine-
induced behavioral plasticity and that increased synaptic con-
nections during chronic drug use may actually limit behavioral
changes associated with drug addiction rather than support
them. Together with the previous literature, our findings suggest
that the increased density of synapses may be a compensatory re-
sponse to decreased activity of these brain reward regions. There-
fore, a focus on enhancing synaptic contacts and neuronal activ-
ity in the NAc may be therapeutic in drug addiction.
CHRISTOPHER W. COWAN, PH.D.
MAKOTO TANIGUCHI, PH.D.
CARLY F. HALE, B.A.
Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NE5.110, Dallas,
TX 75390-9070; Carol.Tamminga@UTSouthwestern.edu (e-mail). Image accepted for publication October 2008 (doi: 10.1176/
A stylized image of a nucleus accumbens medium spiny neuron is illustrated (panel A). Chronic cocaine exposure increases the density of den-
dritic spines, which are structural sites of excitatory synapses. A model for how chronic cocaine and dopamine D1/5 receptor signaling regulate
changes in synaptic connectivity in the striatum is also shown (panel B). Chronic cocaine exposure increases cAMP and protein kinase A (PKA)
signaling, which in turn causes the regulator of calmodulin signaling (RCS) to inhibit calcium signaling events that activate MEF2. Decreased
MEF2 activity is required for cocaine to increase NAc dendritic spine density. However, this appears to be a compensatory mechanism that lim-
its long-lasting maladaptive behavioral effects of cocaine. CaM=Ca2+/calmodulin; CaN=calcineurin; Cdk5=cyclin-dependent kinase 5; mPFC=
medial prefrontal cortex; VTA=ventral tegmental area; L-type VSCC=L-type voltage-sensitive calcium channel; P=phosphorylated amino acid.
Panel A used with permission from Neuron Volume 59, No. 4, 2008. Copyright © Elsevier 2008. Panel A image designed by Genevra Garret.
Panel B adapted/modified with permission from Pulipparacharuvil et al., “Cocaine regulates MEF2 to control synaptic and behavioral plasticity”
[Neuron 2008; 59:621–633]. Copyright © Elsevier 2008.
P P PX
Repeated Cocaine Exposure