Biology Reference
In-Depth Information
(e.g., 3, 15 or 30 days). After the withdrawal period, rodents are placed again in the activity
chamber and locomotor activity is measured over the stipulated time period after a challenge
with a cocaine dose (e.g., 3 mg/kg). Locomotor activity after cocaine challenge is compared
with activity measured before cocaine sensitization treatment. Behavioral sensitization of
motor activity after cocaine challenge is defined as a significant increase in motor activity
compared with measures of activity before cocaine treatment (Kalivas and Duffy, 1993;
Phillips and Di Ciano, 1996).
Some of the cocaine sensitization studies have also assessed the levels of extracellular
dopamine at the same time as measuring locomotor activity. Dopamine determinations are
done through intracranial inserted cannulas, usually placed into the NAc before starting the
experiment. A significant increase was found in the level of extracellular dopamine in the
NAc (usually with a peak response between 20 and 40 mins after cocaine challenge). Then
dopamine levels return to baseline level, approximately 80 mins after the challenge (Kalivas
and Duffy, 1993). The release of dopamine in the NAc from dopaminergic projections arising
in the VTA indicated that this region is required for behavioral sensitization (Kalivas, 1995).
The major cell type in the VTA is the dopaminergic neuron, which receives activating
excitatory input from different cortical and subcortical regions, such as the prefrontal cortex
(Omelchenko and Sesack, 2007). There is an anatomical relationship between neurons in the
VTA and its projection targets, for example
the NAc and the PFC. Dopamine neurons
projecting to the PFC receive reciprocal input from PFC, whereas dopamine neurons
projecting to the NAc do not have such reciprocal projections (Carr and Sesack, 2000).
Electrophysiological experiments have demonstrated that prefrontal cortex activity plays an
important role in the control of the firing pattern of dopamine neurons (White, 1996). The
VTA also receives important excitatory input from the amygdala and bed nucleus of stria
terminalis (Garzon et al., 1999; Georges et al., 2001). Dopaminergic neurons in the VTA are
inhibited by local interneurons, which generate BAGAA receptor-mediated responses, as by
GABA-ergic projections from the NAc and ventral pallidum.
In the VTA there is a close relationship between dopaminergic and glutamatergic
activity. Dopamine neurons express metabotropic and ionotropic glutamate receptors, and
glutamate activity on these receptors activates DA neurons in the VTA (Mercuri et al., 1992;
Overton and Clark, 1997). For example, perfusion of the D1 agonist SKF-82595 in the VTA
produced a dose-dependent increase in extracellular glutamate that, in turn, can be blocked by
coperfusion of the D1 antagonist SCH-23390. Psychostimulants promote dopamine release
into somatodendritic fields of midbrain dopamine neurons (Lacey et al., 1990; Seutin et al.,
1991). For example, systemic administration of cocaine (15 mg/kg i.p.) induces a rapid
increase of extracellular glutamate that lasts for 20 minutes. This increase is prevented by pre-
treating the VTA with the D1 receptor antagonist SCH-23390 (Kalivas and Duffy, 1995).
C
OCAINE
I
NDUCED
S
YNAPTIC
P
LASTICITY IN THE
VTA
Dopamine or glutamate release alone does not explain the long-lasting behavioral
changes induced by repeated cocaine administration in rodents nor the development of
addiction in humans. To understand the enduring and permanent effects induced by the drug,
it is necessary to look at the basic mechanisms of synaptic plasticity, LTP and LTD.
