Biomedical Engineering Reference
In-Depth Information
of withdrawal. Bhargava and Kumar
(51)
treated mice with a sensitizing
regimen of cocaine (10 mg/kg, twice daily for 7 d). Immediately after drug
treatment, [
3
H]MK-801 binding was increased in cerebellum and spinal cord
but decreased in cortex and hypothalamus. After withdrawal, binding remained
decreased in cortex but other changes normalized.
Recent studies have focused on the role of metabotropic glutamate receptors
in sensitization. Mao and Wang
(52)
used quantitative
in situ
hybridization
histochemistry to measure mRNA levels for group I mGluRs (mGluR1 and
mGluR5) in the NAc and striatum in naïve and amphetamine-sensitized rats.
No changes in mGluR1 or mGluR5 mRNA levels were observed in naïve rats
3 h after acute administration of amphetamine. In contrast, 3 h after the last
of fi ve daily amphetamine injections, mGluR1 mRNA levels were increased
in dorsal striatum and NAc. This effect was transient, as no changes were
observed after 7, 14, or 28 d of withdrawal. A different pattern was observed
for mGluR5. Levels of mRNA were decreased markedly 3 h after the fi nal
amphetamine injection, and the reduction persisted at 7-, 14-, and 28-d
withdrawal times. In a rare example of concordance between amphetamine and
cocaine fi ndings, Swanson et al.
(53)
found a small but signifi cant reduction
in mGluR5 protein levels, measured by Western blotting, in the medial NAc of
rats killed 3 wk after discontinuation of repeated cocaine injections. mGluR5
is postsynaptic and can negatively modulate AMPA receptor transmission.
Thus, the authors suggested that cocaine-induced decreases in mGluR5 may
contribute to the potentiation of AMPA receptor-mediated behavioral responses
related to drug-seeking behavior that have been reported after chronic cocaine
administration
(54
,
55)
. In the same study, repeated cocaine administration
attenuated the ability of mGluR1 stimulation to decrease glutamate release and
locomotor activity, but this was not accompanied by alterations in mGluR1
protein levels and may be attributable to altered expression of Homer1b/c, a
scaffolding protein that regulates mGluR signaling
(53)
. Increasing evidence
indicates that mGluRs play an important role in behavioral responses to
psychomotor stimulants
(56)
.
A relatively unexplored question, owing primarily to technical diffi culty, is
whether posttranslational modifi cation of glutamate receptors is altered after
repeated drug treatment. Bibb et al.
(57)
found reduced peak amplitudes of
AMPA/kainate-evoked currents in acutely dissociated striatal neurons from
rats chronically treated with cocaine; other fi ndings suggested that this was
attributable to reduced PKA-dependent phosphorylation of GluR1.
3.3. Summary: NAc and Striatum
As discussed in
Subheading 3.1.
, considerable evidence implicates gluta-
mate receptors in the striatal complex in persistent neuroadaptations associ-
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