Gr. King et al., 5-HT3 AGONIST-INDUCED DOPAMINE OVERFLOW DURING WITHDRAWAL FROM CONTINUOUS OU INTERMITTENT COCAINE ADMINISTRATION, Psychopharmacology, 117(4), 1995, pp. 458-465
This experiment examined alterations in the ability of the highly sele
ctive 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to
induce dopamine (DA) overflow in caudate brain slices obtained from r
ats withdrawn from continuous or intermittent cocaine administration.
Rats were pretreated with 40 mg/kg per day cocaine for 14 days by eith
er subcutaneous injections or osmotic minipumps, and then withdrawn fr
om this regimen for 7 days. Caudate brain slices were obtained, and pe
rfused with artificial cerebrospinal fluid. Following an equilibration
period, the slices were then perfused with 25, 50, or 100 mu M mCPBG.
The samples were assayed for DA content by HPLC with electrochemical
detection. The results indicated that the pretreatment with intermitte
nt cocaine did not consistently alter the ability of mCPBG to induce D
A overflow although there was a reduction in the amount of DA released
by the highest concentration of mCPBG. In contrast, pretreatment with
continuous cocaine administration consistently and significantly atte
nuated the ability of mCPBG to induce DA overflow. The DA overflow ind
uced by mCPBG was partially dependent on extracellular Ca2+ in the per
fusion medium for the saline control and intermittent administration s
ubjects: elimination of Ca2+ from the medium significantly reduced, bu
t did not eliminate, DA overflow for these two groups. In contrast, el
imination of Ca2+ from the perfusion medium had a significant enhancin
g effect on mCPBG-induced DA overflow in the continuous administration
rats. These results suggest that distinct temporal patterns of cocain
e administration differentially alter the ability of a 5-HT3 agonist t
o increase extracellular DA levels, and that this effect may be relate
d to an impairment of Ca2+-dependent release. These results further su
ggest that 5-HT3 receptor subsensitivity may represent a partial mecha
nism for the tolerance following continuous cocaine administration.