Acute withdrawal from chronic escalating-dose binge cocaine administration alters kappa opioid receptor stimulation of [35S] guanosine 5′-O-[gamma-thio]triphosphate acid binding in the rat ventral tegmental area

There is evidence that the kappa opioid system plays an important role in cocaine addiction and that chronic cocaine administration and withdrawal from chronic cocaine alter kappa opioid receptor (KOPr) density. The present study employed in situ [35S]guanosine 5′-O-[gamma-thio]triphosphate acid (GTPγS) binding autoradiography to measure KOPr-stimulated activation of G-protein in the caudate putamen, nucleus accumbens core and shell, lateral hypothalamus, basolateral amygdala, substantia nigra compacta, substantia nigra reticulata and ventral tegmental area (VTA), in response to chronic cocaine administration or acute and chronic withdrawal from chronic cocaine. Male Fischer rats were injected i.p. with saline or cocaine three times daily at 1 h intervals in an escalating-dose paradigm for 14 days (from 3×15 mg/kg/injection on days 1–3 up to 3×30 mg/kg/injection on days 10–14). Identically treated separate groups were withdrawn from cocaine or saline for 24 h or 14 days. No significant change in KOPr agonist U-69593-stimulated [35S]GTPγS was found in the seven regions studied 30 min or 14 days after chronic 14 days escalating-dose binge cocaine administration. However there was an increase in KOPr -stimulated [35S]GTPγS binding in the VTA (P<0.01) of rats withdrawn for 24 h from chronic cocaine. Our results show a cocaine withdrawal induced increase of KOPr signaling in the VTA, and suggest that the KOPr may play a role in acute withdrawal from cocaine.