The fall of homovanillic acid and 5-hydroxyindoleacetic acid concentrations in brains of mice withdrawn from repeated morphine treatment and their restoration by acute morphine administration

Abstract

The striatal homovanillic acid (HVA) and cerebral 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were estimated in male mice withdrawn from 3- to 5-day morphine treatment (total dose: 1,100-2,350 mg/kg). All mice were given probenecid (200 mg/kg, 2 hours). The HVA concentration was decreased (by 26%) in mice withdrawn from 3-day treatment, but the 5-HIAA concentration fell (by 22%) only after 4-day treatment. An acute morphine dose (30 mg/kg, 2 hours) clearly elevated the HVA concentration in mice withdrawn from 4-day treatment, but mice withdrawn from 3-day treatment tended to be tolerant to the HVA concentration elevating effect of morphine. The acute dose increased the 5-HIAA concentration in mice withdrawn from 4-day treatment, by 20-40%, but the mice withdrawn from 3-day treatment were clearly tolerant to this effect of morphine. These results suggest that endogenous activities of dopaminergic and 5-HTergic neurons are attenuated by repeated morphine treatment. However, such attenuation seems to reactivate these neurons to respond to acute morphine administration nearly normally.

The involvement of noradrenergic transmission in the morphine‐induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment

“…In rats on withdrawal from opioids acute opioid challenge accelerates striatal and limbic dopamine (DA) turnover and release more than in naïve controls ( Clouet & Ratner, 1970 ; Ahtee, 1973 ; Attila & Ahtee, 1983 ; 1984 ; Acquas & DiChiara, 1992 ; Ahtee et al ., 1989 ; 1990 ). Similar sensitization to morphine‐induced increase of striatal DA turnover and release during withdrawal has been found in mice ( Ahtee et al ., 1987 ; Airio et al ., 1994 ; Airio & Ahtee, 1997 ).…”

“…All doses refer to the free base. During the repeated treatment ( Ahtee et al ., 1987 ) the mice were given morphine three times daily, at 0800–0900, 1400–1500 and 2200–2300 h, for 5 days. The dose of morphine was increased from 100 mg kg −1 ×3 on day 1 to 150 mg kg −1 ×3 on day 2, and to 200 mg kg −1 ×3 on days 3–5.…”

Postmortem serotonin (5-HT) concentrations in the cerebrospinal fluid of medicolegal cases

“…Otherwise there are findings that the serotonergic system is not responsible for opioid withdrawal [42]. The decreased levels of 5-HT in the collective of opiate fatalities described here could be explained by a decreased endogenous opioid ligand concentration after chronic opioid abuse [31,40]. To our opinion not an irrelevant number of our collective at the time of death was in a state of withdrawal or suicidal intention favouring for decreased 5-HT levels.…”

“…by naloxone and naltrexone [29,[35][36][37][38][39]. Otherwise, during withdrawal from substained morphine or heroine treatment the cerebral 5-HIAA levels are reduced in rats [40], in mice [31] and in man, too [29,41]. These findings are indicative for a reduced cerebral 5-HT turnover during opioid withdrawal.…”

“…Chronic opiate administration was accompanied by a decrease in 5-HT turnover, which is restored by acute morphine application [31]. Acute administration of morphine increased the synthesis of cerebral 5-HT and the formation of 5-hydroxyindolacetic acid (5-HIAA) [32][33][34], furthermore these effects are antagonised e.g.…”