Rat brain neurotransmitter turnover rates altered during withdrawal from chronic cocaine administration.

Abstract This experiment utilized neurotransmitter turnover rates to assess the effects of withdrawal from cocaine on the brain. A triad-littermate design was used to evaluate the importance of response dependency on the effects of withdrawal from chronic cocaine administration upon brain biogenic monoamine and amino acid putative neurotransmitter turnover rates. Each member of a triad was exposed to one of three conditions. Cocaine infusions (0.33 mg/inf) were used to engender and maintain lever pressing by one rat under an FR 2 schedule, while the second and third rats received simultaneous infusions of either cocaine or saline, respectively. After a minimum of 15 days exposure to the three treatment conditions and 24 h after the start of the last drug session, the triads were pulse labeled with [14C]glucose, [3H]tyrosine and [3H]tryptophan and killed 60 or 90 min later by total immersion in liquid nitrogen. The frozen brains were removed and dissected at −20° C into 22 areas. The content and specific radioactivities for dopamine (DA), noradrenaline (NA), serotonin (5-HT), aspartate (Asp), glutamate (Glu), glycine (Gly) and γ-aminobutyric acid (GABA) were determined in each brain region using high pressure liquid chromatography with electrochemical (biogenic monoamines) or fluorescence (amino acids) detection followed by liquid scintillation spectrometry. Turnover rates (TOR) were calculated and compared across treatment conditions. The significant decreases in TOR resulting from chronic cocaine exposure included 5-HT in the frontal cortex, DA in the cingulate cortex, entorhinal-subicular and motor-somatosensory cortices and NA in the inferior colliculus. Significant increases in TOR were also observed which included 5-HT in the preoptic-diagonal band region, DA in the hippocampus and NA in the pyriform and temporal-auditory cortices, the dentate gyrus and brainstem. GABA TOR was also increased in the preoptic-diagonal band region, dentate gyrus and brainstem of both groups receiving cocaine as was Glu TOR in the pyriform cortex and cerebellum. In addition, changes were seen in the rats under the ratio schedule of cocaine self-administration that were not seen in rats receiving yoked-cocaine infusions that included increased TOR of 5-HT in the pyriform cortex, NA in the caudate-putamen and GABA in the pyriform and motor-somatosensory cortices. Decreased 5-HT TO was seen in the motor-somatosensory cortex and dentate gyrus in the rats that had self-administered cocaine compared to the yoked-cocaine infused group. Perhaps the most interesting changes were those seen in the yoked-cocaine group that were reversed in the rats whose responding was maintained by cocaine. These included reversals of changes in GABA TO in the temporal-auditory cortices, caudate-putamen, ventral tegmental area and in DA, NA and GABA TO in the substantia nigra. In general, these data indicate that withdrawal from chronic exposure to cocaine produces changes in brain neuronal activity which may represent rebound increases that could be an indication of an acute withdrawal responses. These data indicate that DA, NA, 5-HT and GABA releasing neurons in selected brain regions are part of these processes. In addition, the effects on some brain neuronal systems may depend on the context under which the drug is presented.