Depletion of mesolimbic dopamine during behavioral despair: partial reversal by chronic imipramine.

Exposure of rate to the behavioral despair test (an animal model of depression) for 40 min resulted in a long-lasting depletion of mesolimbic dopamine output to about 40% of baseline values. The decrease in extracellular dopamine was partially prevented by chronic pretreatment with imipramine (20 mg/kg per day i.p. for 21 days). The results suggest that a fall in mesolimbic dopamine output may be associated with depressive states and indicate that changes in the functional status of the dopamine system contribute to the mechanism of action of imipramine.

Lack of tolerance to ethanol-induced dopamine release in the rat ventral striatum.

The effect of ethanol challenge on the extracellular concentrations of dopamine, 3,4-dihydroxy-phenylacetic acid and homovanillic acid was studied in the ventral striatum of rats repeatedly treated with ethanol. Ethanol-treated animals (1 g/kg i.p. twice a day for 12 days) developed marked tolerance to the behavioral signs of ethanol intoxication when challenged with ethanol (2 g/kg i.p.). However, in ethanol-treated animals the increased output of dopamine and metabolites after ethanol challenge (1 or 2 g/kg i.p.) was not statistically different from that observed in saline-treated rats. These results indicate that tolerance does not develop to the ethanol-induced stimulation of dopamine release and support the hypothesis that activation of the mesolimbic dopamine system contributes to the reinforcing properties of ethanol.

Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats.

Withdrawal of rats from chronic ethanol, morphine, cocaine and amphetamine resulted in a marked reduction in extracellular dopamine (DA) concentration in the ventral striatum as measured by microdialysis. Following ethanol and naloxone-precipitated morphine withdrawal, the time course of DA reduction paralleled that of the withdrawal symptomatology. On the other hand, following discontinuation of chronic cocaine, DA reduction was delayed by over 24 h but persisted for several days. After amphetamine withdrawal the fall in DA occurred more rapidly but the reduction also persisted for several days. The administration of the NMDA receptor antagonist, MK-801, to rats withdrawn from chronic ethanol, morphine or amphetamine, but not from chronic cocaine, readily reversed the fall in DA output. The reduction in extracellular DA during ethanol withdrawal was also reversed by SL 82.0715, another NMDA receptor antagonist.

Biphasic effect of ethanol on noradrenaline release in the frontal cortex of awake rats.

Ethanol elicited a biphasic effects on the extracellular noradrenaline (NA) concentrations in the rat frontal cortex, as assessed by microdialysis in awake animals. A low dose of ethanol (0.2 g/kg i.p.) raised NA output to about 160% of baseline levels. In contrast, a dose of 2 g/kg inhibited NA output to about 70% of pre-drug levels. These results suggest that the decrease in cortical NA output may reflect the sedative-hypnotic properties of ethanol at high doses, whereas the stimulation of extraneuronal NA may represent a biochemical correlate of the arousal and increased alertness elicited by low doses of ethanol.

Repeated treatment with imipramine potentiates cocaine-induced dopamine release and motor stimulation.

The stimulatory effect of cocaine on locomotor activity and on dopamine efflux from the ventral striatum was studied in rats chronically treated with the antidepressant imipramine. Chronic imipramine (20 mg/kg per day for 3 weeks) potentiated by about 2-fold cocaine-stimulated motor activity and extracellular dopamine concentrations. The results indicate that chronic imipramine facilitates mesolimbic dopamine neurotransmission by potentiating the mechanism which is thought to mediate the rewarding effects of cocaine.