Serotonergic Lesion on DA Neuronal Activity

The intracerebroventricular (i.c.v.) injection of the toxin 5,7-dihydroxytryptamine (5,7-DHT) produces a robust and selective decrease in brain 5-HT levels (Prisco et al. 1994; Prisco and Esposito 1995; Di Mascio et al. 1999; Guiard et al. 2008). In fact, the toxin treatment resulted in significant depletions of 5-HT in the corpus striatum (-66.5%) and hippocampus (-90%) (Di Mascio et al. 1999) and in the frontal cortex (-87%) (Guiard et al. 2008). Conversely, 5,7-DHT lesions did not cause any change in the basal interspike interval (ISI) standard characteristics (firing rate, bursting activity) either in the VTA (Prisco et al. 1994; Prisco and Esposito 1995) or in the

SNc (Kelland et al. 1990). The basal firing rate of VTA dopaminergic neurons in 5-HT-depleted rats was higher than in control animals, but this difference was not statistically significant (Prisco et al. 1994; Prisco and Esposito 1995). In addition, depletion of brain 5-HT had little effect on the basal activity of nigrostriatal DA neurons. However, both 5-HT depleters para-chlorophenylalanine (PCPA) and 5,7-DHT produced small but significant reductions in the conduction velocity of these cells (Kelland et al. 1990). Minabe et al. (1996) showed that depletion of brain 5-HT by administration of PCPA produced a significant decrease in the number of spontaneously active DA cells in both the SNc (52%) and VTA (63%) areas, compared with controls. The burst firing analysis indicated that there was a significant increase in the mean interspike interval, with a decrease in both the burst firing pattern and the number of bursts of SNc and VTA DA neurons in PCPA treated animals. The intravenous (IV) administration of 5-hydroxytryptophan and the peripheral aromatic acid decarboxylase inhibitor benserazide, which restores 5-HT content, reversed both the decrease in the number of spontaneously active SNc and VTA DA neurons, as well as the decrease in the percentage of VTA DA neurons exhibiting a bursting pattern.

It was noticeable that although we did not reveal any modification of DA conventional firing characteristics on 5-HT depleted animals (Prisco et al. 1994), in successive experiments, using the nonlinear prediction method combined with Gaussian-scaled surrogate, we showed a decrease in chaos of the electrical activity of VTA DA neurons, extracellularly recorded in vivo lesioned with 5,7-DHT (Di Mascio et al. 1999). The term chaos is here intended to describe a highly erratic yet deterministic behavior. Moreover, in the control (unlesioned) group a positive correlation was found between the functional operator (Y), equivalent to the density power spectrum of the signals and the interspike intervals, and the chaos content measure by nonlinear prediction S score; a relation that was lost in the lesioned group (Di Mascio et al. 1999). We suggested that the decreased chaotic behavior of dopaminergic neurons in lesioned rats, which have a decreased serotonergic tone, might represent a preclinical phenomenon of the onset of psychiatric disorders in humans. In fact, chaotic behavior, more than periodic or stochastic behavior, makes biological systems more capable of responding to different stimuli without causing damage.

Recently, Guiard et al. (2008) showed contrasting results with the above findings, supporting the hypothetical inhibitory 5-HT tone upon DA neurons. In their experimental conditions, 5,7-DHT lesions led to a 36% increase in the discharge rate of VTA DA neurons in rats. This enhancement of DA neuronal activity resulted from a higher number of bursts and spikes per burst (Guiard et al. 2008).

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