The Constitutive Activity of 5HT2C Receptors in the Control of Subcortical DA Release Is Magnified by Halothane Anesthesia

As reported in Table 10.1, the effects on in vivo DA release induced by 5-HT2C antagonists versus 5-HT2C inverse agonists vary depending upon the experimental condition (presence or absence of anesthesia). All the studies showing the participation of the constitutive activity of 5-HT2C receptors have been performed in halothane-anesthetized animals (De Deurwaerdere et al. 2004; Berg et al. 2006; Navailles et al. 2006b). It appears evident that halothane anesthesia may have facilitated the occurrence of the constitutive activity of 5-HT2C receptors in vivo.

The first consideration to take into account is the potential modification of 5-HT levels by halothane. In freely moving rats, 5-HT levels are about 60% higher than in the presence of halothane (Kalen et al. 1988). Despite these high 5-HT levels, the 5-HT2C antagonists SB 242084 and SB 243213 do not affect subcortical DA release (Gobert et al. 2000; Li et al. 2005a; Hutson et al. 2000; Millan et al. 1998; Shilliam and Dawson 2005), while the 5-HT2C inverse agonist SB 206553 still increases DA release, although to a lesser extent than under anesthesia (Gobert et al. 2000; Lucas et al. 2000; see Table 10.1). These data further support the fact that the efficacy of SB 206553 is independent from endogenous 5-HT tone (De Deurwaerdere et al. 2004). Basal DA extracellular levels are also insensitive to changes in 5-HT levels in the presence of halot-hane. Indeed, the decrease in endogenous 5-HT tone induced by either the administration of the 5-HT1A agonist 8-OH-DPAT or the selective lesion of 5-HT neurons in the raphe nuclei do not affect basal DA release in the NAc and the STR of halothane-anesthetized rats (De Deurwaerdere et al. 2004;

Table 10.3 Effect of the local application of 5-HT compounds into the ventral tegmental area (VTA), the nucleus accumbens (NAc), the striatum (STR) or the frontal cortex (FCX) on DA release in the striatum, the NAc and the frontal cortex of freely moving (FM) and anesthetized rats


Frontal cortex





Selective 5-HT,c antagonists SB 242084 VTA

N accumbens FCX

SB 243213 VTA FCX

Nonselective 5-HT,c antagonists SB 206553: 5-HT antagonist/inverse agonist VTA

N accumbens STR 42-112

Clozapine: Nonselective aminergic and 5-HT,c inverse agonist N accumbens

0 25

Ritanserin: 5-HT

, antagonist

Navailles et al. (2006a, 2008); Leggio et al. (2008)

Ferré and Artigas (1995)

Pehek (1996); Benloucif et al. (1993)

De Deurwaerdere and Spampinato 1999; De Deurwaerdere et al. 1998). Thus, the larger increase in DA release induced by SB 206553 in halothane-anesthetized compared with freely moving rats suggests that halothane may favor the expression of the constitutive activity of 5-HT2C receptors. Similarly, the paradoxical loss of effect of selective 5-HT2C antagonists on DA release in freely moving rats suggests that the increase observed in halothane-anesthetized rats may reflect the direct influence of halothane on DA release as well.

Most anesthetics, and particularly halothane, exert an excitatory influence on DA neuron activity (Bunney et al. 1973; Mereu et al. 1984). Basal DA extracellular levels in the STR and the NAc are almost twice in halothane-anesthetized compared with awake animals (Table 10.4) (Lucas et al. 2000). The excitation of the nigrostriatal DA pathway seems to be specific to halothane anesthesia because chloral hydrate, though doubling accumbal DA levels, does not alter basal DA levels in the STR compared with waking conditions (Table 10.4). Strikingly, 5-HT2C antagonists barely alter DA release in the STR of chloral hydrate-anesthetized rats, an effect that has lead some authors to propose a preferential or selective control of 5-HT2C receptors on the mesoaccumbal DA pathway (Di Matteo et al. 1999; Di Giovanni et al. 1999; Di Matteo et al. 2001). In addition to its influence at DA cell bodies, halothane alters DA function at DA terminal regions since it reduces the activity of striatal efferent neurons of type I (Kelland et al. 1991), neurons known to express 5-HT2C receptors mRNA and proteins (Pompeiano et al. 1994; Ward and Dorsa 1996). These simultaneous actions of halothane at different levels of DA transmission may have participated to the maximal increase in DA release induced by SB 206553 compared with waking conditions. Halothane has been shown to increase clozapine-induced subcortical DA release (Adachi et al. 2005) and, as for SB 206553, highlights the ability of clozapine to silence the constitutive activity of 5-HT2C receptors. The combined evidence of these data draw attention to the fact that halothane may trigger the constitutive activity of 5-HT2C receptors in the control of subcortical DA release in vivo.

Table 10.4 Basal DA levels (pg/sample) assessed by in vivo microdialy-sis in the striatum (STR), the nucleus accumbens (NAc) and the frontal Cortex (FCX) of freely moving (FM) and anesthetized rats (Halothane and chloral hydrate)

Dopamine: basal levels STR 9.2 ± 0.4


Halothane Chloral hydrate

17.3 ± 1.6 8.3 ± 1.1 5.4 ± 0.7 5.15 ± 0.5 nd nd nd not determined

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