Systemic Administration of Selective and Nonselective 5HT2 Receptor Ligands to Laboratory Animals

Systemic administration of the 5-HT2A/2C receptor agonists DOI or 1-(2,5-dime-thoxy-4-methylphenyl)-2-aminopropane (DOM) has been shown to reduce SWS and REM sleep and to augment W in the rat (Dugovic and Wauquier 1987; Dugovic et al. 1989; Monti et al. 1990). In addition, systemic or intrathalamic injection of DOI decreased the neocortical high-voltage spindle activity that occurs during relaxed W in the rat (Jâkâlâ et al. 1995). The intraperitoneal (IP) and oral (p.o.)

Table 20.3 The effect of selective and nonselective 5-HT2 receptor agonists administration on sleep and waking in laboratory animals

Compound

Route of administration

W

SWS

REMS Reference

DOI (5-HT2A/2C agonist)

i.P

Î

4

4 (Monti et al. 1990)

DOM (HT2A/2C agonist)

i.p

Î

4

4 (Dugovic and Wauquier

1987; Dugovic et al.

1989)

RO 60-0175 (5-HT2C

i.p. and p.o

Î

n.s

4 (Martin et al. 1998)

agonist)

RO 60-0332 (5-HT2C

i.p. and p.o

Î

n.s.

4 (Martin et al. 1998)

agonist)

DOI (5-HT2A/2C agonist)

Microinjection

n.s.

n.s

4 (Monti and Jantos 2006b)

into the DRN

DOI (5-HT2A/2C agonist)

Microinjection

n.s.

n.s.

4 (Amici et al. 2004)

into the LDT

DRN dorsal raphe nucleus, LDT laterodorsal tegmental nucleus, W waking, SW slow wave sleep, REMS REM sleep, n.s. nonsignificant, \ increased, \ decreased

DRN dorsal raphe nucleus, LDT laterodorsal tegmental nucleus, W waking, SW slow wave sleep, REMS REM sleep, n.s. nonsignificant, \ increased, \ decreased

{[S]-2-(chloro-5-fluoro-indol-1-yl)-1-methyletylamine} administration of the selective 5-HT2C receptor agonists RO 60-O175/ORG 35030 or RO-60-0332/ORG 35035 {[S]-2-[4,4,7-trimethyl-1,4-dihydro-indeno(1,2-b)pyrrol-1-yl]-1- methyleth-ylamine} induced also an increase of W and a reduction of REM sleep in the rat (Martin et al. 1998) (Table 20.3). Injection of the 5-HT2A/2C receptor antagonists ritanserin, ketanserin, ICI 170,809 [2(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline], or sertindole at the beginning of the light period induced a significant increase of SWS and a reduction of REM sleep in the rat. The 5-HT2A/2C antagonist ICI 169,369 [2-(2-dimethylaminoethylthio)-3-phenylquinoline] suppressed REM sleep; however, SWS remained unchanged. Waking was also diminished in most of these studies (Dugovic et al. 1989; Monti et al. 1990; Tortella et al. 1989; Silhol et al. 1991; Coenen et al. 1995; Kirov and Moyanova 1998a, b) (Table 20.4).

More recently, the action of subtype-selective 5-HT2 receptor antagonists on sleep variables was assessed in rats and mice. Subcutaneous administration of the 5-HT2A antagonist EMD 281014 {7-[4-(2-(4-fluorophenyl)ethyl)-piperazine-1-carbonyl]-1H-indole-3-carbonitrile} significantly reduced REM sleep (Monti and Jantos 2006a). On the other hand, administration of the 5-HT2A receptor antagonist MDL 100907 by IP route during the light period augmented NREM sleep and reduced W and REM sleep in adult male mice (Popa et al. 2005). Moreover, oral administration of the 5-HT2C antagonist SB 243213 {5-methyl-1-[[-2-[(-2-methyl-3-pyridyl)oxy]-5-pyridyl] carbamoyl]-6-trifluoromethylindoline} significantly increased SWS and reduced REM sleep during the light period in the rat (Smith et al. 2002). However, REM sleep suppression was the only noticeable effect when the compound was given by the subcutaneous (SC) route (Monti and Jantos 2006a) (Table 20.4). Pretreatment with ritanserin prevented the enhancement of W and the deficit of SWS induced by DOI and DOM, but not the REM sleep suppression

Table 20.4 The effect of selective and nonselective 5-HT2A and 5-HT2C receptor antagonists on sleep and waking in laboratory animals

Route of

Compound

administration

W

SWS REMS

Reference

Ritanserin (5-HT2A/2C

i.p.

n.s.

! 1

(Dugovic and

antagonist)

Wauquier 1987)

Ritanserin (5-HT2A/2C

i.p.

I

! 1

(Dugovic et al. 1989)

antagonist)

Ritanserin (5-HT2A/2C

i.p.

n.s.

!1

(Monti et al. 1990)

antagonist)

Ritanserin (5-HT2A/2C

i.p.

1

!1

(Kirov and Moyanova

antagonist)

1998a)

Ketanserin (5-HT2A/2C

i.p.

1

!1

(Kirov and Moyanova

antagonist)

1998b)

ICI 169,369 (5-HT2A/2C

p.o.

!

n.s. 1

(Tortella et al. 1989)

antagonist)

ICI 170,809 (5-HT2A/2C

p.o.

!

(delayed J

(Tortella et al. 1989)

antagonist)

increase of SWS)

Sertindole (5-HT2A/2C

i.p.

n.s.

!1

(Coenen et al. 1995)

antagonist)

MDL 100907 (5-HT2A

i.p.

I

!1

(Popa et al. 2005)

antagonist)

EMD 281014 (5-HT2A

s.c.

n.s.

n.s. 1

(Monti and Jantos

antagonist)

2006a)

SB-243213 (5-HT2C

s.c.

n.s.

n.s. 1

(Monti and Jantos

antagonist)

2006a)

SB-243213 (5-HT2C

p.o.

n.s.

!1

(Smith et al. 2002)

antagonist)

W waking, SWS slow wave sleep, REMS REM sleep, n.s. nonsignificant, \ increase, J, decrease

W waking, SWS slow wave sleep, REMS REM sleep, n.s. nonsignificant, \ increase, J, decrease

(Dugovic et al. 1989; Monti et al. 1990). Ritanserin also antagonized the DOI-induced decrease of neocortical high-voltage spindle activity (Jakala et al. 1995). In order to gain further insight into the roles of 5-HT2A and 5-HT2C receptors in the DOI-induced disruption of the sleep-wake cycle, animals were pretreated with either EMD 281014 or SB 243213, which selectively block the 5-HT2A or the 5-HT2C receptor, respectively. EMD 281014 prevented the increase of W and the reduction of SWS induced by DOI. However, REM sleep remained suppressed. In contrast SB 243213 failed to reverse the DOI-induced disruption of sleep and W (Monti and Jantos 2006a).

Thus on the basis of these results it appears that 5-HT2A mechanisms predominate following the systemic administration of DOI. However, the role of the 5-HT2C receptor cannot be excluded, and further studies using additional 5-HT2C antagonists are warranted. It should be stressed that the failure of EMD 281014 to prevent the suppression of REM sleep tends to indicate that the effect of DOI is not restricted to the 5-HT system.

In conclusion, systemic administration of selective 5-HT2C or nonselective 5-HT receptor agonists to laboratory animals induced a consistent increase of W

and a reduction of SWS and/or REM sleep. In contrast, systemic injection of selective and nonselective 5-HT2A and 5-HT2C receptor antagonists produced in almost all instances an increase of SWS and a suppression of REM sleep. Waking was found also to be reduced in a number of studies. Differences in species (mouse, rat), route (p.o., SC, IP), time of drug administration during the light phase, drug concentration, and the use of different approaches to analyze data could tentatively explain the discrepancies observed among studies. Is serotonin directly responsible for the increase of W induced by the selective 5-HT2C and nonselective 5-HT2A/2C agonists? It has been shown that systemic administration of DOI inhibits the firing of serotonergic neurons in the DRN and noradrenergic neurons in the LC. In addition, 5-HT and NA levels are diminished at postsynaptic sites. The reduction of the firing rate of serotonergic and noradrenergic cells is reverted by MDL 100907 and ketanserin, respectively (Garratt et al. 1991; Chiang and Aston-Jones 1993). As mentioned earlier, the IP injection of DOI significantly increases the extracellular concentration of ACh in the medial prefrontal cortex and the hippocampus of the rat, and the effect is blocked by the 5-HT2A/2C receptor antagonist LY53-857 (Nair and Gudelsky 2004). Thus, indirect evidence tends to indicate that ACh is involved in the increase of W after systemic DOI. However, to elucidate the mechanisms underlying the 5HT2A/2C receptor agonist-induced increase of W, further investigations are needed.

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