Prefrontal Dependent Learning

The prefrontal cortex receives a dense serotonergic innervation from the raphe nuclei (Smiley and Goldman-Rakic 1996), which constitutes a serotonergic system. Prefrontal pyramidal neurons possess several serotonin receptor subtypes, with a particularly high density of 5-HT1A and 5-HT2A receptors (Feng et al. 2001; Jakab and Goldman-Rakic 1998). Although there is comparatively less evidence on the presence of 5-HT2C receptor mRNA in the prefrontal cortex, several studies have shown the presence of 5-HT2C receptor mRNA in the cingulate cortex or in the anterior cingulate cortex (Pompeiano et al. 1994; Hoffman and Mezey 1989). Additionally, a study in human brain showed a similar distribution of 5-HT2C receptor mRNA as has been found in rat brain, including its expression in the anterior cingulate cortex (Pasqualetti et al. 1999). 5-HT2C mRNA is expressed in the same

Table 24.1 Modulation of striatal dependent learning tasks by 5-HT,c Recepi


Dose, via


Ro 60-0332

5.0 mg/kg. s.c.


5-HT2C agonist mCPP

3.0 and 5.0 mg/kg, i.p.


5"HT1B,2A,2C aS°nist


0.3-3.0 mg/kg, i.p.


5-HT,c agonist Ro 60-0491

3.0 mg/kgi.p.


5-HT,c antagonist SB-206.553

10.0 mg/kg. p.c.


5-HT,b(2C antagonist Ketanserine

0.5, 1.0, 2.0, 4.0 ng


5-HT,a(,c antagonist Ro 60-0175

Intra-striatum 10.0 mg/kgi.p.


5-HT2C agonist WAY-161.503

3.0 mg/kg s.c.


5-HT,c agonist TFMPP

3.0 mg/kg s.c.


5-HTm(2C Agonist mCPP "

1-10 mg/kgi.p.


5"HTib,:a/2c ag°nist Mesurgeline 5-HT2C/;a/7 antagonist

(b) 1-10 mg/kgi.p.



(a) 0.01 and 0.1 mg/kgi.p.


Main result (References)

Revert deficits Impairment

Impairment Block deficit Block deficit Deficit Improvement No effect No effect Impairment a and b. Impairment

(a) Improvement

(b) Impairment

Ameliorate deficits caused by bulbectomy (Martin et al. 1998)

Probably acting through 5-HT1A receptors

Blocked by Ro 60-0491 (Misane and Ogren 2000)

Dose-dependent deficit (Marquis et al. 2007)

Block impairment caused by mCPP (Misaneand Ogren 2000)

Block the effect of WAY-163909 (Marquis et al. 2007)

Dose-dependent deficit (Prado-Alcala et al. 2003b)

Increased number of reinforcements obtained (Martin et al. 1998)

Hypolocomotion (Mosher et al. 2005)

Hypolocomotion (Mosher et al. 2005)

Decrease the rate of conditioned responses (Meneses and Hong 1997)

a and b. Decrease the rate of conditioned responses (Meneses and Hong 1997; Meneses 2007b)

(a) Increase of the rate of conditioned responses (Meneses and Hong 1997)

(b) Decrease of the rate of conditioned responses (Meneses 2007b)

Ketanserine 0.5 mg/kg i. p. ALT

5-HT,a(,c antagonist

Ritanserin 0.001-0.1 mg/kgi.p. ALT

5-HT,a(,c antagonist

SB-200646 2.0 mg/kgi.p. ALT

5-HT,c(,b antagonist

Improvement Increase of the rate of conditioned responses

(Meneses and Hong 1997) Improvement Increase of the rate of conditioned responses

(Meneses and Hong 1997)

(a) No effect (a) Antagonize the impairment induced by mCPP, l-NP^Meneses 2002a)

(b) Improvement (b) Increase of the rate of conditioned responses

(Meneses 2007b)

ALT auto-shaping learning task. PA passive avoidance. DRL-72 differential reinforcement of low rate 72 s operant task brain regions where 5-HT2C receptors are located, and they could be predominately postsynaptic receptors rather than autoreceptors on presynaptic terminals (Clemett et al. 2000). However, the possibility that 5-HT2C receptors act as presynaptic heteroreceptors in some regions cannot be excluded (Alex and Pehek 2007).

5-HT2C receptors also appear to tonically inhibit dopamine release from the mesocortical pathway (Alex and Pehek 2007). Nevertheless, some studies suggest that 5-HT2C receptors localized in the prefrontal cortex do not modulate dopamine release in this region, either tonically (Alex et al. 2005; Pozzi et al. 2002) or phasi-cally (Alex et al. 2005; Pozzi et al. 2002; Pehek et al. 2006). Thus, infusions of SB 206553 directly into the prefrontal cortex did not alter basal, K+-stimulated, or stress-induced cortical dopamine release (Alex et al. 2005; Pehek et al. 2006). However, cortical 5-HT2C receptors modulate dopamine-mediated behaviors because intracortical infusions of a 5-HT2C antagonist potentiated the hyperlocomo-tion induced by a systemic injection of cocaine (Filip and Cunningham 2003), an effect that is not mediated by alterations in extracellular dopamine in the prefrontal cortex (Alex et al. 2005). Nevertheless, serotonin can influence the excitability of pyramidal neurons through several pathways.

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