Selective Antagonism at Dopamine D3 Receptors Enhances Monoaminergic and Cholinergic Neurotransmission in the Rat Anterior Cingulate Cortex

Abstract

Recent neuroanatomical and functional investigations focusing on dopamine (DA) D 3 receptors have suggested a potential role of this receptor in psychiatric diseases such as schizophrenia and drug dependence. In line with the key role of the prefrontal cortex in psychiatric disorders, the present study aimed at assessing the effects of the acute systemic administration of the selective DA D 3 receptor antagonist SB-277011-A on the in vivo extracellular levels of monoamines (DA, norepinephrine (NE), and serotonin (5-HT)) and acetylcholine (ACh) in the anterior cingulate subregion of the medial prefrontal cortex. The in vivo neurochemical profile of SB-277011-A (10 mg/kg, i.p.) in the anterior cingulate cortex was compared with both typical and atypical antipsychotics including clozapine (10 mg/kg, s.c.), olanzapine (10 mg/kg, s.c.), sulpiride (10 mg/kg, s.c.), and haloperidol (0.5 mg/kg, s.c.). The acute administration of SB-277011-A, clozapine, and olanzapine produced a significant increase in extracellular levels of DA, NE, and ACh without affecting levels of 5-HT. Sulpiride also significantly increased extracellular DA, but with a delayed onset over SB-277011-A, clozapine, and olanzapine. In contrast, haloperidol failed to alter any of the three monoamines and ACh in the anterior cingulate cortex. These findings add to a growing body of evidence suggesting a differentiation between typical and atypical antipsychotic drugs (APDs) in the anterior cingulate cortex and a role of DA D 3 receptors in desired antipsychotic drug profile. Similar to their effects on DA and NE, SB-277011-A, clozapine, and olanzapine increased extracellular levels of ACh, whereas haloperidol and sulpiride did not alter ACh. The results obtained in the present study provide evidence of the important role of DA D 3 receptors in the effect of pharmacotherapeutic agents that are used for the treatment of psychiatric disorders such as schizophrenia and drug dependence.

Selective Antagonism at Dopamine D3 Receptors Prevents Nicotine-Triggered Relapse to Nicotine-Seeking Behavior

“…In contrast, SB-277011-A does not modify basal DA neurotransmission in the NAc, but can reverse quineloraneinduced decreases in extracellular DA levels in the same brain area (Reavill et al, 2000). We have recently shown that the acute systemic administration of SB-277011-A can increase extracellular DA levels in the rat anterior cingulate cortex (ACg) (Lacroix et al, 2003). Interestingly, the projections from the ACg terminate more medially and extend further ventrally to include the core of the NAc (Ding et al, 2001).…”

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

“…In vivo brain microdialysis data indicate that administration of SB-277011-A (2.8 mg/kg po) reverses the decrease in extracellular DA levels produced by quinelorane (D 2 /D 3 agonist) in the NAc, but not the dorsal striatum, a regional selectivity consistent with the distribution of DA D 3 receptors in the rat brain [229]. A single ip administration of 10 mg/kg of SB-277011-A significantly increases extracellular levels of DA, norepinephrine (NE), and acetylcholine (ACh) in the anterior cingulate cortex in freely moving rats [160]. It should be pointed out that SB-277011-A does not produce a functional antagonism of D 2 receptors in vivo as, unlike D 2 receptor antagonists, its systemic administration in rats does not (1) elicit catalepsy at doses that exhibit anti-addiction action [229,295]; (2) produce a rightward shift in brain stimulation reward curve [229]; (3) increase plasma prolactin levels [295]; (4) inhibit spontaneous or stimulant-induced locomotion [295]; (5) antagonize the action of quinpirole in the dorsal striatum, a brain region with a high density of D 2 receptors [295]; (6) increase DA levels in the striatum [295]; and (7) increase cocaine self-administration under a schedule of continuous reinforcement ( [84,102,295]; see Section 7.4).…”

“…However, SB-277011-A does not appear to alter memory (as measured using a delayed nonmatched position test, D. Jones and J.J. Hagan, personal communication). Furthermore, acute administration of SB-277011-A significantly increases ACh levels in the anterior cingulate cortex [160] and reverses scopolamine-induced memory deficits as assessed by the threechoice point water labyrinth test [163]. Both of these effects would be expected to improve rather than to interfere with memory.…”

Acute administration of SB‐277011A, NGB 2904, or BP 897 inhibits cocaine cue‐induced reinstatement of drug‐seeking behavior in rats: Role of dopamine D3 receptors

“…30 min prior to testing for reinstatement. The doses of the drugs and the pretreatment times were chosen based upon the previously published pharmacokinetic and pharmacodynamic properties of the three D 3 compounds (Yuan et al, 1998;Pilla et al, 1999;Austin et al, 2001;Beardsley et al, 2001;Robarge et al, 2001;Aujla et al, 2002;Duarte et al, 2003;Garcia-Ladona and Cox, 2003;Heidbreder et al, 2005), our own previous studies (Vorel et al, 2002;Ashby et al, 2003;Campos et al, 2003Campos et al, , 2004Gilbert et al, 2003;Lacroix et al, 2003;Xi et al, 2003Xi et al, , 2004, and pilot studies carried out in preliminary phases of the present investigation.…”