Muscarinic and nicotinic cholinergic receptor antagonists differentially mediate acquisition of fructose-conditioned flavor preference and quinine-conditioned flavor avoidance in rats.

Rats display both conditioned flavor preference (CFP) for fructose, and conditioned flavor avoidance (CFA) following sweet adulteration with quinine. Previous pharmacological analyses revealed that fructose-CFP expression was significantly reduced by dopamine (DA) D1 or D2 antagonists, but not NMDA or opioid antagonists. Fructose-CFP acquisition was significantly reduced by DA D1, DA D2 or NMDA antagonists, but not opioid antagonists. Quinine-CFA acquisition was significantly enhanced and prolonged by DA D1, NMDA or opioid, but not DA D2 antagonists. Cholinergic interneurons and projections interact with DA systems in the nucleus accumbens and ventral tegmental area. Further, both muscarinic and nicotinic cholinergic receptor signaling have been implicated in sweet intake and development of food-related preferences. Therefore, the present study examined whether systemic administration of muscarinic (scopolamine: SCOP) or nicotinic (mecamylamine: MEC) cholinergic receptor antagonists mediated fructose-CFP expression, fructose-CFP acquisition and quinine-CFA acquisition. For fructose-CFP expression, rats were trained over 10 sessions with a CS+ flavor in 8% fructose and 0.2% saccharin and a CS- flavor in 0.2% saccharin. Two-bottle choice tests with CS+ and CS- flavors mixed in 0.2% saccharin occurred following vehicle, SCOP (0.1-10mg/kg) and MEC (1-8mg/kg). For fructose-CFP acquisition, six groups of rats received vehicle, SCOP (1 or 2.5mg/kg), MEC (4 or 6mg/kg) or a limited intake vehicle control 0.5h prior to 10 CS+ and CS- training sessions followed by six 2-bottle CS+ and CS- choice tests in 0.2% saccharin. For quinine-CFA acquisition, five groups of rats received vehicle, SCOP (1 or 2.5mg/kg) or MEC (4 or 6mg/kg) 0.5h prior to 8 one-bottle CS- (8% fructose+0.2% saccharin: FS) and CS+ (fructose+saccharin+quinine (0.030%: FSQ) training sessions followed by six 2-bottle CS- and CS+ choice tests in fructose-saccharin solutions. Fructose-CFP expression was significantly reduced by SCOP (2.5-10mg/kg: 65-68%) and MEC (4-8mg/kg: 67-73%) relative to vehicle (89-90%), that occurred only when antagonist doses reduced total saccharin intake but in which CS+ intake was still significantly higher than CS- intake. Fructose-CFP acquisition was eliminated by SCOP at doses of 1 (40-54%) and 2.5 (45-58%)mg/kg, and was accompanied by a failure to observe CS+ and CS- intake differences during testing relative to vehicle (85-92%) and limited control (74-88%) conditions. In contrast, MEC failed to alter fructose-CFP acquisition. Quinine-CFA acquisition was significantly enhanced and prolonged by MEC at 4 (18-24%) and 6 (11-13%) mg/kg relative to vehicle (34-48%). In contrast, SCOP failed to alter quinine-CFA acquisition. These data implicate the cholinergic receptor system in mediating acquisition (learning) of sugar-induced preferences and quinine-induced aversions with muscarinic receptor signaling controlling the former and nicotinic receptor signaling controlling the latter.

Baclofen differentially mediates fructose-conditioned flavor preference and quinine-conditioned flavor avoidance in rats.

Rats display both fructose-conditioned flavor preference (CFP) and quinine conditioned flavor avoidance (CFA). Dopamine (D1 and D2), muscarinic and nicotinic, but not NMDA or opioid receptor antagonists reduced fructose-CFP expression. Dopamine D1, dopamine D2, muscarinic or NMDA, but not opioid or nicotinic receptor antagonists reduced fructose-CFP acquisition. Dopamine D1, NMDA, nicotinic or opioid, but not dopamine D2 or muscarinic receptor antagonists enhanced quinine-CFA acquisition. Baclofen (BAC), a GABAB receptor agonist, alternately enhances or reduces feeding under specific conditions. The present study examined whether systemic BAC administration mediated fructose-CFP expression and acquisition or quinine-CFA acquisition. Fructose-CFP expression studies trained rats with one flavor (CS+) in 8% fructose and 0.2% saccharin and a second (CS-) flavor in 0.2% saccharin, followed by vehicle (VEH) and BAC (0.5-5 mg/kg) preceding 2-bottle (CS+, CS-) 0.2% saccharin choice tests. Fructose-CFP acquisition studies administered VEH or BAC (3 or 5 mg/kg) prior to CS+ and CS- training sessions followed by six 2-bottle (CS+, CS-) 0.2% saccharin choice tests. Quinine-CFA acquisition studies administered VEH or BAC (3 or 5 mg/kg) prior to CS- (8% fructose+0.2% saccharin) and CS+ (fructose+saccharin+0.030% quinine) training sessions followed by six 2-bottle (CS-, CS+) fructose+saccharin choice tests. BAC (3 mg/kg) minimally (66%) reduced fructose-CFP expression. BAC failed to alter fructose-CFP acquisition. Quinine-CFA acquisition was enhanced by the 5 mg/kg BAC dose (15-25%) relative to VEH (34-48%). These data implicate GABAB receptor signaling in acquisition of quinine avoidance with minimal or no effects upon fructose preferences.

Muscarinic, nicotinic and GABAergic receptor signaling differentially mediate fat-conditioned flavor preferences in rats.

Rats display conditioned flavor preferences (CFP) for fats. Previous studies demonstrated that whereas expression of an already-acquired corn oil (CO)-CFP was mildly reduced by dopamine (DA) D1, DA D2, NMDA or opioid receptor antagonists, the acquisition or learning of CO-CFP was eliminated by NMDA antagonists, and significantly reduced by DA D1 and D2, but not opioid antagonists. Previous studies of fructose-CFP demonstrated that muscarinic (scopolamine) and nicotinic (mecamylamine) cholinergic receptor antagonists and GABAB (baclofen) receptor agonism reduced the expression of this acquired response, and that scopolamine, but not mecamylamine or baclofen eliminated the acquisition or learning of this response. The present study examined scopolamine, mecamylamine or baclofen effects upon expression or acquisition of CO-CFP. For expression, rats were trained over 10 sessions with CS+ (3.5% CO) and CS- (0.9% CO) flavored solutions without drugs. Two-bottle choice tests with CS+ and CS- flavors in 0.9% CO examined preferences following vehicle, scopolamine (1-10mg/kg), mecamylamine (1-8mg/kg) and baclofen (1.5-5mg/kg). In acquisition, eight groups of rats received vehicle, scopolamine (1, 2.5mg/kg), mecamylamine (4, 6mg/kg), baclofen (3, 5mg/kg) or a limited intake vehicle control 0.5h prior to all 10 CS+ and CS- training sessions followed by six 2-bottle CS+ and CS- choice tests in 0.9% CO. CO-CFP expression (percent CS+ intake) was significantly but marginally reduced by scopolamine (70%), mecamylamine (85%) and baclofen (74%) relative to vehicle (98%). CO-CFP acquisition was eliminated (41%) by scopolamine relative to vehicle (88%) and limited control (98%) conditions. Neither mecamylamine nor baclofen altered CO-CFP acquisition. Thus, the muscarinic cholinergic receptor system is essential for acquisition (learning) of both fat-induced and sugar (fructose)-induced preferences. In contrast, muscarinic, nicotinic and GABAB receptors were minimally involved in the expression (maintenance) of fat- and fructose-CFP.

Dopamine receptor signaling in the medial orbital frontal cortex and the acquisition and expression of fructose-conditioned flavor preferences in rats.

Systemic dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC) antagonists blocked fructose-conditioned flavor preference (CFP) acquisition and expression. Fructose-CFP acquisition was eliminated by medial prefrontal cortex (mPFC) SCH and mPFC or amygdala (AMY) RAC. Fructose-CFP expression was reduced following SCH or RAC in AMY or nucleus accumbens (NAc). The present study examined fructose-CFP acquisition and expression following SCH and RAC in the medial orbital frontal cortex (MOFC), another ventral tegmental area DA target. For fructose-CFP acquisition, five groups of rats received vehicle, SCH (24 or 48 nmol) or RAC (24 or 48 nmol) in the MOFC 0.5h prior to 8 training sessions with one flavor (CS+/Fs) mixed in 8% fructose and 0.2% saccharin, and another flavor (CS-/s) mixed in 0.2% saccharin. In six 2-bottle choice tests in 0.2% saccharin, similar fructose-CFP preferences occurred in groups trained with vehicle (76-77%), SCH24 (69-78%), SCH48 (70-74%) and RAC48 (85-92%). RAC24-trained rats displayed significant CS+ preferences during the first (79%) and third (71%), but not second (58%) test pair. For fructose-CFP expression, rats similarly trained with CS+/Fs and CS- solutions received 2-bottle choice tests following MOFC injections of SCH or RAC (12-48 nmol). CS+ preference expression was significantly reduced by RAC (48 nmol: 58%), but not SCH relative to vehicle (78%). A control group receiving RAC in the dorsolateral prefrontal cortex displayed fructose-CFP expression similar to vehicle. These data demonstrate differential frontal cortical DA mediation of fructose-CFP with mPFC D1 and D2 signaling exclusively mediating acquisition, and MOFC D2 signaling primarily mediating expression.