Muscarinic type 2 receptors in the lateral dorsal tegmental area modulate cocaine and food seeking behavior in rats.

paper Cited Public

Authors: Shabani, S; Foster, R; Gubner, N; Phillips, T J; Mark, G P
Year: 2010
Journal: Neuroscience
PMID: 20667466
DOI: 10.1016/j.neuroscience.2010.07.028
PMCID: PMC2936824

The cholinergic input from the lateral dorsal tegmental area (LDTg) modulates the dopamine cells of the ventral tegmental area (VTA) and plays an important role in cocaine taking. Specific pharmacological agents that block or stimulate muscarinic receptors in the LDTg change acetylcholine (ACh) levels in the VTA. Furthermore, manipulations of cholinergic input in the VTA can change cocaine taking. In the current study, the ACh output from the LDTg was attenuated by treatment with the selective muscarinic type 2 (M2) autoreceptor agonist oxotremorine.sesquifumarate (OxoSQ). We hypothesized that OxoSQ would reduce the motivation of rats to self-administer both natural and drug rewards. Animals were tested on progressive ratio (PR) schedules of reinforcement for food pellets and cocaine. On test days, animals on food and on cocaine schedules were bilaterally microinjected prior to the test. Rats received either LDTg OxoSQ infusions or LDTg artificial cerebrospinal fluid (aCSF) infusions in a within-subjects design. In addition, infusions were delivered into a dorsal brain area above the LDTg as an anatomical control region. OxoSQ microinjection in the LDTg, compared to aCSF, significantly reduced both the number of self-administered pellets and cocaine infusions during the initial half of the session; this reduction was dose-dependent. OxoSQ microinjections into the area just dorsal to the LDTg had no significant effect on self-administration of food pellets or cocaine. Animals were also tested in locomotor activity chambers for motor effects following the above microinjections. Locomotor activity was mildly increased by OxoSQ microinjection into the LDTg during the initial half of the session. Overall, these data suggest that LDTg cholinergic neurons play an important role in modifying the reinforcing value of natural and drug rewards. These effects cannot be attributed to significant alterations of locomotor behavior and are likely accomplished through LDTg muscarinic autoreceptors.

#	Section	Preview
0	Introduction	Cocaine is a highly addictive drug with severe detrimental physical and mental health effects.…
1	Introduction	Carboni et al, 2001, Pettit and Justice, 1989). This increase in dopamine, which lingers in the…
2	Introduction	DA released in the NAc from the ventral tegmental area (VTA), is critical for the rewarding effects…
3	Introduction	One important source of cholinergic modulation of VTA DAergic neurons arises from the lateral dorsal…
4	Introduction	however, the initial peak of ACh in the VTA (which was short in duration) depended upon the history…
5	Introduction	rats trained to self-administer cocaine in short access sessions do not show escalation of cocaine…
6	Introduction	Pharmacological manipulation of the LDTg may provide new insights about the role of ACh in cocaine…
7	Introduction	in the LDTg with an M2 antagonist can block the hyperpolarizing effects of ACh (Leonard and Llinas,…
8	Introduction	Self-administration studies in rats have been performed frequently when addressing mechanisms…
9	Materials and Methods — Animals	Twenty five male Sprague-Dawley rats (Charles River Laboratories), weighing approximately 375 grams…
10	Materials and Methods — Drug preparation	Cocaine hydrochloride was obtained from The Research Triangle Institute (Research Triangle Park, NC)…
11	Materials and Methods — Operant Training	Operant conditioning chambers (Med Associates Inc.; St. Albans, VT) were housed inside sound…
12	Materials and Methods — Operant Training	Prior to surgery, all animals were trained to lever press for 45mg Noyes food pellets (BioServe;…
13	Materials and Methods — Operant Training	were four hours. Food training for the PR schedule was essential for increasing the number of…
14	Materials and Methods — Operant Training	When animals achieved a BP of FR25 or higher for food reward, they underwent the following…
15	Materials and Methods — Operant Training	schedules for food pellet rewards in sessions that were a maximum of 3 hr in duration; these animals…
16	Materials and Methods — Operant Training	= 8) were conducted beginning 2 hours into the dark phase; however, for technical reasons, a smaller…
17	Materials and Methods — Operant Training	Animals that had stabilized PR schedules within ± 3 BP and a minimum of FR-32 were then habituated…
18	Materials and Methods — Operant Training	with baseline (i.e. no microinjection) days between infusions. In all cases where microinjections…
19	Materials and Methods — Operant Training	two baseline sessions before receiving the next treatment. Some animals, however, had only one…

Name	Type
Acepromazine	drug
acetylcholine	drug
ACh	drug
acquisition of self-administration behavior local	phenotype
aCSF	drug
active lever local	anatomy
active lever pressing	phenotype
alcohol self-administration	phenotype
anesthetic cocktail local	drug
animals	cohort
artificial cerebrospinal fluid	drug
behavioral seeking responses local	phenotype
brain	anatomy
Break point local	phenotype
breakpoint (BP) local	phenotype
Brevital	drug
CaCl2	drug
carbachol	drug
CBAS heparin-coated PU catheter local	drug
central nucleus of the inferior colliculus local	anatomy
Charles River Laboratories local	cohort
cholinergic input local	phenotype
cholinergic neurons	phenotype
cholinomimetics local	drug
CHRM2	gene
CHRM4	gene
Chrm5	gene
CIC local	anatomy
CIC local	drug
cocaine	phenotype
cocaine group	cohort
Cocaine hydrochloride local	drug
cocaine-induced DA levels in NAc local	phenotype
cocaine infusion local	phenotype
cocaine seeking reinstatement local	phenotype
cocaine self-administration	phenotype
cocaine study local	cohort
Cocaine taking local	phenotype
conditioned place preference	phenotype
DA	drug
DA levels in NAc local	phenotype
Dark phase local	phenotype
dark phase animals local	cohort
dental acrylic local	drug
depressive behavior	phenotype
depressive-like behaviors local	phenotype
dopamine	drug
dopamine efflux	drug
dopaminergic neurons	anatomy
Dopamine transporter	drug
drug	drug
drug-seeking behavior	phenotype
dura	anatomy
Escalation of cocaine self-administration local	phenotype
fluid	drug
Food group local	cohort
food pellet	drug
food pellet group local	cohort
food seeking local	phenotype
food self-administration local	phenotype
glucose	drug
glutamate	drug
glutamatergic input local	phenotype
guide cannulae local	drug
head shields local	drug
heparin	drug
higher than FR-25 local	phenotype
inactive lever local	anatomy
inactive lever pressing	phenotype
Increased arousal local	phenotype
Increased expenditure of time and energy local	phenotype
Inwardly rectifying potassium channel local	drug
ionotropic glutamate receptor antagonist local	drug
IPSP local	phenotype
isoflurane	drug
Isopentane	drug
IV catheter local	drug
IV cocaine self-administration training local	phenotype
KCl	drug
ketamine	drug
KH2PO4 local	drug
lateral dorsal tegmental area local	anatomy
lateral dorsal tegmental nucleus local	anatomy
lateral periaqueductal gray local	anatomy
laterodorsal tegmental nucleus	anatomy
LDTg	anatomy
LDTg/PPTg local	anatomy
lever pressing local	phenotype
Lever pressing local	phenotype
lever pressing for cocaine	phenotype
lever press ratio local	phenotype
light phase animals local	cohort
locomotion	phenotype
locomotor activity	phenotype
locus coeruleus	anatomy
loss of control	phenotype
M2 antagonist local	drug
M2 receptor	drug
M2R -/- mice local	cohort
M5R +/+ mice local	cohort
M5R +/- mice local	cohort
M5R -/- mice local	cohort
mecamylamine	drug
medial prefrontal cortex	anatomy
Medial subdivision of LDTg local	anatomy
mesocorticolimbic pathway local	anatomy
methoctramine local	drug
MgCl2	drug
motivated behavior	phenotype
motivation for cocaine self-administration local	phenotype
Motor ability local	phenotype
muscarine local	drug
Muscarinic acetylcholine receptor	drug
NAc	anatomy
NAc DA levels local	phenotype
NaHCO3	drug
NaOH	drug
neostigmine local	drug
nicotine	drug
nicotinic acetylcholine receptor	drug
Noyes food pellets local	drug
nucleus accumbens	anatomy
nucleus accumbens shell	anatomy
OxoSQ local	drug
OxoSQ 10 nmol local	drug
Oxotremorine sesquifumarate local	drug
pedunculopontine nucleus local	anatomy
PPTg	anatomy
PR behavior local	phenotype
rats	cohort
Reinforcing properties	phenotype
reward	phenotype
rewarding effects of cocaine	phenotype
Reward seeking behavior local	phenotype
reward seeking behaviors local	phenotype
saline	drug
scopolamine	drug
self-administration of cocaine local	phenotype
Silica local	drug
SLC6A3	gene
Sprague-Dawley rats	cohort
stainless steel screws local	drug
tether local	drug
Thionin	drug
ticarcillin local	drug
Ticarcillin local	drug
Timentin local	drug
ventral tegmental area	anatomy
VTA	anatomy
VTA dopaminergic neurons local	anatomy
water	drug
xylazine	drug

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