Role of α1-Adrenoceptors of the Locus Coeruleus in Self-Stimulation of the Medial Forebrain Bundle

Yang, Lin; Vaca, Soledad Cabeza de; Stone, Eric A.

doi:10.1038/sj.npp.1301145

Cited by 20 publications

(17 citation statements)

References 54 publications

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“…Prior studies strongly implicate a permissive function of α1-ARs in the reinforcement associated with MFB self-stimulation [31][32][33][34]. In the present study, systemic administration of the α1-AR antagonist prazosin, at doses that block cocaine-induced hyperactivity and hypophagia [22], was noted to significantly reduce breakpoint ratio scores (i.e.…”

Section: Discussionmentioning

confidence: 55%

Lobeline attenuates progressive ratio breakpoint scores for intracranial self-stimulation in rats

Wellman

Elliott

Barbee

et al. 2008

Physiology & Behavior

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The alkaloid lobeline inhibits the function of vesicular monoamine and dopamine transporters and diminishes the behavioral and neurochemical effects of nicotine and amphetamines. In the present study, we examined the interaction of systemic administration of lobeline on breakpoint scores on a progressive ratio (PR) schedule of intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB). Rats were run in two 30 min sessions, separated by a 10 min timeout period. At the end of the first session, each rat was injected with either 0, 0.5, 1.0 or 2.0 mg/kg (i.p.) lobeline. Positive controls known to suppress and to augment ICSS responding included the adrenergic antagonist prazosin (0, 0.5 and 2.0 mg/kg, i.p.) and the psychostimulant cocaine (0, 1.25, and 5.0 mg/kg, i.p.). Analyses of changes in average PR breakpoint scores between the 2 sessions revealed that lobeline significantly suppressed PR scores at doses of 0.5, 1.0 and 2.0 mg/kg, as did 0.5 mg/kg and 2.0 mg/ kg prazosin. These changes are unlikely to reflect motoric effects of these drugs inasmuch as neither lobeline nor prazosin alter locomotion at these doses. In contrast, PR breakpoint scores were significantly increased at 5.0 mg/kg cocaine, a dose that is sufficient to elevate locomotion in the rat. These results are consistent with the view that lobeline modulates brain reinforcement processes. Keywords Nicotinic receptors; Prazosin; CocaineMultiple behavioral assays can be used to index abuse potential [1][2][3] including the capacity of a drug to induce hyperlocomotion [4] and the capacity to induce conditioned place preference [5]. Rats will self-administer drugs such as cocaine or amphetamine into their vascular system [6]. Such drug infusions are thought to act on the neural substrates of reward. Electrodes placed along the path of the medial forebrain bundle (MFB) will support intracranial self-stimulation (ICSS) [7] and drugs of abuse are known to reduce the threshold current required to support ICSS [4,8,9]. Additionally, drugs of abuse are known to elevate progressive ratio (PR) responding for ICSS [10,11]. The latter types of studies are important in that a PR schedule, relative to a continuous reinforcement schedule, may be more sensitive to changes in reward engendered by neurotransmitter receptor antagonism [12].The alkaloid lobeline is derived from lobelia inflata [13]. Lobeline attenuates the hyperactivity induced by methamphetamine in rats and diminishes methamphetamine self-administration in rats [14][15][16]. The aforementioned results suggest that lobeline may function as a therapeutic tool for the treatment of methamphetamine abuse. Inasmuch as the impact of lobeline on ICSS responding has not been previously reported, the present study considered the impact of lobeline on breakpoints on a PR schedule of ICSS reinforcement. In this paradigm, the response requirement for reinforcement is increased systematically within a 30 min session [17]. Following completion of the first session, each rat was injected (i.p.)...

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Section: Discussionmentioning

confidence: 55%

Lobeline attenuates progressive ratio breakpoint scores for intracranial self-stimulation in rats

Wellman

Elliott

Barbee

et al. 2008

Physiology & Behavior

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“…If CRF does function in the positive system, one would predict that CRFR1 antagonists may under some conditions have behaviorally depressing effects. Furthermore, while the LC and DR are activated by stress, LC activation has also been shown to be involved in the rewarding effects of lateral hypothalamic self stimulation (Lin et al, 2007a), and DR activation in voluntary wheel running in mice (Rhodes et al, 2003), both forms of positively motivated behavior. Therefore, it may be that low to moderate activity in stress regions is necessary for the activation of positively motivated behavior and that an inhibitory effect only becomes apparent at high levels of activation.…”

Section: Recent Work By Kroes Et Al (In Pressmentioning

confidence: 99%

“…Pharmacological blockade of these receptors abolishes many of the above fos responses as well as the positively motivated behaviors in the above conditions (Stone et al, 2006b;Bing et al, 1991;O'Neill et al, 1998;Kauffman et al, 2005). Activation of the α 1B -adrenoceptor in a wide range of positive network locations induces vigorous exploratory behavior of mice in familiar environments and may also enhance reward processes (Lin et al, 2007a;Stone et al, 2004;Drouin et al, 2002). Brain sites from which exploratory behavior have been elicited by α 1 -receptor stimulation include the secondary motor and piriform cortex, NAC, POA, LC and vermis cerebellum, DR.…”

Section: ) Positive Motivational Networkmentioning

confidence: 99%

“…These authors studied c-fos expression or the phosphorylation of ERK1/2, two measures of neural activity (Hoffman and Lyo, 2002;Pascoli et al, 2005), to a motivating stimulus in a number of mouse brain regions previously shown to be involved in positively motivated behavior or stress responses (Stone et al, 2006a;2007a). The positive regions included the secondary motor cortex, anterior piriform cortex, posterior cingulate gyrus, and nucleus accumbens whereas the stress areas included the paraventricular hypothalamus (PVH) and bed nucleus of the stria terminalis (BNST).…”

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confidence: 99%

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A final common pathway for depression? Progress toward a general conceptual framework

Stone

Yang

Quartermain

2008

Neuroscience & Biobehavioral Reviews

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Functional neuroimaging studies of depressed patients have converged with functional brain mapping studies of depressed animals in showing that depression is accompanied by a hypoactivity of brain regions involved in positively motivated behavior together with a hyperactivity in regions involved in stress responses. Both sets of changes are reversed by diverse antidepressant treatments. It has been proposed that this neural pattern underlies the symptoms common to most forms of the depression, which are the loss of positively motivated behavior and increased stress. The paper discusses how this framework can organize diverse findings ranging from effects of monoamine neurotransmitters, cytokines, corticosteroids and neurotrophins on depression. The hypothesis leads to new insights concerning the relationship between the prolonged inactivity of the positive motivational network during a depressive episode and the loss of neurotrophic support, the potential antidepressant action of corticosteroid treatment, and to the key question of whether antidepressants act by inhibiting the activity of the stress network or by enhancing the activity of the positive motivational system. Keywords depression; neuroimaging; fos; final common pathway; cytokines; corticosteroids; monoamines; neurotrophins; theory The quest for a final common pathway has long been goal of research in depression. Famous candidates in this search have included dysregulated brain monoamines (Schildkraut, 1965;

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“…This hypothesis could be tested by specific optogenetic activation or silencing of dopaminergic neurons or their afferents. Optogenetic activation and silencing could also test the hypothesis (Lin et al, 2007) that excitatory input to VTA dopamine neurons from locus ceruleus NE neurons makes a synergistic contribution to the rewarding effect of MFB stimulation. Thus, the combination of powerful new methods for altering signal flow in specific neural populations with the reward-mountain method should provide new insights about the neural circuitry underlying reward seeking.…”

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confidence: 99%

Role of Dopamine Tone in the Pursuit of Brain Stimulation Reward

et al. 2012

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Dopaminergic neurons contribute to intracranial self-stimulation (ICSS) and other reward-seeking behaviors, but itis not yet known where dopaminergic neurons intervene in the neural circuitry underlying reward pursuit or which psychological processes are involved. In rats working for electrical stimulation of the medial forebrain bundle, we assessed the effect of GBR-12909 (1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-[3-phenylpropyl]piperazine), a specific blocker of the dopamine transporter. Operant performance was measured as a function of the strength and cost of electrical stimulation. GBR-12909 increased the opportunity cost most subjects were willing to pay for a reward of a given intensity. However, this effect was smaller than that produced by a regimen of cocaine administration that drove similar increases in nucleus accumbens (NAc) dopamine levels in unstimulated rats. Delivery of rewarding stimulation to drug-treated rats caused an additional increase in dopamine concentration in the NAc shell in cocaine-treated, but not GBR-12909-treated, rats. These behavioral and neurochemical differences may reflect blockade of the norepinephrine transporter by cocaine but not by GBR-12909. Whereas the effect of psychomotor stimulants on ICSS has long been attributed to dopaminergic action at early stages of the reward pathway, the results reported here imply that increased dopamine tone boosts reward pursuit by acting at or beyond the output of the circuitry that temporally and spatially summates the output of the directly stimulated neurons underlying ICSS. The observed enhancement of reward seeking could be attributable to a decrease in the value of competing behaviors, a decrease in subjective effort costs, or an increase in reward-system gain.

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Role of α1-Adrenoceptors of the Locus Coeruleus in Self-Stimulation of the Medial Forebrain Bundle

Cited by 20 publications

References 54 publications

Lobeline attenuates progressive ratio breakpoint scores for intracranial self-stimulation in rats

Lobeline attenuates progressive ratio breakpoint scores for intracranial self-stimulation in rats

A final common pathway for depression? Progress toward a general conceptual framework

Role of Dopamine Tone in the Pursuit of Brain Stimulation Reward

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