Differential effects of intra-midbrain raph� and systemic 8-OH-DPAT on VTA self-stimulation thresholds in rats

Ahn, Kee-Chan; Pazderka, Hannah; Clements, Robert L.; Ashcroft, R.; Ali, Talal F.; Morse, Cheryl L.; Greenshaw, Andrew J.

doi:10.1007/s00213-004-2031-3

Cited by 17 publications

(12 citation statements)

References 49 publications

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“…This lack of abuse-related effect in an ICSS procedure agrees with a previous report that flibanserin failed to produce a conditioned place preference in male rats [13]. Conversely, the present results with flibanserin contrast with effects in rats reported for relatively low doses of the 5HT1A agonist 8-OH-DPAT, which usually facilitates ICSS [16, 17] (but see [42]) and produces conditioned place preferences [15]. The present results are not likely to reflect evaluation of an inadequate flibanserin dose range, because flibanserin was tested across a 10-fold dose range from low doses that produced no effect to high doses that only depressed ICSS, and flibanserin doses tested here also produce a range of other behavioral effects in rats (e.g.…”

Section: Discussionsupporting

confidence: 93%

Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

Lazenka

Blough

Negus

2016

The Journal of Sexual Medicine

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INTRODUCTION Flibanserin is a serotonin receptor subtype 1A (5HT1A) agonist and 2A (5HT2A) antagonist that has been approved by the Food and Drug Administration for treating female sexual interest/arousal disorder. Little is known about the abuse potential of flibanserin. AIM This study examined abuse-related effects of flibanserin in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to evaluate abuse potential of other drugs. METHODS Adult female and male Sprague-Dawley rats with electrodes implanted in the medial forebrain bundle were trained to lever press for electrical brain stimulation under a “frequency-rate” ICSS procedure. In this procedure, increasing frequencies of brain stimulation maintain increasing rates of responding. Drugs of abuse typically increase (or “facilitate”) ICSS rates and produce leftward/upward shifts in ICSS frequency-rate curves, whereas drugs that lack abuse potential typically do not alter or only decrease ICSS rates. Initial studies determined the potency and time course of effects on ICSS produced by acute flibanserin (1.0, 3.2 and 10.0 mg/kg). Subsequent studies determined effects of flibanserin (3.2–18 mg/kg) before and after a regimen of repeated flibanserin administration (5.6 mg/kg/day x 5 days). Effects of the abused stimulant amphetamine (1.0 mg/kg) were examined as a positive control. MAIN OUTCOME MEASURE Flibanserin effects on ICSS frequency-rate curves in female and male rats were examined and compared to effects of amphetamine. RESULTS Baseline ICSS frequency-rate curves were similar in female and male rats. Both acute and repeated administration of flibanserin produced only decreases in ICSS rates, and rate-decreasing effects of the highest flibanserin dose (10 mg/kg) were greater in females than males. In contrast to flibanserin, amphetamine produced an abuse-related increase in ICSS rates that did not differ between females and males. CONCLUSIONS These results suggest that flibanserin has low abuse potential. Additionally, this study suggests that females may be more sensitive than males to rate-decreasing effects of high flibanserin doses.

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Section: Discussionsupporting

confidence: 93%

Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

Lazenka

Blough

Negus

2016

The Journal of Sexual Medicine

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“…However, the direction (positive or negative) of its effects should be analyzed carefully because it may vary depending on the method used to modulate 5-HT levels (e.g., systemic or local), the location of self-stimulation (Ahn et al, 2005), or the kinds of behavioral test used (Mosher et al, 2005; Hayes et al, 2009). …”

Section: -Ht and The Reward Circuitmentioning

confidence: 99%

The role of the dorsal raphé nucleus in reward-seeking behavior

Nakamura¹

2013

Front. Integr. Neurosci.

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Pharmacological experiments have shown that the modulation of brain serotonin levels has a strong impact on value-based decision making. Anatomical and physiological evidence also revealed that the dorsal raphé nucleus (DRN), a major source of serotonin, and the dopamine system receive common inputs from brain regions associated with appetitive and aversive information processing. The serotonin and dopamine systems also have reciprocal functional influences on each other. However, the specific mechanism by which serotonin affects value-based decision making is not clear. To understand the information carried by the DRN for reward-seeking behavior, we measured single neuron activity in the primate DRN during the performance of saccade tasks to obtain different amounts of a reward. We found that DRN neuronal activity was characterized by tonic modulation that was altered by the expected and received reward value. Consistent reward-dependent modulation across different task periods suggested that DRN activity kept track of the reward value throughout a trial. The DRN was also characterized by modulation of its activity in the opposite direction by different neuronal subgroups, one firing strongly for the prediction and receipt of large rewards, with the other firing strongly for small rewards. Conversely, putative dopamine neurons showed positive phasic responses to reward-indicating cues and the receipt of an unexpected reward amount, which supports the reward prediction error signal hypothesis of dopamine. I suggest that the tonic reward monitoring signal of the DRN, possibly together with its interaction with the dopamine system, reports a continuous level of motivation throughout the performance of a task. Such a signal may provide “reward context” information to the targets of DRN projections, where it may be integrated further with incoming motivationally salient information.

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“…Within these genes two single nucleotide polymorphisms (SNPs), rs6295 and rs6311, code for receptor 5-HT1A and receptor 5-HT2A, respectively. Administration of a 5-HT1A agonist, 8-OH-DPAT, increased reward in rodents (Ahn et al, 2005), and reinforced the rewarding properties of cocaine in monkeys (Czoty, McCabe & Nader, 2005). The 5-HT2A seems integral in mediating the effects of some abused drugs such as 3,4-methylenedioxy- N -methylamphetamine (MDMA) (Liechti, Saur, Gamma, Hell & Vollenweider, 2000).…”

Section: Introductionmentioning

confidence: 99%

Association between serotonin Cumulative Genetic Score and the Behavioral Approach System (BAS): Moderation by early life environment

Pearson

McGeary

Beevers

2014

Personality and Individual Differences

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The present study investigates if genetic variation in the serotonergic system interacts with early adversity to predict changes in the Behavioral Approach System (BAS), a system that taps into reward processing. In a sample of community adults (N= 236) the influence of single serotonergic candidate polymorphisms on BAS was analyzed, we also examined the aggregate contribution of these genetic variants by creating a Cumulative Genetic Score (CGS). A CGS quantifies an individual’s cumulative risk by aggregating the number of risk alleles across the candidate polymorphisms. After individual gene analysis, three candidate genes rs7305115 (TPH2), rs6311 (HTR2A), and rs6295 (HTR1A) were combined into the CGS. There were no significant interactions between individual candidate polymorphisms and childhood adversity, but the CGS interacted with childhood adversity to explain a significant amount of variance (11.6%) in the BAS. Findings suggest that genetic variations in the serotonergic system in combination with childhood adversity contribute to individual differences in reward sensitivity.

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Differential effects of intra-midbrain raph� and systemic 8-OH-DPAT on VTA self-stimulation thresholds in rats

Cited by 17 publications

References 49 publications

Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

The role of the dorsal raphé nucleus in reward-seeking behavior

Association between serotonin Cumulative Genetic Score and the Behavioral Approach System (BAS): Moderation by early life environment

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