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Distinct Neuropsychological Mechanisms May Explain Delayed- Versus Rapid-Onset Antidepressant Efficacy.

Stuart SA, Butler P, Munafò MR, Nutt DJ, Robinson ES - Neuropsychopharmacology (2015)

Bottom Line: The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits.We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala.We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine.

View Article: PubMed Central - PubMed

Affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.

ABSTRACT
The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits. This study used a novel rodent assay to investigate how different antidepressant drugs act to modify affective biases that have been implicated in depression. In this bowl-digging task, rats encounter two equal value learning experiences on separate days (one during an affective manipulation and the other during control conditions). This induces an affective bias that is quantified using a preference test in which both digging substrates are presented together and the individual rats' choices recorded. The assay can be used to measure affective biases associated with learning (when the treatment is given at the time of the experience) or examine the modification of previously acquired biases (when the treatment is administered before the preference test). The rapid-onset antidepressant ketamine, but not the delayed-onset antidepressant, venlafaxine, attenuated the previously acquired FG7142-induced negative bias following systemic administration. Venlafaxine but not ketamine induced a positive bias when administered before learning. We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala. Using a modified protocol we also showed that positive and negative biases amplified further when the numbers of substrate-reinforcer associations are increased. We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine.

No MeSH data available.


Related in: MedlinePlus

Affective biases amplify with additional learning experiences. Utilizing a modified protocol (a), the effects of additional substrate–reinforcer pairing sessions were investigated. The effects of venlafaxine (b) treatment further amplified when the number of substrate–reinforcer pairing sessions was increased. The effects were significant from week 2 onward, consistent with the standard protocol (Figure 1a), and this increased further with each successive postdrug encounter with the reinforcer-paired substrate. Using the same procedure the prodepressant drug treatment rimonabant (c) and psychosocial stress manipulation (d) were shown to induce a negative bias that also amplified with each successive experience. Data shown as mean±SEM, n=15–16. Data analyzed using repeated measures ANOVA, *p<0.05, **p<0.01, ***p<0.001 vs theoretical mean of 0% choice bias, #p<0.05 paired t-test.
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fig4: Affective biases amplify with additional learning experiences. Utilizing a modified protocol (a), the effects of additional substrate–reinforcer pairing sessions were investigated. The effects of venlafaxine (b) treatment further amplified when the number of substrate–reinforcer pairing sessions was increased. The effects were significant from week 2 onward, consistent with the standard protocol (Figure 1a), and this increased further with each successive postdrug encounter with the reinforcer-paired substrate. Using the same procedure the prodepressant drug treatment rimonabant (c) and psychosocial stress manipulation (d) were shown to induce a negative bias that also amplified with each successive experience. Data shown as mean±SEM, n=15–16. Data analyzed using repeated measures ANOVA, *p<0.05, **p<0.01, ***p<0.001 vs theoretical mean of 0% choice bias, #p<0.05 paired t-test.

Mentions: The study investigating the effects of multiple (more than two) pairing sessions after affective manipulation was examined using a modified protocol involving each rat receiving one treatment-pairing session and one vehicle-pairing session each week, followed by a preference test (Figure 4a, full details in Supplementary Table S1). This protocol was repeated each week with the same substrate pairings for 5 consecutive weeks using venlafaxine (3 mg/kg, i.p. vs vehicle). The same protocol was also used to test the effects of prodepressant manipulations using once weekly psychosocial stress (vs control housing), or the CB1 antagonist, rimonabant (3 mg/kg, i.p., vs vehicle). These studies did not include a separate control group but compared experience encountered under manipulation against control/vehicle pairing session (Supplementary Table S1). Previous studies have established the validity of this experiment design (Stuart et al, 2013).


Distinct Neuropsychological Mechanisms May Explain Delayed- Versus Rapid-Onset Antidepressant Efficacy.

Stuart SA, Butler P, Munafò MR, Nutt DJ, Robinson ES - Neuropsychopharmacology (2015)

Affective biases amplify with additional learning experiences. Utilizing a modified protocol (a), the effects of additional substrate–reinforcer pairing sessions were investigated. The effects of venlafaxine (b) treatment further amplified when the number of substrate–reinforcer pairing sessions was increased. The effects were significant from week 2 onward, consistent with the standard protocol (Figure 1a), and this increased further with each successive postdrug encounter with the reinforcer-paired substrate. Using the same procedure the prodepressant drug treatment rimonabant (c) and psychosocial stress manipulation (d) were shown to induce a negative bias that also amplified with each successive experience. Data shown as mean±SEM, n=15–16. Data analyzed using repeated measures ANOVA, *p<0.05, **p<0.01, ***p<0.001 vs theoretical mean of 0% choice bias, #p<0.05 paired t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487826&req=5

fig4: Affective biases amplify with additional learning experiences. Utilizing a modified protocol (a), the effects of additional substrate–reinforcer pairing sessions were investigated. The effects of venlafaxine (b) treatment further amplified when the number of substrate–reinforcer pairing sessions was increased. The effects were significant from week 2 onward, consistent with the standard protocol (Figure 1a), and this increased further with each successive postdrug encounter with the reinforcer-paired substrate. Using the same procedure the prodepressant drug treatment rimonabant (c) and psychosocial stress manipulation (d) were shown to induce a negative bias that also amplified with each successive experience. Data shown as mean±SEM, n=15–16. Data analyzed using repeated measures ANOVA, *p<0.05, **p<0.01, ***p<0.001 vs theoretical mean of 0% choice bias, #p<0.05 paired t-test.
Mentions: The study investigating the effects of multiple (more than two) pairing sessions after affective manipulation was examined using a modified protocol involving each rat receiving one treatment-pairing session and one vehicle-pairing session each week, followed by a preference test (Figure 4a, full details in Supplementary Table S1). This protocol was repeated each week with the same substrate pairings for 5 consecutive weeks using venlafaxine (3 mg/kg, i.p. vs vehicle). The same protocol was also used to test the effects of prodepressant manipulations using once weekly psychosocial stress (vs control housing), or the CB1 antagonist, rimonabant (3 mg/kg, i.p., vs vehicle). These studies did not include a separate control group but compared experience encountered under manipulation against control/vehicle pairing session (Supplementary Table S1). Previous studies have established the validity of this experiment design (Stuart et al, 2013).

Bottom Line: The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits.We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala.We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine.

View Article: PubMed Central - PubMed

Affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.

ABSTRACT
The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits. This study used a novel rodent assay to investigate how different antidepressant drugs act to modify affective biases that have been implicated in depression. In this bowl-digging task, rats encounter two equal value learning experiences on separate days (one during an affective manipulation and the other during control conditions). This induces an affective bias that is quantified using a preference test in which both digging substrates are presented together and the individual rats' choices recorded. The assay can be used to measure affective biases associated with learning (when the treatment is given at the time of the experience) or examine the modification of previously acquired biases (when the treatment is administered before the preference test). The rapid-onset antidepressant ketamine, but not the delayed-onset antidepressant, venlafaxine, attenuated the previously acquired FG7142-induced negative bias following systemic administration. Venlafaxine but not ketamine induced a positive bias when administered before learning. We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala. Using a modified protocol we also showed that positive and negative biases amplified further when the numbers of substrate-reinforcer associations are increased. We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine.

No MeSH data available.


Related in: MedlinePlus