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Ventral and dorsal striatal dopamine efflux and behavior in rats with simple vs. co-morbid histories of cocaine sensitization and neonatal ventral hippocampal lesions.

Chambers RA, Sentir AM, Engleman EA - Psychopharmacology (Berl.) (2010)

Bottom Line: DA efflux curves corresponded time dependently with the cocaine injection and locomotor curves and varied significantly by striatal region: Baseline DA levels increased 5-fold while cocaine-stimulated DA efflux decreased by half across a ventral to dorsal striatal gradient.However, NVHLs, prior cocaine history, and individual differences in behavior were not underpinned by differential DA efflux overall or within any striatal region.Differences in ventral/dorsal striatal DA efflux are not present in and are not required for producing differential levels of acute cocaine-induced behavioral activation in NVHLs with and without a behaviorally sensitizing cocaine history.

View Article: PubMed Central - PubMed

Affiliation: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, 46202, USA. robchamb@iupui.edu

ABSTRACT

Rational: Exposing animal models of mental illness to addictive drugs provides an approach to understanding the neural etiology of dual diagnosis disorders. Previous studies have shown that neonatal ventral hippocampal lesions (NVHL) in rats produce features of both schizophrenia and addiction vulnerability.

Objective: This study investigated ventral and dorsal striatal dopamine (DA) efflux in NVHL rats combined with behavioral sensitization to cocaine.

Methods: Adult NVHL vs. SHAM-operated rats underwent a 5-day injection series of cocaine (15 mg/kg/day) vs. saline. One week later, rats were cannulated in nucleus accumbens SHELL, CORE, or caudate-putamen. Another week later, in vivo microdialysis sampled DA during locomotor testing in which a single cocaine injection (15 mg/kg) was delivered.

Results: NVHLs and cocaine history significantly increased behavioral activation approximately 2-fold over SHAM-saline history rats. DA efflux curves corresponded time dependently with the cocaine injection and locomotor curves and varied significantly by striatal region: Baseline DA levels increased 5-fold while cocaine-stimulated DA efflux decreased by half across a ventral to dorsal striatal gradient. However, NVHLs, prior cocaine history, and individual differences in behavior were not underpinned by differential DA efflux overall or within any striatal region.

Conclusion: Differences in ventral/dorsal striatal DA efflux are not present in and are not required for producing differential levels of acute cocaine-induced behavioral activation in NVHLs with and without a behaviorally sensitizing cocaine history. These findings suggest other neurotransmitter systems, and alterations in striatal network function post-synaptic to DA transmission are more important to understanding the interactive effects of addictive drugs and mental illness.

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%DA efflux across post-injection bins (1–9) according to cannulation region. Significant main effects of region (**p < 0.01) and bins × region (***p < 0.001) were identified. Data depicted as means ± SEM include all rats in the study regardless of drug history or lesion status (SHELL (N = 31); CORE (N = 30); CAPU (N = 31))
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Fig5: %DA efflux across post-injection bins (1–9) according to cannulation region. Significant main effects of region (**p < 0.01) and bins × region (***p < 0.001) were identified. Data depicted as means ± SEM include all rats in the study regardless of drug history or lesion status (SHELL (N = 31); CORE (N = 30); CAPU (N = 31))

Mentions: In contrast to post-injection behavior, post-injection %DA efflux did not show main effects of lesion or drug history, though the lesion effect was marginal (F(1, 80) = 3.0, p = 0.09) due to lower %DA efflux (mean across post-injection bins) in NVHLs (N = 44; 249 ± 21%) compared to SHAMs (N = 48; 307 ± 32%). Bins were also strongly significant (F(8, 640) = 31.5, p < 0.001) consistent with the effect of cocaine in causing a pronounced rise then fall of %DA efflux. Similar to the pre-injection %DA data, cannulation region again showed a significant effect (F(2, 80) = 6.8, p < 0.01) and a region × bins interaction (F(15, 640) = 3.8, p < 0.001; Fig. 5). However, the %DA efflux gradient expressed opposite to the baseline DA concentrations; % DA efflux (mean across post-injection bins) in the SHELL (N = 31; 365 ± 45) was marginally higher in comparison to CORE (N = 30; 272 ± 30, p = 0.098) and significantly higher than CAPU (N = 31; 201 ± 12; p < 0.01). Pearson correlation including all rats in the study confirmed a significant inverse relationship between mean baseline DA levels and mean post-injection %DA efflux (R = −0.284, p < 0.01). No other interactions between main effects or bins were noted in post-injection %DA with the exception of a complex significant four-way interaction (lesion × drug history × region × bins: F(16, 640) = 1.68, p < 0.05). Post hoc examinations of %DA efflux performed at each post-injection bin that compared the 12 subgroups (indexed by lesion status, drug history, cannulation region) revealed that SHELL-cannulated SHAM-COC rats showed significantly greater %DA efflux than five of the 11 other subgroups (all four of the CAPU-cannulated groups and the CORE-NVHL-SAL group), across the second, third, and fourth post-injection bins (p < 0.05), while none of the other 11 subgroups were mutually different at any post-injection bin (Fig. 6). While suggestive of a neurochemical sensitization isolated to SHAM-COC rats in the early portion of the %DA curve, this finding was not robust to secondary repeated measures ANOVAs performed on %DA efflux for each region separately (lesion × drug history × bins). Neither lesion nor drug history significantly modulated %DA as main effects or interactions, in the SHELL, CORE, or CAPU, although bins were again robustly significant in all regions (SHELL (F(8, 216) = 11.8, p < 0.001); CORE (F(8, 208) = 18.2, p < 0.001); CAPU (F(8, 216) = 26.1, p < 0.001)). Notably, significant behavioral effects of lesion or drug history would still be detectible given the same ANOVA of post-injection locomotion at each region separately: (SHELL (bins: F(8, 216) = 24.6, p < 001; lesion: F(1, 27) = 7.5, p < 0.01)), (CORE (bins: F(8,208) = 25.6, p < 0.001; drug history: F(1, 26) = 4.6, p < 0.05; drug history × bins: F(8, 208) = 2.1, p < 0.05)), (CAPU (bins: F(8, 216) = 35.2, p < 0.001; lesion F(1, 27) = 8.2, p < 0.01)).Fig. 5


Ventral and dorsal striatal dopamine efflux and behavior in rats with simple vs. co-morbid histories of cocaine sensitization and neonatal ventral hippocampal lesions.

Chambers RA, Sentir AM, Engleman EA - Psychopharmacology (Berl.) (2010)

%DA efflux across post-injection bins (1–9) according to cannulation region. Significant main effects of region (**p < 0.01) and bins × region (***p < 0.001) were identified. Data depicted as means ± SEM include all rats in the study regardless of drug history or lesion status (SHELL (N = 31); CORE (N = 30); CAPU (N = 31))
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2921051&req=5

Fig5: %DA efflux across post-injection bins (1–9) according to cannulation region. Significant main effects of region (**p < 0.01) and bins × region (***p < 0.001) were identified. Data depicted as means ± SEM include all rats in the study regardless of drug history or lesion status (SHELL (N = 31); CORE (N = 30); CAPU (N = 31))
Mentions: In contrast to post-injection behavior, post-injection %DA efflux did not show main effects of lesion or drug history, though the lesion effect was marginal (F(1, 80) = 3.0, p = 0.09) due to lower %DA efflux (mean across post-injection bins) in NVHLs (N = 44; 249 ± 21%) compared to SHAMs (N = 48; 307 ± 32%). Bins were also strongly significant (F(8, 640) = 31.5, p < 0.001) consistent with the effect of cocaine in causing a pronounced rise then fall of %DA efflux. Similar to the pre-injection %DA data, cannulation region again showed a significant effect (F(2, 80) = 6.8, p < 0.01) and a region × bins interaction (F(15, 640) = 3.8, p < 0.001; Fig. 5). However, the %DA efflux gradient expressed opposite to the baseline DA concentrations; % DA efflux (mean across post-injection bins) in the SHELL (N = 31; 365 ± 45) was marginally higher in comparison to CORE (N = 30; 272 ± 30, p = 0.098) and significantly higher than CAPU (N = 31; 201 ± 12; p < 0.01). Pearson correlation including all rats in the study confirmed a significant inverse relationship between mean baseline DA levels and mean post-injection %DA efflux (R = −0.284, p < 0.01). No other interactions between main effects or bins were noted in post-injection %DA with the exception of a complex significant four-way interaction (lesion × drug history × region × bins: F(16, 640) = 1.68, p < 0.05). Post hoc examinations of %DA efflux performed at each post-injection bin that compared the 12 subgroups (indexed by lesion status, drug history, cannulation region) revealed that SHELL-cannulated SHAM-COC rats showed significantly greater %DA efflux than five of the 11 other subgroups (all four of the CAPU-cannulated groups and the CORE-NVHL-SAL group), across the second, third, and fourth post-injection bins (p < 0.05), while none of the other 11 subgroups were mutually different at any post-injection bin (Fig. 6). While suggestive of a neurochemical sensitization isolated to SHAM-COC rats in the early portion of the %DA curve, this finding was not robust to secondary repeated measures ANOVAs performed on %DA efflux for each region separately (lesion × drug history × bins). Neither lesion nor drug history significantly modulated %DA as main effects or interactions, in the SHELL, CORE, or CAPU, although bins were again robustly significant in all regions (SHELL (F(8, 216) = 11.8, p < 0.001); CORE (F(8, 208) = 18.2, p < 0.001); CAPU (F(8, 216) = 26.1, p < 0.001)). Notably, significant behavioral effects of lesion or drug history would still be detectible given the same ANOVA of post-injection locomotion at each region separately: (SHELL (bins: F(8, 216) = 24.6, p < 001; lesion: F(1, 27) = 7.5, p < 0.01)), (CORE (bins: F(8,208) = 25.6, p < 0.001; drug history: F(1, 26) = 4.6, p < 0.05; drug history × bins: F(8, 208) = 2.1, p < 0.05)), (CAPU (bins: F(8, 216) = 35.2, p < 0.001; lesion F(1, 27) = 8.2, p < 0.01)).Fig. 5

Bottom Line: DA efflux curves corresponded time dependently with the cocaine injection and locomotor curves and varied significantly by striatal region: Baseline DA levels increased 5-fold while cocaine-stimulated DA efflux decreased by half across a ventral to dorsal striatal gradient.However, NVHLs, prior cocaine history, and individual differences in behavior were not underpinned by differential DA efflux overall or within any striatal region.Differences in ventral/dorsal striatal DA efflux are not present in and are not required for producing differential levels of acute cocaine-induced behavioral activation in NVHLs with and without a behaviorally sensitizing cocaine history.

View Article: PubMed Central - PubMed

Affiliation: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, 46202, USA. robchamb@iupui.edu

ABSTRACT

Rational: Exposing animal models of mental illness to addictive drugs provides an approach to understanding the neural etiology of dual diagnosis disorders. Previous studies have shown that neonatal ventral hippocampal lesions (NVHL) in rats produce features of both schizophrenia and addiction vulnerability.

Objective: This study investigated ventral and dorsal striatal dopamine (DA) efflux in NVHL rats combined with behavioral sensitization to cocaine.

Methods: Adult NVHL vs. SHAM-operated rats underwent a 5-day injection series of cocaine (15 mg/kg/day) vs. saline. One week later, rats were cannulated in nucleus accumbens SHELL, CORE, or caudate-putamen. Another week later, in vivo microdialysis sampled DA during locomotor testing in which a single cocaine injection (15 mg/kg) was delivered.

Results: NVHLs and cocaine history significantly increased behavioral activation approximately 2-fold over SHAM-saline history rats. DA efflux curves corresponded time dependently with the cocaine injection and locomotor curves and varied significantly by striatal region: Baseline DA levels increased 5-fold while cocaine-stimulated DA efflux decreased by half across a ventral to dorsal striatal gradient. However, NVHLs, prior cocaine history, and individual differences in behavior were not underpinned by differential DA efflux overall or within any striatal region.

Conclusion: Differences in ventral/dorsal striatal DA efflux are not present in and are not required for producing differential levels of acute cocaine-induced behavioral activation in NVHLs with and without a behaviorally sensitizing cocaine history. These findings suggest other neurotransmitter systems, and alterations in striatal network function post-synaptic to DA transmission are more important to understanding the interactive effects of addictive drugs and mental illness.

Show MeSH
Related in: MedlinePlus