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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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Mapping of lesions and cannulation tracks of animals included in the study. Upper left sections show the largest (black) and smallest (white inset) lesion extents of NVHL animals used in the study. Upper right micrographs show typically sized NVHL damage vs. SHAM. Lower sections show cannulation placement for all rats included in the study (N = 92) by cannulation region. Coordinates are relative to bregma (Swanson 2004)
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Fig2: Mapping of lesions and cannulation tracks of animals included in the study. Upper left sections show the largest (black) and smallest (white inset) lesion extents of NVHL animals used in the study. Upper right micrographs show typically sized NVHL damage vs. SHAM. Lower sections show cannulation placement for all rats included in the study (N = 92) by cannulation region. Coordinates are relative to bregma (Swanson 2004)

Mentions: Rats were sacrificed immediately after microdialysis, after which probes were injected with methylene blue, followed by whole brain removal and rapid freezing in isopentane. Cryostat-cut coronal brain sections (40 μm) were mapped for probe placements (blue tracks) rostrally and for lesion verification caudally. Sections cut through the hippocampus were dehydrated, fixed, and thionin-stained. Lesion verification, mapping of probe placement, and examination of the fidelity of HPLC/DA detection were all conducted independently and blind from behavioral results. All of these conditions were assessed as sources of attrition. Exclusions were called on lesioned animals with only unilateral ventral hippocampal dysmorphology or significant extra-hippocampal damage, extra-striatal probe placement or related intracranial hemorrhage, dialysis probe blockage/bursting, operational failure of HPLC, or contaminants obscuring DA signal. A total of 211 rats were carried though at least cannulation in 27 cohorts of eight over a 3-year period toward a goal of reaching seven to nine non-excluded rats per group (indexed by lesion status, drug history, and cannulation site). Cohorts were balanced by lesion status and drug history, while two of three cannulation regions were rotated in across cohorts. Dialysate from each cohort was HPLC analyzed in the same batch, 2–4 weeks after microdialysis. At study completion, 92 of 211 (44%) rats survived the sources of attrition allowing subsequent analysis of sub-group Ns as indexed in Table 1. Success rates of lesions or the behavioral microdialysis/HPLC analysis were 74% and 59%, respectively. Lesion and cannulation mappings of included animals are shown in Fig. 2.Table 1


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)

Mapping of lesions and cannulation tracks of animals included in the study. Upper left sections show the largest (black) and smallest (white inset) lesion extents of NVHL animals used in the study. Upper right micrographs show typically sized NVHL damage vs. SHAM. Lower sections show cannulation placement for all rats included in the study (N = 92) by cannulation region. Coordinates are relative to bregma (Swanson 2004)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2921051&req=5

Fig2: Mapping of lesions and cannulation tracks of animals included in the study. Upper left sections show the largest (black) and smallest (white inset) lesion extents of NVHL animals used in the study. Upper right micrographs show typically sized NVHL damage vs. SHAM. Lower sections show cannulation placement for all rats included in the study (N = 92) by cannulation region. Coordinates are relative to bregma (Swanson 2004)
Mentions: Rats were sacrificed immediately after microdialysis, after which probes were injected with methylene blue, followed by whole brain removal and rapid freezing in isopentane. Cryostat-cut coronal brain sections (40 μm) were mapped for probe placements (blue tracks) rostrally and for lesion verification caudally. Sections cut through the hippocampus were dehydrated, fixed, and thionin-stained. Lesion verification, mapping of probe placement, and examination of the fidelity of HPLC/DA detection were all conducted independently and blind from behavioral results. All of these conditions were assessed as sources of attrition. Exclusions were called on lesioned animals with only unilateral ventral hippocampal dysmorphology or significant extra-hippocampal damage, extra-striatal probe placement or related intracranial hemorrhage, dialysis probe blockage/bursting, operational failure of HPLC, or contaminants obscuring DA signal. A total of 211 rats were carried though at least cannulation in 27 cohorts of eight over a 3-year period toward a goal of reaching seven to nine non-excluded rats per group (indexed by lesion status, drug history, and cannulation site). Cohorts were balanced by lesion status and drug history, while two of three cannulation regions were rotated in across cohorts. Dialysate from each cohort was HPLC analyzed in the same batch, 2–4 weeks after microdialysis. At study completion, 92 of 211 (44%) rats survived the sources of attrition allowing subsequent analysis of sub-group Ns as indexed in Table 1. Success rates of lesions or the behavioral microdialysis/HPLC analysis were 74% and 59%, respectively. Lesion and cannulation mappings of included animals are shown in Fig. 2.Table 1

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