Ventral Tegmental Area Of Male Rats Research Articles

Ventral Tegmental Area Amylin Receptor Activation Differentially Modulates Mesolimbic Dopamine Signaling in Response to Fat versus Sugar.

Amylin, a pancreatic hormone that is cosecreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely throughout the brain and are coexpressed on mesolimbic dopamine neurons. Activation of amylin receptors is known to reduce food intake, but the neurochemical mechanisms behind this remain to be elucidated. Amylin receptor activation in the ventral tegmental area (VTA), a key dopaminergic nucleus in the mesolimbic reward system, has a potent ability to suppress intake of palatable fat and sugar solutions. Although previous work has demonstrated that VTA amylin receptor activation can dampen mesolimbic dopamine signaling elicited by random delivery of sucrose, whether this is also the case for fat remains unknown. Herein we tested the hypothesis that amylin receptor activation in the VTA of male rats would attenuate dopamine signaling in the nucleus accumbens core in response to random intraoral delivery of either fat or sugar solutions. Results show that fat solution produces a greater potentiation of accumbens dopamine than an isocaloric sucrose solution. Moreover, activation of VTA amylin receptors elicits a more robust suppression of accumbens dopamine signaling in response to fat solution than to sucrose. Taken together these results shed new light on the amylin system as a therapeutic target for obesity and emphasize the reinforcing nature of high-fat/high-sugar diets.

Activation of VTA GABA neurons disrupts reward seeking by altering temporal processing

The role of ventral tegmental area (VTA) dopamine in reward, cue processing, and interval timing is well characterized. Using a combinatorial viral approach to target activating DREADDs (Designer Receptors Exclusively Activated by Designer Drugs, hM3D) to GABAergic neurons in the VTA of male rats, we previously showed that activation disrupts responding to reward-predictive cues. Here we explored how VTA GABA neurons influence the perception of time in two fixed interval (FI) tasks, one where the reward or interval is not paired with predictive cues (Non-Cued FI), and another where the start of the FI is signaled by a constant tone that continues until the rewarded response is emitted (Cued FI). Under vehicle conditions in both tasks, responding was characterized by “scalloping” over the 30 s FI, in which responding increased towards the end of the FI. However, when VTA GABA neurons were activated in the Non-Cued FI, the time between the end of the 30 s interval and when the rats made a reinforced response increased. Additionally, post-reinforcement pauses and overall session length increased. In the Cued FI task, VTA GABA activation produced erratic responding, with a decrease in earned rewards. Thus, while both tasks were disrupted by VTA GABA activation, responding that is constrained by a cue was more sensitive to this manipulation, possibly due to convergent effects on timing and cue processing. Together these results demonstrate that VTA GABA activity disrupts the perception of interval timing, particularly when the timing is set by cues.

Unanticipated Stressful and Rewarding Experiences Engage the Same Prefrontal Cortex and Ventral Tegmental Area Neuronal Populations.

Brain networks that mediate motivated behavior in the context of aversive and rewarding experiences involve the prefrontal cortex (PFC) and ventral tegmental area (VTA). Neurons in both regions are activated by stress and reward, and by learned cues that predict aversive or appetitive outcomes. Recent studies have proposed that separate neuronal populations and circuits in these regions encode learned aversive versus appetitive contexts. But how about the actual experience? Do the same or different PFC and VTA neurons encode unanticipated aversive and appetitive experiences? To address this, we recorded unit activity and local field potentials (LFPs) in the dorsomedial PFC (dmPFC) and VTA of male rats as they were exposed, in the same recording session, to reward (sucrose) or stress (tail pinch) spaced 1 h apart. As expected, experience-specific neuronal responses were observed. Approximately 15–25% of single units in each region responded by excitation or inhibition to either stress or reward, and only stress increased LFP theta oscillation power in both regions and coherence between regions. But the largest number of responses (29% dmPFC and 30% VTA units) involved dual-valence neurons that responded to both stress and reward exposure. Moreover, the temporal profile of neuronal population activity in dmPFC and VTA as assessed by principal component analysis (PCA) were similar during both types of experiences. These results reveal that aversive and rewarding experiences engage overlapping neuronal populations in the dmPFC and the VTA. These populations may provide a locus of vulnerability for stress-related disorders, which are often associated with anhedonia.

Elevated Expression of Serotonin 5-HT2A Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine

The dopamine mesocorticoaccumbens pathway which originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens and prefrontal cortex is a circuit important in mediating the actions of psychostimulants. The function of this circuit is modulated by the actions of serotonin (5-HT) at 5-HT2A receptors (5-HT2AR) localized to the VTA. In the present study, we tested the hypothesis that virally mediated overexpression of 5-HT2AR in the VTA would increase cocaine-evoked locomotor activity in the absence of alterations in basal locomotor activity. A plasmid containing the gene for the 5-HT2AR linked to a synthetic marker peptide (Flag) was created and the construct was packaged in an adeno-associated virus vector (rAAV-5-HT2AR-Flag). This viral vector (2 μl; 109–10 transducing units/ml) was unilaterally infused into the VTA of male rats, while control animals received an intra-VTA infusion of Ringer’s solution. Virus-pretreated rats exhibited normal spontaneous locomotor activity measured in a modified open-field apparatus at 7, 14, and 21 days following infusion. After an injection of cocaine (15 mg/kg, ip), both horizontal hyperactivity and rearing were significantly enhanced in virus-treated rats (p < 0.05). Immunohistochemical analysis confirmed expression of Flag and overexpression of the 5-HT2AR protein. These data indicate that the vulnerability of adult male rats to hyperactivity induced by cocaine is enhanced following increased levels of expression of the 5-HT2AR in the VTA and suggest that the 5-HT2AR receptor in the VTA plays a role in regulation of responsiveness to cocaine.

Maternal separation affects the number, proliferation and apoptosis of glia cells in the substantia nigra and ventral tegmental area of juvenile rats

Adverse early life experiences can increase the risk of psychiatric and neurological disorders as the result of interference with brain development and maturation. In the present study, we tested whether early life stress, that is, maternal separation (MS), affects cell number, cell proliferation and constitutive apoptotic processes in the substantia nigra (SN) and the ventral tegmental area (VTA) of juvenile male and female rats. It was found that MS decreased the total number of glia but not neuronal cells in the SN pars compacta (SNc) and VTA of males. Moreover, MS reduced the number of S-100β-immunoreactive (IR) glial cells in the SN of females and in the VTA of males. It was also observed that MS decreased the rate of proliferation (as measured by Ki-67-immunoreactivity) in the SN pars reticulata (SNr) and VTA of both males and females. Additionally, MS reduced the number of TUNEL-positive cells in the SNc of both males and females and in the SNr and VTA of males only. Moreover, MS decreased the number of cleaved caspase-9-IR cells in the SN and VTA of male rats. Cleaved caspase-9 was present in microglia cells, which exhibited the morphological hallmarks of apoptosis, but not in neuronal, astrocytic or oligodendrocytic cells. On the contrary, MS increased the number of cleaved caspase-3-IR cells in the SN and VTA of both male and female rats. Cleaved caspase-3-IR cells did not display signs of apoptosis and had an astrocytic phenotype (S-100β-IR). In males exposed to MS, a decrease in caspase-3 enzymatic activity in the SN was also observed. In summary, the results of the present study revealed that early life stress affects the number, proliferation and naturally occurring apoptosis of glia cells in the SN and VTA in a sex-dependent manner and consequently may impair brain functions that are regulated by these structures.

Distribution of serotonin 5-HT 2C receptors in the ventral tegmental area

Serotonin 2C receptors (5-HT 2CR) appear to exert tonic inhibitory influence over dopamine (DA) neurotransmission in the ventral tegmental area (VTA), the origin of the mesolimbic DA system, thought to be important in psychiatric disorders including addiction and schizophrenia. Current literature suggests that the inhibitory influence of 5-HT 2CR on DA neurotransmission occurs via indirect activation of GABA inhibitory neurons, rather than via a direct action of 5-HT 2CR on DA neurons. The present experiments were performed to establish the distribution of 5-HT 2CR protein on DA and GABA neurons in the VTA of male rats via double-label immunofluorescence techniques. The 5-HT 2CR protein was found to be co-localized with the GABA synthetic enzyme glutamic acid decarboxylase (GAD), confirming the presence of the 5-HT 2CR on GABA neurons within the VTA. The 5-HT 2CR immunoreactivity was also present in cells that contained immunoreactivity for tyrosine hydroxylase (TH), the DA synthetic enzyme, validating the localization of 5-HT 2CR to DA neurons in the VTA. While the degree of 5-HT 2CR+GAD co-localization was similar across the rostro-caudal levels of VTA subnuclei, 5-HT 2CR+TH co-localization was highest in the middle relative to rostral and caudal levels of the VTA, particularly in the paranigral, parabrachial, and interfascicular subnuclei. The present results suggest that the inhibitory influence of the 5-HT 2CR over DA neurotransmission in the VTA is a multifaceted and complex interplay of 5-HT 2CR control of the output of both GABA and DA neurons within this region.