The late consolidation of an aversive memory is promoted by VTA dopamine release in the dorsal hippocampus.

The hippocampus has been implicated in the processing and storage of aversive memories but the precise mechanisms by which these memories persist in time remain elusive. We have demonstrated that dopaminergic neurotransmission in the dorsal hippocampus regulates the long-term storage of both appetitive and aversive memories at a critical time point known as "late consolidation" (12 hr after the learning experience). This modulation appears to have opposite effects depending on the valence of the stimuli, with hippocampal dopamine release peaking immediately and 13-17 hr after a rewarding experience. Here, we determined the release pattern of hippocampal dopamine following an aversive experience, in order to better understand this opposite modulation process. We observed significant increases in dopamine levels at several times (6-8, 11-12, and 15 hr) after subjecting rats to a conditioned place aversion (CPA) task with the aversive agent lithium chloride (LiCl). Early pharmacological blockade of hippocampal DA receptors impaired CPA memory consolidation. In addition and consistent with previous findings showing that late post-training infusions of dopaminergic agents into the hippocampus modulate the long-term storage of aversive memories, we found that the photostimulation of dopaminergic VTA fibers in the dorsal hippocampus 11-12 hr after CPA training was enough to transform a short-lasting long-term memory into a long-lasting one. The fact that the persistence of an aversive memory can still be affected several hours after the learning experience opens new avenues to develop behavioral and pharmacological strategies for the treatment of a variety of mental disorders.

Feeding and Reward Are Differentially Induced by Activating GABAergic Lateral Hypothalamic Projections to VTA.

Electrical stimulation of the lateral hypothalamus (LH) has two motivational effects: long trains of stimulation induce drive-like effects such as eating, and short trains are rewarding. It has not been clear whether a single set of activated fibers subserves the two effects. Previous optogenetic stimulation studies have confirmed that reinforcement and induction of feeding can each be induced by selective stimulation of GABAergic fibers originating in the bed nucleus of the LH and projecting to the ventral tegmental area (VTA). In the present study we determined the optimal stimulation parameters for each of the two optogenetically induced effects in food-sated mice. Stimulation-induced eating was strongest with 5 Hz and progressively weaker with 10 and 20 Hz. Stimulation-induced reward was strongest with 40 Hz and progressively weaker with lower or higher frequencies. Mean preferred duration for continuous 40 Hz stimulation was 61.6 s in a "real-time" place preference task; mean preferred duration for 5 Hz stimulation was 45.6 s. The differential effects of high- and low-frequency stimulation of this pathway seem most likely to be due to differential effects on downstream targets.

Dopamine D1/D5 receptors in the dorsal hippocampus are required for the acquisition and expression of a single trial cocaine-associated memory.

The role of the hippocampus in memory supporting associative learning between contexts and unconditioned stimuli is well documented. Hippocampal dopamine neurotransmission modulates synaptic plasticity and memory processing of fear-motivated and spatial learning tasks. Much less is known about the involvement of the hippocampus and its D1/D5 dopamine receptors in the acquisition, consolidation and expression of memories for drug-associated experiences, more particularly, in the processing of single pairing cocaine conditioned place preference (CPP) training. To determine the temporal dynamics of cocaine CPP memory formation, we trained rats in a one-pairing CPP paradigm and tested them at different time intervals after conditioning. The cocaine-associated memory lasted 24 h but not 72 h. Then, we bilaterally infused the dorsal hippocampus with the GABA A receptor agonist muscimol or the D1/D5 dopamine receptor antagonist SCH 23390 at different stages to evaluate the mechanisms involved in the acquisition, consolidation or expression of cocaine CPP memory. Blockade of D1/D5 dopamine receptors at the moment of training impaired the acquisition of cocaine CPP memories, without having any effect when administered immediately or 12 h after training. The expression of cocaine CPP memory was also affected by the administration of SCH 23390 at the moment of the test. Conversely, muscimol impaired the consolidation of cocaine CPP memory only when administered 12 h post conditioning. These findings suggests that dopaminergic inputs to the dorsal hippocampus are required for the acquisition and expression of one trial cocaine-associated memory while neural activity of this structure is required for the late consolidation of these types of memories.

Lateral hypothalamic glutamatergic inputs to VTA glutamatergic neurons mediate prioritization of innate defensive behavior over feeding.

The lateral hypothalamus (LH) is involved in feeding behavior and defense responses by interacting with different brain structures, including the Ventral Tegmental Area (VTA). Emerging evidence indicates that LH-glutamatergic neurons infrequently synapse on VTA-dopamine neurons but preferentially establish multiple synapses on VTA-glutamatergic neurons. Here, we demonstrated that LH-glutamatergic inputs to VTA promoted active avoidance, long-term aversion, and escape attempts. By testing feeding in the presence of a predator, we observed that ongoing feeding was decreased, and that this predator-induced decrease in feeding was abolished by photoinhibition of the LH-glutamatergic inputs to VTA. By VTA specific neuronal ablation, we established that predator-induced decreases in feeding were mediated by VTA-glutamatergic neurons but not by dopamine or GABA neurons. Thus, we provided evidence for an unanticipated neuronal circuitry between LH-glutamatergic inputs to VTA-glutamatergic neurons that plays a role in prioritizing escape, and in the switch from feeding to escape in mice.

VTA glutamatergic projections to the nucleus accumbens suppress psychostimulant-seeking behavior.

Converging evidence indicates that both dopamine and glutamate neurotransmission within the nucleus accumbens (NAc) play a role in psychostimulant self-administration and relapse in rodent models. Increased NAc dopamine release from ventral tegmental area (VTA) inputs is critical to psychostimulant self-administration and NAc glutamate release from prelimbic prefrontal cortex (PFC) inputs synapsing on medium spiny neurons (MSNs) is critical to reinstatement of psychostimulant-seeking after extinction. The regulation of the activity of MSNs by VTA dopamine inputs has been extensively studied, and recent findings have demonstrated that VTA glutamate neurons target the NAc medial shell. Here, we determined whether the mesoaccumbal glutamatergic pathway plays a role in psychostimulant conditioned place preference and self-administration in mice. We used optogenetics to induce NAc release of glutamate from VTA inputs during the acquisition, expression, and reinstatement phases of cocaine- or methamphetamine-induced conditioned place preference (CPP), and during priming-induced reinstatement of cocaine-seeking behavior. We found that NAc medial shell release of glutamate resulting from the activation of VTA glutamatergic fibers did not affect the acquisition of cocaine-induced CPP, but it blocked the expression, stress- and priming-induced reinstatement of cocaine- and methamphetamine CPP, as well as it blocked the priming-induced reinstatement of cocaine-seeking behavior after extinction. These findings indicate that in contrast to the well-recognized mesoaccumbal dopamine system that is critical to psychostimulant reward and relapse, there is a parallel mesoaccumbal glutamatergic system that suppresses reward and psychostimulant-seeking behavior.

VTA Glutamatergic Neurons Mediate Innate Defensive Behaviors.

The ventral tegmental area (VTA) has dopamine, GABA, and glutamate neurons, which have been implicated in reward and aversion. Here, we determined whether VTA-glutamate or -GABA neurons play a role in innate defensive behavior. By VTA cell-type-specific genetic ablation, we found that ablation of glutamate, but not GABA, neurons abolishes escape behavior in response to threatening stimuli. We found that escape behavior is also decreased by chemogenetic inhibition of VTA-glutamate neurons and detected increases in activity in VTA-glutamate neurons in response to the threatening stimuli. By ultrastructural and electrophysiological analysis, we established that VTA-glutamate neurons receive a major monosynaptic glutamatergic input from the lateral hypothalamic area (LHA) and found that photoinhibition of this input decreases escape responses to threatening stimuli. These findings indicate that VTA-glutamate neurons are activated by and required for innate defensive responses and that information on threatening stimuli to VTA-glutamate neurons is relayed by LHA-glutamate neurons.

Opioids for hedonic experience and dopamine to get ready for it.

BACKGROUND AND RATIONALE: More than two decades ago, Wise proposed his "anhedonia hypothesis" to explain the role of dopamine in motivated behaviors. The hypothesis posits that dopamine mediates the pleasure experienced by reward obtainment. However, some experimental findings have contested this hypothesis and several authors have proposed alternative functions for dopamine with regard to motivation. Brain dopamine has been suggested to rather code for the preparatory aspects of behavior, while brain opioids seem to mediate the perception of the hedonic properties of rewards. OBJECTIVES: The main goal of this review is to reexamine dopamine and opioids involvement in feeding when different aspects such as the anticipatory, motivational and consummatory components of this behavior are taken into account, but also when the physiologic state of the organism and the palatability of the food are considered. RESULTS AND CONCLUSIONS: Altogether, the data presented point out for an implication of dopamine in the anticipatory/preparatory aspects of feeding more than on the motivational and consummatory aspects. However, dopamine involvement in the anticipatory/preparatory component of feeding seems specifically related to very relevant stimuli, such as highly palatable foods. On the other hand, our data, as well as those present in the literature, strongly suggest a role for opioids in food intake through their modulation of the hedonic perception of food. As a consequence, opioids are involved in those aspects of motivation driven by food palatability rather than by food homeostatic need.

Various aspects of feeding behavior can be partially dissociated in the rat by the incentive properties of food and the physiological state.

The authors investigated the role of food incentive properties and homeostatic state on the motivational, anticipatory, and consummatory aspects of feeding. Behavioral tests were carried out on food-sated and food-restricted rats that were presented with 2 kinds of food differing in their palatability level. Both food-sated and food-restricted rats consumed large quantities and were highly motivated when presented with very palatable food. In contrast, only food-restricted rats developed anticipatory responses, regardless of the kind of food presented. These data suggest that food incentive properties play a key role in the control of consummatory and motivational components of feeding but seem less involved in the regulation of anticipatory behavior.

Mesolimbic dopamine drives the diurnal variation in opiate-induced feeding.

Brain opioid peptides modulate feeding behavior and opiate drugs have powerful orexigenic effects in mammals. Recent studies have shown that opiate-induced eating depends, though not exclusively, on mu-opioid receptors located in the ventral striatum. Here we report that morphine orexigenic effects vary with the time of day according to a biphasic pattern. The effects first increase and then decrease during the light phase, with the peak effect occurring in the middle of this phase. This diurnal profile is shifted toward the dark phase after dopamine deafferentation of the ventral striatum. Consequently, the peak effect of morphine is delayed and occurs just before the dark phase. This finding suggests that mesolimbic dopamine transmission contributes to the neural mechanisms that normally drive the circadian timing of opioid-dependent feeding.

Dopamine in the dorsal hippocampus impairs the late consolidation of cocaine-associated memory.

Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.

Involvement of dopamine and opioids in the motivation to eat: influence of palatability, homeostatic state, and behavioral paradigms.

RATIONALE: Motivation for food depends on several variables including food palatability, the homeostatic state of the organism, and the nature of the behavior required to obtain the reward. However, few studies to date have tried to evaluate motivation for food considering all these variables at the same time. Since dopamine and opioids have been deeply involved in the regulation of feeding, it is of interest to investigate their role considering all the mentioned variables. OBJECTIVES: In this study, we evaluated the involvement of dopamine and endogenous opioids on food consumption and food motivation using behavioral paradigms that differ in the motor requirement to gain access to the reward, when food palatability and homeostatic state were taken into account. MATERIALS AND METHODS: Pellets differentiated on palatability were offered to sated and restricted rats in consummatory tests and in different behavioral paradigms measuring motivational state, but requiring different motor outputs (runway and an operant progressive ratio 3 task). Peripheral injections of naloxone or flupenthixol were administered when these tasks were learned and stable. RESULTS: Naloxone decreased food intake when pellets were palatable, while flupenthixol was without any effect. When considering motivation, naloxone decreased performances in both the runway and progressive ratio tests while flupenthixol was only effective in the progressive ratio test. CONCLUSIONS: Impairing the opioid neurotransmission diminishes motivation to obtain food, possibly through a decrease in the perceived palatability of the food reward. The dopaminergic system appears to be more involved in the modulation of motivation to obtain food in a cost/benefit-related manner.