Control of food approach and eating by a GABAergic projection from lateral hypothalamus to dorsal pons.

Electrical or optogenetic stimulation of lateral hypothalamic (LH) GABA neurons induces rapid vigorous eating in sated animals. The dopamine system has been implicated in the regulation of feeding. Previous work has suggested that a subset of LH GABA neurons projects to the ventral tegmental area (VTA) and targets GABA neurons, inhibiting them and thereby disinhibiting dopaminergic activity and release. Furthermore, stimulation-induced eating is attenuated by dopamine lesions or receptor antagonists. Here we explored the involvement of dopamine in LH stimulation-induced eating. LH stimulation caused sated mice to pick up pellets of standard chow with latencies that varied based on stimulation intensity; once food was picked up, animals ate for the remainder of the 60-s stimulation period. However, lesion of VTA GABA neurons failed to disrupt this effect. Moreover, direct stimulation of VTA or substantia nigra dopamine cell bodies failed to induce food approach or eating. Looking further, we found that some LH GABA fibers pass through the VTA to more caudal sites, where they synapse onto neurons near the locus coeruleus (LC). Similar eating was induced by stimulation of LH GABA terminals or GABA cell bodies in this peri-LC region. Lesion of peri-LC GABA neurons blocked LH stimulation-induced eating, establishing them as a critical downstream circuit element for LH neurons. Surprisingly, lesions did not alter body weight, suggesting that this system is not involved in the hunger or satiety mechanisms that govern normal feeding. Thus, we present a characterization of brain circuitry that may promote overeating and contribute to obesity.

The dopamine motive system: implications for drug and food addiction.

Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction.

Dopamine, behavior, and addiction.

Addictive drugs are habit-forming. Addiction is a learned behavior; repeated exposure to addictive drugs can stamp in learning. Dopamine-depleted or dopamine-deleted animals have only unlearned reflexes; they lack learned seeking and learned avoidance. Burst-firing of dopamine neurons enables learning-long-term potentiation (LTP)-of search and avoidance responses. It sets the stage for learning that occurs between glutamatergic sensory inputs and GABAergic motor-related outputs of the striatum; this learning establishes the ability to search and avoid. Independent of burst-firing, the rate of single-spiking-or "pacemaker firing"-of dopaminergic neurons mediates motivational arousal. Motivational arousal increases during need states and its level determines the responsiveness of the animal to established predictive stimuli. Addictive drugs, while usually not serving as an external stimulus, have varying abilities to activate the dopamine system; the comparative abilities of different addictive drugs to facilitate LTP is something that might be studied in the future.

Dopamine and Addiction.

Addiction is commonly identified with habitual nonmedical self-administration of drugs. It is usually defined by characteristics of intoxication or by characteristics of withdrawal symptoms. Such addictions can also be defined in terms of the brain mechanisms they activate; most addictive drugs cause elevations in extracellular levels of the neurotransmitter dopamine. Animals unable to synthesize or use dopamine lack the conditioned reflexes discussed by Pavlov or the appetitive behavior discussed by Craig; they have only unconditioned consummatory reflexes. Burst discharges (phasic firing) of dopamine-containing neurons are necessary to establish long-term memories associating predictive stimuli with rewards and punishers. Independent discharges of dopamine neurons (tonic or pacemaker firing) determine the motivation to respond to such cues. As a result of habitual intake of addictive drugs, dopamine receptors expressed in the brain are decreased, thereby reducing interest in activities not already stamped in by habitual rewards.

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.

Differentiating the rapid actions of cocaine.

The subjective effects of intravenous cocaine are felt almost immediately, and this immediacy plays an important part in the drug's rewarding impact. The primary rewarding effect of cocaine involves blockade of dopamine reuptake; however, the onset of this action is too late to account for the drug's initial effects. Recent studies suggest that cocaine-predictive cues--including peripheral interoceptive cues generated by cocaine itself--come to cause more direct and earlier reward signalling by activating excitatory inputs to the dopamine system. The conditioned activation of the dopamine system by cocaine-predictive cues offers a new target for potential addiction therapies.

Bidirectional modulation of cocaine expectancy by phasic glutamate fluctuations in the nucleus accumbens.

While glutamate in the nucleus accumbens (NAS) contributes to the promotion of drug-seeking by drug-predictive cues, it also appears to play a role in the inhibition of drug-seeking following extinction procedures. Thus we measured extracellular fluctuations of NAS glutamate in response to discriminative stimuli that signaled either cocaine availability or cocaine omission. We trained rats to self-administer intravenous cocaine and then to recognize discriminative odor cues that predicted either sessions where cocaine was available or alternating sessions where it was not (saline substituted for cocaine). Whereas responding in cocaine availability sessions remained stable, responding in cocaine omission sessions progressively declined to chance levels. We then determined the effects of each odor cue on extracellular glutamate in the core and shell subregions of NAS preceding and accompanying lever pressing under an extinction condition. Glutamate levels were elevated in both core and shell by the availability odor and depressed in the core but not the shell by the omission odor. Infusion of kynurenic acid (an antagonist for ionotropic glutamate receptors) into core but not shell suppressed responding associated with the availability odor, but had no effect on the suppression associated with the omission odor. Thus cocaine-predictive cues appear to promote cocaine seeking in part by elevating glutamatergic neurotransmission in the core of NAS, whereas cocaine-omission cues appear to suppress cocaine seeking in part by depressing glutamatergic receptor activation in the same region.

Satiating effects of cocaine are controlled by dopamine actions in the nucleus accumbens core.

Intravenous cocaine intake in laboratory animals is characterized by periods of apparent drug satiety between regularly spaced earned injections. The reinforcing properties of cocaine are linked primarily to dopaminergic neurotransmission in the shell and not the core of nucleus accumbens. To determine whether the satiating effects of cocaine are similarly mediated, we perfused dopamine receptor agonists into the core or the shell during intravenous cocaine self-administrations by rats. Neither D1-type (SKF38393) nor D2-type (quinpirole) agonist was effective when given alone. However, a combination of the two agonists perfused into the core but not the shell significantly increased the time between cocaine self-injections, decreasing the amount of earned intake. Together with previous findings, the current data suggest that the satiating and reinforcing effects of cocaine are mediated by different ventral striatal output neurons.

Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral ß1 receptors.

Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic ß1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.

A new peptide input to learning and addiction.

In this issue of Neuron, Borgland et al. report that the arousal-associated peptide orexin enhances LTP-like changes in glutamatergic excitability of ventral tegmental dopamine neurons. This parallels a similar effect of corticotropin-releasing factor and suggests a form of neuroadaptation that increases the likelihood of addiction relapse.

Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: conditioned and unconditioned contributions to reward and motivation.

Microdialysis was used to assess the contribution to cocaine seeking of cholinergic input to the mesocorticolimbic dopamine system in ventral tegmental area (VTA). VTA acetylcholine (ACh) was elevated in animals lever pressing for intravenous cocaine and in cocaine-experienced and cocaine-naive animals passively receiving similar "yoked" injections. In cocaine-trained animals, the elevations comprised an initial (first hour) peak to approximately 160% of baseline and a subsequent plateau of 140% of baseline for the rest of the cocaine intake period. In cocaine-naive animals, yoked cocaine injections raised ACh levels to the 140% plateau but did not cause the initial 160% peak. In cocaine-trained animals that received unexpected saline (extinction conditions) rather than the expected cocaine, the initial peak was seen but the subsequent plateau was absent. VTA ACh levels played a causal role and were not just a correlate of cocaine seeking. Blocking muscarinic input to the VTA increased cocaine intake; the increase in intake offset the decrease in cholinergic input, resulting in the same VTA dopamine levels as were seen in the absence of the ACh antagonists. Increased VTA ACh levels (resulting from 10 microM VTA neostigmine infusion) increased VTA dopamine levels and reinstated cocaine seeking in cocaine-trained animals that had undergone extinction; these effects were strongly attenuated by local infusion of a muscarinic antagonist and weakly attenuated by a nicotinic antagonist. These findings identify two cholinergic responses to cocaine self-administration, an unconditioned response to cocaine itself and a conditioned response triggered by cocaine-predictive cues, and confirm that these cholinergic responses contribute to the control of cocaine seeking.

Ventral tegmental glutamate: a role in stress-, cue-, and cocaine-induced reinstatement of cocaine-seeking.

Ventral tegmental dopamine neurons are activated by primary rewards and, when such rewards are predictable' by reward-predicting stimuli. Glutamatergic input to the ventral tegmental area contributes to this activation: in animals trained to self-administer cocaine, cocaine-predictive cues trigger ventral tegmental glutamate release and dopaminergic activation. Mild footshock stress similarly causes glutamate release and dopaminergic activation in cocaine-trained but not cocaine-naïve animals. The ability of cocaine-predictive and stress-associated cues to activate the dopamine system and to trigger cocaine craving appears to be related to changes in the ability of glutamate to activate dopaminergic neurons, changes known to be caused by experience with stress or with drugs of abuse.

Cocaine and cocaine expectancy increase growth hormone, ghrelin, GLP-1, IGF-1, adiponectin, and corticosterone while decreasing leptin, insulin, GIP, and prolactin.

The dopamine system-essential for mood and movement-can be activated in two ways: by excitatory inputs that cause burst firing and stamp-in learning or by slow excitatory or inhibitory inputs-like leptin, insulin, ghrelin, or corticosterone-that decrease or increase single-spike (pacemaker) firing rate and that modulate motivation. In the present study we monitored blood samples taken prior to and during intravenous cocaine or saline self-administration in rats. During cocaine-taking, growth hormone and acetylated ghrelin increased 10-fold; glucagon-like peptide-1 (GLP-1) doubled; non-acetylated ghrelin, insulin-like growth factor-1 (IGF-1), and corticosterone increased by 50% and adiponectin increased by 17%. In the same blood samples, leptin, insulin, gastric inhibitory polypeptide (GIP), and prolactin decreased by 40-70%. On the first day of testing under extinction conditions-where the animals earned unexpected saline instead of cocaine-5-fold increases were seen for growth hormone and acetylated ghrelin and equal changes-in amplitude and latency-were seen in each of the other cases except for IGF-1 (which increased at a slower rate). Single-spike firing affects the tonic activation level of the dopamine system, involving very different controls than those that drive burst firing; thus, the present data suggest interesting new targets for medications that might be used in the early stages of drug abstinence.

Brain reward circuitry: insights from unsensed incentives.

The natural incentives that shape behavior reach the central circuitry of motivation trans-synaptically, via the five senses, whereas the laboratory rewards of intracranial stimulation or drug injections activate reward circuitry directly, bypassing peripheral sensory pathways. The unsensed incentives of brain stimulation and intracranial drug injections thus give us tools to identify reward circuit elements within the associational portions of the CNS. Such studies have implicated the mesolimbic dopamine system and several of its afferents and efferents in motivational function. Comparisons of natural and laboratory incentives suggest hypotheses as to why some habits become compulsive and give insights into the roles of reinforcement and of prediction of reinforcement in habit formation.

Long-term upregulation of protein kinase A and adenylate cyclase levels in human smokers.

Repeated injections of cocaine and morphine in laboratory rats cause a variety of molecular neuroadaptations in the cAMP signaling pathway in nucleus accumbens and ventral tegmental area. Here we report similar neuroadaptations in postmortem tissue from the brains of human smokers and former smokers. Activity levels of two major components of cAMP signaling, cAMP-dependent protein kinase A (PKA) and adenylate cyclase, were abnormally elevated in nucleus accumbens of smokers and in ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of the catalytic subunit of PKA were correspondingly higher in the ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of other candidate neuroadaptations, including glutamate receptor subunits, tyrosine hydroxylase, and other protein kinases, were within normal range. These findings extend our understanding of addiction-related neuroadaptations of cAMP signaling to tobacco smoking in human subjects and suggest that smoking-induced brain neuroadaptations can persist for significant periods in former smokers.

A role for conditioned ventral tegmental glutamate release in cocaine seeking.

Initiation of cocaine self-administration in rats was associated with release of glutamate in the ventral tegmental area (VTA). The glutamate release was transient, despite continued cocaine intake. Similar glutamate release was seen in rats earning, for the first time, unexpected saline rather than expected cocaine. VTA glutamate release was not seen in similarly trained rats earning saline instead of cocaine for the 13th time. VTA glutamate release was also seen in similarly trained rats that received yoked rather than earned cocaine injections on test day. VTA glutamate release was not seen in a group of rats that had never earned cocaine but had received yoked injections during the training period. Glutamate release was also not seen in a group of rats that received yoked injections but had no previous experience with cocaine. VTA GABA levels did not fluctuate during any aspect of cocaine seeking. Blockade of VTA glutamate receptors appeared to attenuate the rewarding effects of intravenous cocaine injections and blocked almost completely the conditioned responding normally seen during extinction trials. These findings indicate that VTA glutamate release is a conditioned response dependent on an associative process and is not a simple consequence of previous cocaine exposure. The findings implicate glutamate as at least one of the sources of VTA signals from reward-associated environmental stimuli.

Functional implications of glutamatergic projections to the ventral tegmental area.

Glutamatergic afferents of the ventral tegmental area (VTA) play an important role in the functioning of the VTA and are involved in the pathophysiology of drug addiction. It has recently been demonstrated that the VTA is densely innervated by glutamatergic axons and that glutamatergic neurons projecting to the VTA are situated in almost all structures that project there. While the projection from the prefrontal cortex is essentially entirely glutamatergic, subcortical glutamatergic neurons innervating the VTA intermingle with non-glutamatergic, most likely GABAergic and/or peptidergic VTA-projecting neurons. The first part of this review focuses on the origins and putative functional implications of various glutamatergic projections to the VTA. In the second part we consider how different neuropeptides via different mechanisms modulate glutamatergic actions in the VTA. We conclude by developing a model of how the glutamatergic afferents might together contribute to the functions of the VTA.

Dopamine and reward: the anhedonia hypothesis 30 years on.

The anhedonia hypothesis--that brain dopamine plays a critical role in the subjective pleasure associated with positive rewards--was intended to draw the attention of psychiatrists to the growing evidence that dopamine plays a critical role in the objective reinforcement and incentive motivation associated with food and water, brain stimulation reward, and psychomotor stimulant and opiate reward. The hypothesis called to attention the apparent paradox that neuroleptics, drugs used to treat a condition involving anhedonia (schizophrenia), attenuated in laboratory animals the positive reinforcement that we normally associate with pleasure. The hypothesis held only brief interest for psychiatrists, who pointed out that the animal studies reflected acute actions of neuroleptics whereas the treatment of schizophrenia appears to result from neuroadaptations to chronic neuroleptic administration, and that it is the positive symptoms of schizophrenia that neuroleptics alleviate, rather than the negative symptoms that include anhedonia. Perhaps for these reasons, the hypothesis has had minimal impact in the psychiatric literature. Despite its limited heuristic value for the understanding of schizophrenia, however, the anhedonia hypothesis has had major impact on biological theories of reinforcement, motivation, and addiction. Brain dopamine plays a very important role in reinforcement of response habits, conditioned preferences, and synaptic plasticity in cellular models of learning and memory. The notion that dopamine plays a dominant role in reinforcement is fundamental to the psychomotor stimulant theory of addiction, to most neuroadaptation theories of addiction, and to current theories of conditioned reinforcement and reward prediction. Properly understood, it is also fundamental to recent theories of incentive motivation.

Drive and Reinforcement Circuitry in the Brain: Origins, Neurotransmitters, and Projection Fields.

Brain stimulation has identified two central subsets of stimulation sites with motivational relevance. First, there is a large and disperse set of sites where stimulation is reinforcing, increasing the frequency of the responses it follows, and second, a much more restricted set of sites where-along with reinforcement-stimulation also has drive-like effects, instigating feeding, copulation, predation, and other motivated acts in otherwise sated or peaceful animals. From this work a dispersed but synaptically interconnected network of reinforcement circuitry is emerging: it includes afferents to the ventral tegmental area and substantia nigra; the dopamine systems themselves; glutamatergic afferents to the striatum; and one of two dopamine-receptor-expressing efferent pathways of the striatum. Stimulation of a limited subset of these sites, including descending inhibitory medial forebrain bundle fibers, induces both feeding and reinforcement, and suggests the possibility of a subset of fibers where stimulation has both drive-like and reinforcing effects. This review stresses the common findings of sites and connectivity between electrical and optogenetic studies of core drive and reinforcement sites. By doing so, it suggests the biological importance of optogenetic follow-up of less-publicized electrical stimulation findings. Such studies promise not only information about origins, neurotransmitters, and connectivity of related networks, by covering more sensory and at least one putative motor component they also promote a much deeper understanding of the breadth of motivational function.

Two brain sites for cannabinoid reward.

The recent findings that Delta9tetrahydrocannabinol (Delta9THC), the active agent in marijuana and hashish, (1) is self-administered intravenously, (2) potentiates the rewarding effects of electrical brain stimulation, and (3) can establish conditioned place preferences in laboratory animals, suggest that these drugs activate biologically primitive brain reward mechanisms. Here, we identify two chemical trigger zones for stimulant and rewarding actions of Delta9THC. Microinjections of Delta9THC into the posterior ventral tegmental area (VTA) or into the shell of the nucleus accumbens (NAS) increased locomotion, and rats learned to lever-press for injections of Delta9THC into each of these regions. Substitution of vehicle for drug or treatment with a cannabinoid CB1 receptor antagonist caused response cessation. Microinjections of Delta9THC into the posterior VTA and into the posterior shell of NAS established conditioned place preferences. Injections into the core of the NAS, the anterior VTA, or dorsal to the VTA were ineffective. These findings link the sites of rewarding action of Delta9THC to brain regions where such drugs as amphetamines, cocaine, heroin, and nicotine are also thought to have their sites of rewarding action.