Reward as well as motivation itself has two components, conscious and unconscious or subjective and objective. When, as a result of motivational behavior, an organism accepts reward, it receives the two components. The first is pleasure, or the conscious component of reward, which encourages further voluntary actions and metabolic improvement. The second, unconscious component of reward ameliorates homeostatic imbalance causing the current motivation. Existence of two components ensures proper functioning of a motivational system. The conscious component is accepted immediately, while the metabolic component needs time for consumption. If, for instance, an animal has received a portion of a meal, its utilization and recovering of energetic stores takes tens of minutes. However, the animal must interrupt eating earlier, otherwise it will be overfeeding, although some animals do eat until gorged and then lie down to digest over some time.
Place of rewards in motivational behavior
When we discussed localization of memory in topic 1, we compared two ideas. The first one assumed that every image or event stored in memory has a definite address in the brain. Certainly, each image is the combination of elemental features. However, not only such elemental features, but an integral image itself, as a whole, has a specific location in the brain tissue. The second idea located data in numerous neurons. Each neuron remembers the entire image, but very roughly. At the moment of identification, every neuron is involved in recognition in the degree to which its stored image corresponds to a current interrogation. We were susceptible to this second idea.
Now, when we are considering the arrangement of goal-directed behavior, this problem arises anew. If motivation and punishment are connected with excitation and neuronal injury, as we have suggested, then reward can be expected to inhibit and protect neurons. Therefore, if each neuron is the source of its own particular behavior, then motivation, action and satisfaction ought to be concentrated in each neuron. This would be perplexing if during the origin of a motivation, certain neurons are injured (in the motivational centers), while reward and, correspondingly, protection is directed to other neurons. On the other hand, there are examples of the steady functioning of collectives, where only a few persons receive rewards while the majority of other persons work hardy almost for nothing. The word "almost" here is essential. The member of a collective needs in some minimal satisfaction, even if this minimum is a continuation of its own life. Nevertheless, evidence points, at least at first sight, to the implementation of this type of brain performance. We had explained earlier that the closed logic chain of goal-directed behavior at the neuronal level may not coincide with the global motivational behavior of an entire animal. Additional explanation of this contradiction may be also found in an ambivalent conception of reward.
Conscious components of reward and motivation usually activate only partially overlapping brain areas. Thus, when a feeding reward is predictable, brain regions recruited during expectation are partly dissociable from areas responding to the actual receipt of the reward [904]. For example, ^-opioid circuits in the medial shell can stimulate food intake via either hedonistic or nonhedonic mechanisms, depending on the precise location [954]. Opioid receptors are widely distributed in the brain, close to main rewarding areas [520], whereas hedonic "liking" circuits for electrical self-stimulation may be more tightly (a single cubic millimeter) localized, for instance in the rostro-medial shell of the nucleus accumbens [954] and some other areas. Many other aspects of motivational behavior also may be directed to specific neurons. Administration of the same drug in the close brain areas may elicit an opposite effect, or administration of agonist and antagonist to the same drug may evoke the same result15.
Nevertheless, in certain conditions, the same neurons may participate in both the motivational and rewarding behaviors. We will demonstrate later that such capability is not the inalienable belonging of some special neuron. Quite the opposite, an arbitrary neuron in special experimental conditions may demonstrate an entire motivational behavior.
Comprehension of the essence of the conscious reward has increased during the last few years [9, 115, 206, 270, 297, 299, 656, 799, 1098, 1137, 1345, 1354, 1169, 888]. Reward and reinforcement are related notions, but although reinforcements are causally concerned with rewards, it is possible to differentiate between the two phenomena. Motivation is satisfied by a reward or by avoidance of punishment, while reinforcement signals the success of a behavior. Reinforcement is a criterion for desirable increase or decrease in the rate of a beneficial behavior following modification in the environment. The meso-corticolimbic dopamine systems originating in the ventral tegmental area and their connections with the prefrontal cortex, striatum, nucleus accumbens and amygdala with their glutamatergic, GABAergic inputs and opioid receptors are responsible for reinforcement and reward. While opioids, dopamine and GABA fulfill their actions in the reward system through inhibition, glutamate accomplishes an intermittent role, as an excitatory messenger. Participation of other neurotransmitters in the organization of the reward system, for instance serotonin, is also well known.
Chemical mediators of a conscious reward
When one receives a reward, in some brain areas the opioids, dopamine and GABA transmitter systems are implicated. Moreover, activation of these systems evokes a euphoric sense, so that animals work in order to reach administration of these substances during self-introduction, place preference, etc. At present we know, where rewarding areas are located in the brain and which substances are rewarding. We also understand that just these brain zones and not other are rewarding; just in these areas, rewarding substances are produced and their receptors are located just in these zones, although producing areas and receptive areas are only partially coincided.
All rewarding substances affect neurons through various receptors and their outcome depends on the class of chemoreceptors. The dopamine system participate in a reward mostly through dopamine2 receptors. However, this is not certain. There is a message that dopaminei receptors in the ventral tegmental area are involved in intravenous cocaine reward and food reward [1122]. Besides, there are at least fourteen serotonin receptor subtypes and many of these have been shown to interact with dopamine [22]. As well, although euphoric effects of GABA are usually achieved through GABA^ receptors, some drugs of abuse act through GABA_g inhibition of nucleus ac-cumbens neurons and stimulation of dopamine transmission [981]. Similarly, y-, S- and K-opioid receptors participate in the reception of reward, although y-opioid receptors may play a more prominent role [287, 80]. Nevertheless, this knowledge does not fully supplement our comprehension of the phenomenon of reward. It would be constructive to understand how one feels pleasure when some special chemical events have happened.
Both reward and reinforcement are connected with the opioid and dopamine systems: phasic influences of endogenous opioids are more related to a hedo-nic impact of reward, while phasic activity of dopamine neurons is related to reinforcement, or triggers the events that instantiate the incentive salience of rewards [115]. The midbrain dopamine system is rapidly activated (50-200 ms) by rewarding events that are better than predicted and are depressed by events that are worse than predicted. Dopamine neuron activation with a slower timescale has been observed during expectation of reward for various forms of behavior: feeding, drinking, punishment, stress, sex, drug reward, and social behavior. After learning the dopamine system becomes responsive for reward predictors and unresponsive to the reward "itself" [1098]. Various classes of drugs of abuse, psychostimulants, opioids, ethanol, cannabinoids and nicotine increase dopamine transmission in limbic regions of the brain. However, only psychostimulants increase dopamine transmission clearly both necessary and sufficient to promote rewarding effects of drugs of abuse [977]. This is in a poor agreement with the decisive role of dopamine in the reception of a reward. Particularly, dopamine neurons are highly sensitive to vital aversive stimuli [1068]. There is an optimal level of dopamine in the nucleus accumbens for self-administration of cocaine and this also contradicts the role of dopamine as an endogenous reward. In drug abusers, cyclic AMP production increases and this is connected with dopamine 1 receptor enhancement and with a reduction in dopamine2 receptors [887, 910]. This indicates a slow participation of the dopamine system in a motivational behavior and therefore also contradicts the role of dopamine as a direct endogenous reward.
It has been supposed that brain mesolimbic dopamine systems mediate ‘wanting’ rather than sensory pleasure [113, 206]. Both the mesocorticolimbic dopamine1 system and the nigrostriatal dopamine2 system involve a GABAer-gic mechanism [30, 656] and, according to various data, both dopamine1 and dopamine2 receptors are involved in the interaction with opioids during reinforcement, although dopamine2 receptors are usually inhibitory and predominate in reinforcement [910, 22], while dopamine1 receptor is important during acquisition of new habits [614], that is during motivational behavior. It is possible that dopamine2 receptors participate more in the reward system, while dopamine1 receptors in the punishment system and the abstinent syndrome. Thus, in spite of the obvious participation of the dopaminergic system in reception of rewards, dopamine is hardly likely to be the main rewarding substance that immediately protects neurons. Rather, dopamine signals the ingress of the reward into the organism.
The presumed mechanism of action of opioids in the nucleus accum-bens involves disinhibition of the dopamine system by inhibition of nearby GABAergic neurons that normally hold their dopaminergic neighbors under inhibitory control [1345, 80], though opioids can affect directly through specific chemoreceptors. Consequently, activation of the dopamine system is not at all the first sign of reward in the brain. By the way, just GABA_g receptor stimulation is responsible for inhibition of dopamine release in the ventral tegmental region by acting on the nucleus accumbens, but just stimulation of GABA^ receptors counteract anxiety. Therefore GABA, probably, can exert a rewarding action apart from dopamine pathways.
Dopaminergic system, the potent modulator of gap junctions [963] is, probably, a sensor of the GABA level at the scales of damage-protection and negative-positive feeling. Neuroleptic haloperidol, antagonist of dopamine2 receptors or depletion of accumbens dopamine, prevented carrying out those instrumental tasks in rats that required large effort for successful behavior, although rats worked properly when task was simple [1067]. Considering that the dopamine system is responsive for reward predictors and unresponsive to the reward consumption, this system is a good candidate, as a participant of intentional actions.
The GABA and, to some extent, serotonin systems are tightly implicated in the development of a positive state in the brain. Pleasure is the most dependent on opioid and GABA systems [184]. While the opioid system is implicated in brain activity mostly during urgent circumstances, GABA is a continuously- acting factor. GABA is both the most widespread inhibitory transmitter and potent regulator of a background level of positive feeling. Acute positive states after receipt of reward also depend on the GABA system, its interaction with opioids and dopamine systems and counteraction with the excitatory glutamate system. So, a reduction of GABA^ergic inhibition in the basolateral amygdale promotes anxiety [674], sleep [491], temperature regulation [580], an acute reaction to drugs [895, 1182, 619, 1436], sexual approval [822, 1221] and respiration [907].
One distinction of defensive motivation is an absence of physical substrate for the consummatory phase; a positive outcome in this case is the removal of danger. A real consummatory phase is absent also in related sexual motivation; only pleasure serves, as a reward. Therefore, a conscious component of reward is in given cases a single one, because a metabolic component is absent. Neuronal mediators of pleasure are endogenous opioids. Therefore, endogenous opioids are involved not only in antinociception and avoidance, but also in reward and reinforcement. Opioids may induce sensitization to the effects of other drugs [282]. The opioid system is an ultimate linkage in the reward systems for various motivations: sexual behavior, stress responses, respiration, temperature regulation, drug dependence, alcoholism, drinking, feeding, and social play behavior [270, 910, 1293, 1297]. For instance, endogenous opioid peptides are involved in the expression of physical nicotine dependence [112]; another example is that mice pups lacking specific y-opioid receptors don’t cry when separated from their mother [96]. This suggests that reward systems of various simple motivations are based on a rewarding substance in the defensive motivation, perhaps the most important motivation for the maintenance of an individual life. Besides, a rewarding substance for defensive motivation is exactly matched to avoidance from an apparent threat, whereby conscious and unconscious components of reward almost coincide. For other motivations, the same chemical means are, evidently, used as a conscious signal for future metabolic improvement.
The motivational system defends an organism from danger through adjustment of its interaction with the environment. An organism also defends itself at the expense of inner resources, without participation of consciousness. These inner protectors are homeostasis and the immune system. As we have demonstrated, homeostasis is tightly connected with motivation and it may be elevated at the conscious level. The immune system is not elevated at the conscious level, but it is also connected with motivation. Neural and immune functions tightly interact. Neurotransmitters serve as immuno-modulators through their release and diffusion from nervous tissue, action to lymphocyte cell-surface receptors and the modulation of immune function, but neurotransmitters (dopamine, glutamate, opioids, etc.) can also be released from leukocytes [406]. The origin of the opioid system, probably, dates from the advent of the immune system, as a signal for avoidance of danger. Opioids reduce cellular immunity [1057]: they decrease cell proliferation and inhibit migration. Unavoidable stress affects the progression of a variety of tumors, and, in most cases, it exacerbates tumor metastasis [819], but moderate stress has a defensive function. Immunity is defense mechanism and motivations also fulfill defensive function, while opioids signal avoidance of danger. Opioids do not defend by themselves but they temporally ameliorate destructive consequences of stressful reactions, pain, fear and immune attack. When the opioid system fails in neuropathic animals [1439], they become helpless. Opioids give an opportunity to organize defense.
Inhibitory actions of rewards
A reward, as well as a punishment, usually evokes powerful excitation everywhere in the brain, or almost everywhere, but not in the rewarding system of brain. Satisfaction of motivations is connected with the development of inhibitory processes in the motivationally-specific areas, as for example during feeding [1164, 1375], mating [1134, 802, 605], recuperating of temperature [498], consumption of narcotic drugs [935, 887], drinking [697] and falling asleep [1179].
As to drug-induced rewards, intravenous self-administration of cocaine inhibits the firing of neurons in the nucleus accumbens [960]. Acute ethanol exposure suppressed excitability and shifted the balance between excitatory and inhibitory synaptic transmission toward inhibition [234]. The neurons of the ventral tegmental area are activated during drug-seeking behavior (heroin self-administration), but they are inhibited during drug taking behavior [638]. Passive drug injections, in contrast, cause a weak tonic increase in activity.
Natural reward-evoked reinforcement induces inhibition of activity. Con-summatory feeding events [715] inhibit the firing of the nucleus accumbens neurons. A high extracellular glucose concentration, which inhibits feeding, induces hyperpolarization of orexin neurons, while a low extracellular glucose concentration excites these neurons [1375]. This inhibition, evidently, counteracts to excitotoxicity and protects cells against the damage that has give rise motivation.
A dramatic increase in the activity of a majority of the neurons in the medial preoptic nucleus (sexual center) during sexual arousal in male rats ceases abruptly after intromission (lasting for a seconds), and activity remains greatly reduced for protracted period (about 2 min) after ejaculation [1134, 802]. The neurons of the preoptic area of female rats revealed more subtle and transitory changes during sexual behavior, but half of the neurons were also inhibited after intromission [605]. Immediately after orgasm and for over 1 h following orgasm, plasma prolactin concentration increases in both men and women [679]. Prolactin secretion is controlled by inhibitory signals and the primary inhibitory input for prolactin secretion is dopamine. Mating induced activation of endogenous opioids is provided by the increase in pain thresholds following ejaculation [802]. Inhibitory influence of sexual reward may be endorsed also by a decrease in excitatory influence of glutamate. Glu-tamate plays a pivotal role in the consequence of events during copulatory behavior [333]. Concentrations of extracellular glutamate in mail rats, mi-crodialysate samples from the medial preoptic area before, during, and after copulation, reveal a slight rise when the female was presented, a significant increase during periods of mounting and intromitting, and a very large increase in samples collected during ejaculation. A precipitous fall in levels occurred in the first postejaculatory sample; the magnitude of this fall was highly correlated with the length of the postejaculatory interval of quiescence. Increase in glutamate levels in the medial preoptic area before and during mating can elicit genital reflexes in anesthetized rats (without consciousness), while glu-tamate receptor antagonists impair copulation. Nevertheless, investigation of neuronal activity offers results that are more precise, than microdialyse. Concentration of glutamate in the medial preoptic area did not reveal short-term fall after intromission. The fall in neuronal activity after intromission was too short, a few seconds. For measurement of glutamate concentration, one need collect microdialysate samples from the medial preoptic area during couple of minutes. This consumes time and set a limit on a resolving power of the method.
Rewarding substances, as a rule, inhibit neurons. In the nucleus accum-bens, dopamine 1 receptors mediated either inhibition or facilitation, while dopamine2 receptors, which are usually responsible for rewarding effects, predominantly mediate inhibition [457]. Dopamine through the dopamine2-receptor inhibits midbrain neurons on a millisecond timescale [97]. Dopamine also modulates cortical and thalamic glutamatergic signals and dopamine1 receptor signaling enhances dendritic excitability and glutamatergic signaling, whereas dopamine2 receptor exerts the opposite effect [1197].
Rewarding action of GABA is connected with its inhibitory action. GABAer-gic system is not only the same wide-spread inhibitory system that penetrates a whole brain [590]. GABA^ receptors are present already in Hydra vulgaris, one of the most primitive organisms with a nervous system. Accordingly, GABA^ antagonists stimulate feeding, while GABA^ receptor agonists suppress ingestion [1248] and inhibit sexual behavior and drinking [939]. Inhibition can be achieved by excitation of inhibitory neurons, such as ethanol augments GABAergic transmission within the amygdala [813, 895]. Satisfaction of defensive motivation also proceeds through inhibition and participation of GABA inhibition is essential. Extinction of fear conditioning requires participation of medial prefrontal cortex and amygdala [628]. The glutamatergic efferents from the medial prefrontal cortex synapse on amygdala GABAer-gic neurons and contribute to the extinction of hostile experience [628, 16]. Excitation does not injure GABAergic neurons, since interneurons containing GABA are weakly vulnerable to damage [588]. Expectation of reward after learning may augment GABA inhibition in forestalling manner: the firing rate of a subpopulation of GABA neurons in the ventral tegmental area increases in anticipation of brain stimulation reward [706].
Protection against excitotoxic damage decreases pain, but GABA receptors are not the only target for an attack against hurtful excitation of various kind. Compensatory inhibition may also be connected with taurine. Taurine is released simultaneously with or slightly later than an excess of glu-tamate under various neuron-damaging conditions. For instance, after passive avoidance training, both glutamate and taurine in the hyperstriatum were increased [286]. Reduction in excitability protects cell from damage and has analgetic properties. Particularly, suppression of Na+-channels has analgesic effects [627]. Preventive treatment against the migraine, a common episodic pain disorder, include antidepressants, gap junction inhibition and antiepilep-tic drugs, which enhances antinociception [1142].
Opioids as well decrease negative motivations and ought to inhibit neurons. Indeed, during presentation of emotionally salient stimuli, higher baseline f-opioid receptor binding in the brain was associated with lower regional cerebral blood flow in this region and this is consistent with an inhibitory/anxiolytic role of the endogenous opioid system [736]. Cyclic AMP system is inhibited by opioids and subsequent inhibition of voltage-dependent cation channels may be a mechanism by which opioids inhibit excitability and relieve pain [577].
Nevertheless, rewarding substances sometimes evoke excitation, depen-dently on concentration and localization of receptors in the brain. For example, opioid receptors can couple through stimulatory or inhibitory Gs/Gj proteins to both ion channels and adenylyl cyclase [520, 569] and, correspondingly, can exert not only inbitory, but also excitatory effects to neurons. Ultra-low concentrations (pmol) of opioids increase the AP duration and are thus excitatory. However, higher concentrations (nmol or micromol) of opioids, which evoke antinociception and are therefore physiologically relevant, decrease the AP duration and are thus inhibitory. The protective properties of opioids, sometimes attributed only to the S-opioids protecting cells up to high concentrations (10-20 mg/kg). However, small concentrations of y-opioids (200400 yg/kg) [650, 859] and S-opioids (10-10-10-15 M) [755, 1014] also protect neurons. For instance, morphine can produce analgesia via spinal y opioid receptors in the absence of y-opioid receptors. [1373]. After the brief repeated exposures of y-opioids, the excitation was enhanced, but the inhibition was desensitized and potentiating action was distinct from the inhibition in that it had a long time course (minutes to develop and last tens of minutes) [666]. This demonstrates transient inhibitory action of opioids.
Motivationally-relevant substances as well affect excitability of specific neurons. It is natural to suppose that a substance that increases motivations excites neurons, while a substance decreasing motivations has an inhibitory effect. In support of this assumption, orexins [1156, 1199], substance P [806, 957, 1001], galanin [1021], estrogen [118], oxytocin [1008], vasopressin [1323], angiotensin II [382], and estrogen [118] exert excitatory action in physiologically relevant concentrations, although androgens have less consistent effects. Conversely, substances that decrease motivations such as, alcohol [331, 334], cholecystokinin via feeding satiation-related A-receptors [294], insulin and leptin [1375] usually inhibit neurons. Receptors for satiated substances, insulin and leptin, are present in the specific hypothalamic regions that control energy homeostasis, and these hormones reduce food intake in lean rats and hyperpolarize glucose-responsive neurons in the hypothalamus of lean rats [1164]. The excitatory effect of cholecystokinin has also been reported, but it either occurs at high concentrations or was mediated mainly via B-receptors, connected with anxiety [294, 531, 1193]. Nevertheless, this assumption is not absolutely compatible with all the experimental data. Drugs may affect many different cells, many points of a cell and may act via different receptors. Drugs may also affect both excitatory and inhibitory neurons and both presynaptic and postsynaptic sites. In some cases, even GABA [295] and glycine [142] excite neurons, while excitatory amino acids sometimes induce inhibition [1101]. Besides, the dependence on the concentration of motivationally-relevant substance actions of both neuronal activity and behavior are non-linear. For instance, neuropeptide Y [621], substance P [1001], galanin [1338], and oxytocin [869], which increase motivations, inhibit neurons at higher concentrations. On the whole, the direct action of motivationally-relevant substances at physiologically relevant concentrations on neurons in motivational centers more frequently tends to be excitation, if the motivationally-relevant substance increases motivation, and tends to be inhibition if the motivationally-relevant substance decreases it.
Our consideration has demonstrated that as well as excessive excitation is a distinctive property of motivations, intense inhibition in motivational areas is connected with satisfaction of motivation and with a reward. This conclusion appears a trivial. However, excessive excitation in given case leads to neuronal damage, while intense inhibition promote homeostatic protection.
Specialized neurons generate motivations and accept rewards
While we considered rewarding substances, inducing pleasure, we concentrated on neuronal mechanisms of conscious reward. Much less is known about the metabolic component of reward, although this appears to be simpler.
Obviously, neurons in motivational centers are specially tuned to detect homeostatic discrepancies. They appear to have higher sensitivity to these specific factors and their resistance to damage is attenuated. Neurons that express the orexigenic peptides are exceptionally sensitive to injury [588, 1120, 1374]. They lack the calcium-binding proteins parvalbumin and calbindin [721], which normally decrease any rise in intracellular Ca?+ and promote cell survival following glutamate excitotoxicity [859]. Distribution of the inhibitory neurotransmitter taurine provides an example of the specific tuning of neurons in thirst motivational centers. The highest taurine concentrations are in the hypothalamic nucleus connected with water balance and the lowest – in the remainder of the hypothalamus [573]. It is possible that taurine’s compensatory inhibition protects neurons during necrotic swelling and thus may prevent detection of homeostatic imbalance in hypothalamic areas not connected with water balance. High sensitivity to injury in motivationally-relevant neurons is necessary in order to detect slight disturbances in homeostasis.
The specialization of neurons in the primary motivational centers must result in a difference between the reactions to rewarding stimuli in the primary motivational centers and in the rest of the brain. An example of specific tuning of the neurons in motivational centers is the feeding motivation. A connection between motivation and hyperthermia appears to oppose the essence of the feeding motivation that relates to a fall in energy and a reduction in thermogenesis. However, in reality, primary feeding neurons detect a decrease in body energy. Neuropeptide Y and orexin neurons in the arcuate nucleus act homeostatically to restore normal energy balance; they become overactive following a critical fall in the body’s energy stores [1209, 1341, 1375]. In addition, feeding neurons in the lateral hypothalamus are stimulated when the level of glucose falls, while neurons of the ventromedial hypothalamic nucleus increase their firing rate as the level of glucose rises [1341]. Correspondingly, consumption of a food reward enhances glucose and inhibits specific feeding neurons, while exciting a majority of neurons in the brain. Medulla inspi-ratory neurons respond to hypoxia, hypercapnia or acidic stimuli with an increase in electrical activity, while most of the other neurons in the brain are either inhibited or unaffected [613, 1224, 1319]. An increase in extracellular osmolarity depolarizes thirst neurons, but does not excite other neurons [29], while lowering of extracellular osmolarity inhibits thirst neurons but causes a reversible increase of both excitatory and inhibitory postsynaptic currents and Ca2+-mediated inward currents in the hippocampus [567]. Neurons in the male medial preoptic nucleus demonstrate powerful excitation during sexual behavior, but their activities abruptly decrease after intromission and especially after ejaculation [846, 1134]. At the same time, ejaculation activates related neuronal clusters outside of the medial preoptic nucleus in both males and females and suppresses neuronal activity in the medial preoptic nucleus as a negative feedback [1299]. Behavioral positive affective reactions cause activation in corresponding brain areas, but they usually increase motivation and do not induce pleasure [113]. We therefore suggest that acceptance of a reward inhibits neurons in primary motivational centers while it excites a majority of other neurons.
Opioid-mediated conscious rewards are widely distributed in the brain, sometimes far out of primary motivational areas. For example, primary respiratory neurons in the ventral medulla, which are activated by CO2 and by low pH [867], are opioid-insensitive, in contrast to neurons in the pre-Botzinger complex [378], which is the site for respiratory-related rhythm generation and where inspiratory bursts depend on a Ca2+-activated current linked to glutamate receptors [930]. Therefore, just the neurons sensing a disturbance in oxygen homeostasis do not react to an opioid reward and control only the harmony in homeostasis itself. This is especially essential with regards to that opioids suppress respiratory rhythm [81, 960]. It is natural, that rewarding centers connected to euphoria only partially match the motivational centers. Opioid signals transiently ameliorate neuronal damage (see next subdivision), promote a positive subjective feeling and thus contribute to goal-directed behavior, but metabolic improvement cannot be replaced by opioids. We may assume that the set of neurons producing motivations and experiencing injury coincides with the neurons receiving protection, but only partially coincides with the neurons receiving conscious reward. Therefore, in producing a motivation neurons control an entire cycle of motivational behavior. Incomplete coincidence between the set of primary motivational neurons and the set of neurons that are sensitive to rewarding substances cannot prevent the proper performance of this whole unit of the neuronal system.
Protective actions of rewards
The first indirect indication to protective influence of rewards is their powerful inhibitory interaction with the neurons in motivational centers and what’s more, this is a general rule. Protective influences exert positive feeling, decrease anxiety and produce euphoria. For example, neuroprotection evoked by the a1 receptor activation decreases anxiety [808], while neuronal damage, evoked by chronic ethanol is reduced by acute nicotine [959]. The substances that evoke or increase brain reward (opioids, dopamine and GABA) protect brain tissue from damage. Acute opioids not only protect cells against motivation-induced injury and against pain and anxiety, but even defend cells against ischemia and hypoxia, too [520, 141]. This concerns to activation of various opioid receptors, such as f-opioids [630, 986], ^-opioids [151, 1107, 1189, 1425] and f-opioids in low concentration [755, 1014]. Taking into consideration that opioids evoke dependence, protective action is observed, certainly, after their acute implementations. Chronic their action, as we already discussed lead to opposite effects: chronic consumption of opi-oids evokes irreversible damage of brain cells. Many other rewarding substances, such as cocaine [1153], caffeine [602], alcohol [331], and cholecys-tokinin [803, 1229] protect neurons from damage. However, because of the development of compensatory processes, chronic cocaine ingestion [709], chronic or high doses of alcohol [331, 334], etc. increase excitability and exacerbate damage. Serotonin also plays a pivotal role in the homeostasis of neural tissue [69], as it interacts with neurosteroids and opioids and affects the morphology of target cells [1053, 1370].
Action of motivationally-relevant substances to behavior is also can be connected with their influence to damage-protection of neurons. Usually such substances protect cells, if they decrease motivations, though this is not always the case, since their affect by a complex way depends on concentration and this is difficult task to compare effective concentrations of substances in different experiments.
Besides these relatively direct results concerning protective influences of resulting satisfaction, consumption of rewarding substances activates metabolic events in the brain, which, typically, decrease damage. Both opioids and stimulants cause a global decrease in brain metabolism [287]. Protective action of the acute y-opioids is exhibited also in stimulation of Na+,K+-ATPase activity [1357] and in reduction of the Ca2+ current by y-opiod agonists. Intravenous cocaine injection directly inhibits Na+ channels [637]. The opioid antagonist naloxon unexpectedly protects cells against damage, but this protection is mediated by its inhibition of microglial activity, and its stereoisomer, inactive for opioid receptor, protects neurons with equal potency [753].
The dopamine2 receptor agonists that presumable exert rewarding effect activate K + channels in the rat striatum and these channels open under energy-depleting conditions in the absence of a dopaminergic agonist [741]. These agonists also arrest Ca2+ dependent AP, hyperpolarize the membrane of growth hormone-secreting cells by means of K + conductance increase [1210] and affects Ca2+ evoked arachidonic acid release, while they produce inhibition of cyclic AMP [320, 1092]. Dopamine1 agonist has the opposite effect of arachidonic acid and increases cyclic AMP activity [320, 1092]. Dopamine-containing neurons are very stable [803, 1380] and dopamine receptors are connected with the inhibitory Gj protein [1422]. Dopamine1 and dopamine2 receptors usually have an opposite influence on intracellular events, in accordance with their opposite action to neuronal excitability and neuronal protection [887]. In the majority of cases, dopamine through dopamine2-receptor protects cells against damage [789, 1107, 159]. However, both dopamine1 and dopamine2 -receptors might contribute to the toxic action of dopamine and dopamine-induced cell death is not restricted to neuronal cells [159]. For instance, neuroleptic haloperidol, dopamine2 -like antagonist, induces loss of cell membrane integrity that is typical for necrosis [870].
Another important reward substance GABA besides vast inhibitory influences also protects cells against damage [593, 1300]. Protective role of GABAergic neurons is augmented by means of gap junctions. Coupling of inhibitory GABAergic interneurons via gap junctions facilitates to integration of inhibition. The threshold for self-stimulation coincided with the threshold for electrical coupling between GABA neurons, the degree of responding for self-stimulation was also proportional to the magnitude of electrical coupling between GABA neurons, and gap junction blockers increased the threshold for self-stimulation without affecting performance [706]. The reinforcement-relevant substance cholecystokinin, too, inhibits and protects neurons. Chole-cystokinin A- and B-receptors, as well as dopamine1 and dopamine2 receptors differently affect motivation and satisfaction and correspondingly exert a different effect states of neurons. Cholecystokinin B-receptors reduce potassium leak conductance, resulting in an excitation of the neuron and connect with stressory reactions, whereas cholecystokinin A-receptor-related inhibition was associated with a membrane hyperpolarization and a decrease in input resistance that developed 2-6 min after the arrival of the drug into the extracellular medium [161]. Inhibitory current was generated by potassium currents.
Thus, rewarding substances usually protects neurons, although this protection is insufficiently in order to substitute the natural reward itself that supplies organism by liquid, nutrients and energy, recovers metabolism and protect cell from damage. Rewarding substances ensuring a conscious component of rewards have two functions. They temporarily decrease stress after acute action of malefactors, guarantee proper interaction with an environment and signal the appearance of a metabolic component of rewards. Therefore, closed cycle of motivational behavior in neurons do not coincide with the entire behavioral course of action.
