Merce Correa

Abstract Classical definitions of motivation typically involve two main components: direction and activation. Motivated behavior is directed toward or away from particular stimuli (i.e., appetitive and aversive motivation). Furthermore, activational aspects of motivation refer to the observation that motivated behavior is characterized by substantial activity, vigor, persistence, and exertion of effort in both the initiation and maintenance of behavior. Although separate neural systems direct organisms toward distinct motivational stimuli (e.g., food, water, sex), there appears to be a common circuitry regulating behavioral activation and the exertion of effort. Mesolimbic dopamine is one of the brain systems mediating activational aspects of motivation and exertion of effort. This system integrates aspects of motivation and motor control functions involved in the instigation of action. Research on the neurobiology of effort has contributed to our understanding of the pathophysiology of neurological and psychiatric disorders that are characterized by motivational dysfunction.

Abstract Definitions of motivation typically emphasize both directional and activation aspects of behavior. Motivated behavior is directed toward or away from particular stimuli, and also is characterized by substantial activity, vigor, persistence, and exertion of effort in both the initiation and maintenance of behavior. Some neural systems direct organisms toward distinct motivational stimuli such as food, water, and sex, and there appears to be a common neural circuitry regulating behavioral activation and the exertion of effort. The mesolimbic dopamine system, particularly the innervation of nucleus accumbens, is one of the brain systems mediating activational aspects of motivation and exertion of effort. This system integrates aspects of motivation and motor control functions involved in the instigation of goal-directed action. Dopamine transmission exerts a bidirectional regulation of exertion of effort in animal models and human studies. Interference with accumbens dopamine transmission reduces the tendency of rodents to work for food, and alters effort-related choice, but leaves other aspects of food motivation intact. These studies have implications for understanding the neurochemical interactions that underlie activational aspects of motivation. Moreover, research on the neurobiology of effort has contributed to our understanding of the pathophysiology of neurological and psychiatric disorders that are characterized by motivational dysfunction.

The impact of caffeine on ethanol consumption and abuse has become a topic of great interest due to the rise in popularity of energy drinks. Energy drinks have many different components, although the main active ingredient is caffeine. These drinks are frequently taken in combination with alcohol, with the belief that caffeine can offset some of the intoxicating effects of ethanol. However, scientific research has not universally supported the idea that caffeine can reduce the effects of ethanol in humans or in rodents, and the mechanisms mediating caffeine–ethanol interactions are not well understood. Caffeine acts as a nonselective adenosine A1 and A2A receptor antagonist, while ethanol has been demonstrated to increase the basal adenosinergic tone via multiple mechanisms. In this chapter, we discuss animal studies that have assessed the impact of ethanol plus caffeine combinations on social processes related to motivation, emotion, and cognition.

BackgroundCaffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)‐related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD‐1 mice.MethodsAcute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol‐induced (1.5 to 3.5 g/kg) changes in open‐field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor‐dependent phosphorylation markers were assessed: extracellular signal‐regulated kinase (pERK), and dopamine‐and cAMP‐regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP‐32‐Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol‐sensitized (1.5 g/kg) mice.ResultsAcute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol ‐induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol‐induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol‐sensitized mice in an ethanol‐free state resulted in blunted stimulant effects compared with those seen in ethanol‐naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP‐32(Thr75) immunoreactivity.ConclusionsThe present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol‐sensitized animals.

Substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia that receives GABAergic projections from neostriatum and globus pallidus. Previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements in rats. Tremulous jaw movements are defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at a particular stimulus, and evidence indicates that these movements share many characteristics with parkinsonian tremor in humans. In order to investigate the role of GABA in motor functions related to tremor, the present study tested the GABA uptake blocker beta-alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In a parallel experiment, the effect of an active dose of beta-alanine on dialysate levels of GABA in SNr was assessed using microdialysis methods. GABA levels in dialysis samples were measured using high performance liquid chromatography with electrochemical detection. beta-Alanine (250-500 mg/kg) significantly reduced tremulous jaw movements induced by pilocarpine (4.0 mg/kg). Moreover, systemic administration of beta-alanine at a dose that reduced tremulous jaw movements (500 mg/kg) resulted in a substantial increase in extracellular levels of GABA in SNr compared to the pre-injection baseline. Thus, the present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. This research may lead to a better understanding of how parkinsonian symptoms are modulated by SNr GABA mechanisms.

Several studies have shown that a number of pharmacological and neurochemical conditions in rats can induce jaw movements that are described as "vacuous" or "tremulous". For several years, there has been some debate about the clinical significance of various drug-induced oral motor syndromes. Nevertheless, considerable evidence now indicates that the non-directed, chewing-like movements induced by cholinomimetics have many of the characteristics of parkinsonian tremor. These movements are characterized largely by vertical deflections of the jaw, which occur in the same 3-7 Hz peak frequency that is typical of parkinsonian tremor. Cholinomimetic-induced tremulous jaw movements are suppressed by a number of different antiparkinsonian drugs, including scopolamine, benztropine, L-DOPA, apomorphine, bromocriptine, ropinirole, pergolide, amantadine, diphenhydramine and clozapine. A combination of anatomical and pharmacological research in rats has implicated M4 receptors in the ventrolateral neostriatum in the generation of tremulous jaw movements. Mice also show cholinomimetic-induced jaw movements, and M4 receptor knockout mice demonstrate subtantially reduced levels of jaw movement activity, as well as increased locomotion. Taken together, these data are consistent with the hypothesis that a centrally-acting M4 antagonist may be useful as a treatment for parkinsonian symptoms, including tremor.