Energy metabolism theory affirms that body weight stability is achieved as over time the average energy intake equals the average energy expenditure, a state known as energy balance. Here it is demonstrated, however, that weight stability coexists with a persistent energy imbalance. Such unexpected result emerges as a consequence of the answers to three fundamental problems: 1. Is it possible to model body weight fluctuations without the energy balance theory? And if so, what are the benefits over the energy balance strategy? 2. During energy balance, how the oxidized macronutrient distribution that underlies the average energy expenditure is related to the macronutrient distribution of the average energy intake? 3. Is energy balance possible under a low-fat diet that simultaneously satisfies the following conditions? (a) The fat fraction of the absorbed energy intake is always less than the oxidized fat fraction of the energy expenditure. (b) The carbohydrate fraction of the absorbed energy intake is always greater or equal to the oxidized carbohydrate fraction of the energy expenditure. The first of these issues is addressed with the axiomatic method while the rest are managed through analythical arguments. On the whole, this analysis identifies inconsistencies in the principle of energy balance. The axiomatic approach results also in a simple mass balance model that fits experimental data and explains body composition alterations. This model gives rise to a convincing argument that appears to elucidate the advantage of low-carbohydrate diets over isocaloric low-fat diets. It is concluded, according to the aforementioned model, that weight fluctuations are ultimately dependent on the difference between daily food mass intake and daily mass loss (e.g., excretion of macronutrient oxidation products) and not on energy imbalance. In effect, it is shown that assuming otherwise may caused unintended weight gain.

Alterations in the state of excitability of midbrain dopamine (DA) neurons from the ventral tegmental area (VTA) may underlay changes in the synaptic plasticity of the mesocorticolimbic system. Here, we investigated norepinephrine's (NE) regulation of VTA DA cell excitability by modulation of the hyperpolarization-activated cation current, I h in whole cell recordings. Current clamp recordings show that NE (40 µM) hyperpolarizes spontaneously firing VTA DA cells (11.23 ±4 mV; n = 8). In voltage clamp, NE (40 µM) induces an outward current (100 ± 24 pA; n = 8) at − 60 mV that reverses at about the Nernst potential for potassium (−106 mV). In addition, NE (40 µM) increases the membrane cord conductance (179 ± 42%; n = 10) and reduces I h amplitude (68 ± 3% of control at −120 mV; n = 10). The noradrenergic alpha-1 antagonist prazosin (40 µM; n = 5) or the alpha-2 antagonist yohimbine (40 µM; n = 5) did not block NE effects. All NE-evoked events were blocked by the D 2 antagonists sulpiride (1 µM) and eticlopride (100 nM) and no significant reduction of I h took place in the presence of the potassium channel blocker BaCl 2 (300 µM). Therefore, it is concluded that NE inhibition of I h was due to an increase in membrane conductance by a non-specific activation of D 2 receptors that induce an outward potassium current and not a result of a second messenger system acting on h-channels. The results also suggest that I h channels are mainly located at dendrites of VTA DA cells and thus their inhibition may facilitate the transition from single spike firing to burst firing and vice versa.

The progressive augmentation of motor activity that results from repeated cocaine administration is termed behavioral sensitization. This phenomenon is thought to be a critical component in compulsive drug taking and relapse. Still, the cellular mechanisms that underlie sensitization remain elusive. Cocaine abuse, nonetheless, is known to evoke neuroplastic adaptations in dopamine (DA) neurotransmission originating from the midbrain's ventral tegmental area (VTA). Here, we report that concomitant with the development of locomotor sensitization to cocaine the hyperpolarization-activated cation current (I(h)) amplitude is depressed by ∼40% in VTA DA cells. Such effect did not result from a negative shift in I(h) voltage dependence. Nonstationary fluctuation analysis indicates that this inhibition was caused by an ∼45% reduction in the number of h-channels with no change in their unitary properties. The cocaine-induced I(h) depression was accompanied by a reduction in cell capacitance of similar magnitude (∼33%), leaving h-current density unaltered. Two implications follow from these data. First, I(h) inhibition may contribute to cocaine addiction by increasing bursting probability in DA cells and this effect could be intensified by the decrease in cell capacitance. Second, the cocaine-induced diminution of DA cell capacitance may also lead to reward tolerance promoting drug-seeking behaviors.

The ventral tegmental area (VTA) is the source of dopaminergic projections innervating cortical structures and ventral forebrain. Dysfunction of this mesocorticolimbic system is critically involved in psychiatric disorders such as addiction and schizophrenia. Changes in VTA dopamine (DA) neuronal activity can alter neurotransmitter release at target regions which modify information processing in the reward circuit. Here we studied the effect of α-2 noradrenergic receptor activation on the hyperpolarization-activated cation current (I h ) in DA neurons of the rat VTA. Brain slice preparations using whole-cell current and voltage-clamp techniques were employed. Clonidine and UK14304 (α-2 receptor selective agonists) were found to decrease I h amplitude and to slow its rate of activation indicating a negative shift in the current's voltage dependence. Two non-subtypeselective α-2 receptor antagonists, yohimbine and RS79948, prevented the effects of α-2 receptor activation. RX821002, a noradrenergic antagonist specific for α-2A and α-2D did not prevent I h inhibition. This result suggests that clonidine might be acting via an α-2C subtype since this receptor is the most abundant variant in the VTA. Analysis of a second messenger system associated with the α-2 receptor revealed that I h inhibition is independent of cyclic adenosine monophosphate (cAMP) and resulted from the activation of protein kinase C. It is suggested that the α-2 mediated hyperpolarizing shift in I h voltage dependence can facilitate the transition from pacemaker firing to afferent-driven burst activity. This transition may play a key role on the changes in synaptic plasticity that occurs in the mesocorticolimbic system under pathological conditions.