Dopamine contributes to corticostriatal plasticity and motor learning. Dopamine denervation profoundly alters motor performance, as in Parkinson's disease (PD); however, the extent to which these symptoms reflect impaired motor learning is unknown. Here, we demonstrate a D2 receptor blockade-induced aberrant learning that impedes future motor performance when dopamine signaling is restored, an effect diminished by coadministration of adenosine antagonists during blockade. We hypothesize that an inappropriate corticostriatal potentiation in striatopallidal cells of the indirect pathway underlies aberrant learning. We demonstrate synaptic potentiation in striatopallidal neurons induced by D2 blockade and diminished by application of an adenosine antagonist, consistent with behavioral observations. A neurocomputational model of the basal ganglia recapitulates the behavioral pattern and further links aberrant learning to plasticity in the indirect pathway. Thus, D2-mediated aberrant learning may contribute to motor deficits in PD, suggesting new avenues for the development of therapeutics.

The dopaminergic neurons of the ventral tegmental area (DA VTA neurons) are important for the rewarding and reinforcing properties of drugs of abuse, including ethanol. Ethanol increases the firing frequency of DA VTA neurons from rats and mice. Because of a recent report on block of ethanol excitation in mouse DA VTA neurons with ZD7288, a selective blocker of the hyperpolarization-activated cationic current I_h, we examined the effect of ZD7288 on ethanol excitation in DA VTA neurons from C57Bl/6J and DBA/2J mice and Fisher 344 rats. Ethanol (80 mM) caused only increases in firing rate in mouse DA VTA neurons in the absence of ZD7288, but in the presence of ZD7288 (30 μM), ethanol produced a more transient excitation followed by a decrease of firing. This same biphasic phenomenon was observed in DA VTA neurons from rats in the presence of ZD7288 only at very high ethanol concentrations (160–240 mM) but not at lower pharmacologically relevant concentrations. The longer latency ethanol-induced inhibition was not observed in DA VTA neurons from mice or rats in the presence of barium (100 μM), which blocks G protein–linked potassium channels (GIRKs) and other inwardly rectifying potassium channels. Ethanol may have a direct effect to increase an inhibitory potassium conductance, but this effect of ethanol can only decrease the firing rate if I_his blocked.

Ca²⁺ homeostasis is essential for multiple neuronal functions and thus, Ca²⁺ dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies implicate Ca²⁺ mishandling in AD, the cellular basis for loss of cognitive function remains under investigation. The process of synaptic degradation and degeneration in AD is slow, and constitutes a series of maladaptive processes each contributing to a further destabilization of the Ca²⁺ homeostatic machinery. Ca²⁺ homeostasis involves precise maintenance of cytosolic Ca²⁺ levels, despite extracellular influx via multiple synaptic Ca²⁺ channels, and intracellular release via organelles such as the endoplasmic reticulum (ER) via ryanodine receptor (RyRs) and IP₃R, lysosomes via transient receptor potential mucolipin channel (TRPML) and two pore channel (TPC), and mitochondria via the permeability transition pore (PTP). Furthermore, functioning of these organelles relies upon regulated inter-organelle Ca²⁺ handling, with aberrant signaling resulting in synaptic dysfunction, protein mishandling, oxidative stress and defective bioenergetics, among other consequences consistent with AD. With few effective treatments currently available to mitigate AD, the past few years have seen a significant increase in the study of synaptic and cellular mechanisms as drivers of AD, including Ca²⁺ dyshomeostasis. Here, we detail some key findings and discuss implications for future AD treatments.

Enhancements in behavior that accompany repeated, intermittent administration of abused drugs (sensitization) endure long after drug administration has ceased. Such persistence reflects changes in intracellular signaling cascades and associated gene transcription factors in brain regions that are engaged by abused drugs. This process is not characterized for the most potent psychomotor stimulant, methamphetamine. Using motor behavior as an index of brain state in rats, we verified that five once-daily injections of 2.5 mg/kg methamphetamine induced behavioral sensitization that was demonstrated (expressed) 3 and 14 days later. Using immunoblot procedures, limbic brain regions implicated in behavioral sensitization were assayed for extracellular signal-regulated kinase and its phosphorylated form (pERK/ERK, a signal transduction kinase), cAMP response element binding protein and its phosphorylated form (pCREB/CREB, a constitutively expressed transcriptional regulator), and DeltaFosB (a long-lasting transcription factor). pERK, ERK, and CREB levels were not changed for any region assayed. In the ventral tegmental area, pCREB and DeltaFosB also were not changed. pCREB (activated CREB) was elevated in the frontal cortex at 3 days withdrawal, but not at 14 days. pCREB levels were decreased at 14 days withdrawal in the nucleus accumbens and ventral pallidum. Accumbal and pallidal levels of DeltaFosB were increased at 3 days withdrawal, and this increase persisted to 14 days in the pallidum. Thus, only the ventral pallidum showed changes in molecular processes that consistently correlated with motor sensitization, revealing that this region may be associated with this enduring behavioral phenotype initiated by methamphetamine. The present findings expand our understanding of the neuroanatomical and molecular substrates that may play a role in the persistence of druginduced sensitization.

Activation of μ-opioid receptors in the ventral pallidum (VP) is important for the induction of behavioral sensitization to morphine in rats. The present study was designed to ascertain if neurons within the VP demonstrate sensitization at a time when morphine-induced behavioral sensitization occurred (ie 3 or 14 days after five once-daily injections of 10 mg/kg i.p. morphine) in rats. Western blotting was used to evaluate transcription factors altered by opiates, CREB and ΔFosB. CREB levels did not change in the VP, but there was a significant decrease in levels of its active, phosphorylated form (pCREB) at both 3- and 14-days withdrawal. ΔFosB levels were elevated following a 3-day withdrawal, but returned to normal by 14 days. This profile also was obtained from nucleus accumbens tissue. In a separate group of similarly treated rats, in vivo electrophysiological recordings of VP neuronal responses to microiontophoretically applied ligands were carried out after 14-days withdrawal. The firing rate effects of local applications of morphine were diminished in rats withdrawn from i.p. morphine. Repeated i.p. morphine did not alter GABA-mediated suppression of firing, or the rate enhancing effects of the D1 dopamine receptor agonist SKF82958 or glutamate. However, VP neurons from rats withdrawn from repeated i.p. morphine showed a higher propensity to enter a state of depolarization inactivation to locally applied glutamate. Overall, these findings reveal that decreased pCREB in brain regions such as the VP accompanies persistent behavioral sensitization to morphine and that this biochemical alteration may influence the excitability of neurons in this brain region.