A potassium channel blocker induces a long-lasting enhancement of corticostriatal responses.

Disruptions in synaptic plasticity in the dorsal striatum may contribute to the pathophysiology underlying Parkinson's disease. Here we report a novel, chemically-induced form of plasticity induced by application of the potassium channel blocker tetraethylammonium (TEA) in the dorsolateral striatum of the adult rat. Transient application of TEA persistently increased synaptically-evoked extracellularly-recorded corticostriatal responses in an activity-, concentration- and time-dependent manner. Pharmacological experiments suggest that this plasticity is dependent on L-type calcium channel and protein kinase C (PKC) activation. Striatal dopamine depletion induced by nigrostriatal dopamine lesions with 6-hydroxydopamine significantly reduced, but did not abolish, TEA-mediated enhancement of the corticostriatal response. Intracellular recordings demonstrate that this TEA-mediated plasticity is associated with an increase in EPSP size and slope, as well as input resistance. Collectively, these findings demonstrate a novel form of L-type calcium channel-dependent plasticity in the adult dorsal striatum that is induced in the absence of dopaminergic input.

Norepinephrine modulates glutamatergic transmission in the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) and its adrenergic input are key components in stress-induced reinstatement and maintenance of drug use. Intra-BNST injections of either beta-adrenergic receptor (beta-AR) antagonists or alpha2-adrenergic receptor (alpha2-AR) agonists can inhibit footshock-induced reinstatement and maintenance of cocaine- and morphine-seeking. Using electrophysiological recording methods in an in vitro slice preparation from C57/Bl6j adult male mouse BNST, we have examined the effects of adrenergic receptor activation on excitatory synaptic transmission in the lateral dorsal supracommissural BNST (dBNST) and subcommissural BNST (vBNST). Alpha2-AR activation via UK-14,304 (10 microM) results in a decrease in excitatory transmission in both dBNST and vBNST, an effect predominantly dependent upon the alpha2A-AR subtype. Beta-AR activation via isoproterenol (1 microM) results in an increase in excitatory transmission in dBNST, but not in vBNST. Consistent with the work with receptor subtype specific agonists, application of the endogenous ligand norepinephrine (NE, 100 microM) elicits two distinct effects on glutamatergic transmission. In dBNST, NE elicits an increase in transmission (62% of dBNST NE experiments) or a decrease in transmission (38% of dBNST NE experiments). In vBNST, NE elicits a decrease in transmission in 100% of the experiments. In dBNST, the NE-induced increase in synaptic transmission is blocked by beta1/beta2- and beta2-, but not beta1-specific antagonists. In addition, this increase is also reduced by the alpha2-AR antagonist yohimbine and is absent in the alpha2A-AR knockout mouse. In vBNST, the NE-induced decrease in synaptic transmission is markedly reduced in the alpha2A-AR knockout mouse. Further experiments demonstrate that the actions of NE on glutamatergic transmission can be correlated with beta-AR function.

High-frequency stimulation induces ethanol-sensitive long-term potentiation at glutamatergic synapses in the dorsolateral bed nucleus of the stria terminalis.

Anatomical and functional data support a critical role for the bed nucleus of the stria terminalis (BNST) in the interaction between stress and alcohol/substance abuse. We report here that neurons of the dorsal anterolateral BNST respond to glutamatergic synaptic input in a synchronized way, such that an interpretable extracellular synaptic field potential can be readily measured. High-frequency stimulation of these glutamatergic inputs evoked NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). We found that an early portion of this LTP is reduced by acute exposure to ethanol in a GABA(A) receptor-dependent manner. This effect of ethanol is accompanied by a significant and reversible dose-dependent attenuation of isolated NMDAR signaling and is mimicked by incomplete NMDAR blockade.

Dorsal and ventral distribution of excitable and synaptic properties of neurons of the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) is a structure uniquely positioned to integrate stress information and regulate both stress and reward systems. Consistent with this arrangement, evidence suggests that the BNST, and in particular the noradrenergic input to this structure, is a key component of affective responses to drugs of abuse. We have utilized an in vitro slice preparation from adult mice to determine synaptic and membrane properties of these cells, focusing on the dorsal and ventral subdivisions of the anterolateral BNST (dBNST and vBNST) because of the differential noradrenergic input to these two regions. We find that while resting membrane potential and input resistance are comparable between these subdivisions, excitable properties, including a low-threshold spike (LTS) likely mediated by T-type calcium channels and an Ih-dependent potential, are differentially distributed. Inhibitory and excitatory postsynaptic potentials (IPSPs and EPSPs, respectively) are readily evoked in both dBNST and vBNST. The fast IPSP is predominantly GABAA-receptor mediated and is partially blocked by the AMPA/kainate-receptor antagonist CNQX. In the presence of the GABAA-receptor antagonist picrotoxin, cells in dBNST but not vBNST are more depolarized and have a higher input resistance, suggesting tonic GABAergic inhibition of these cells. The EPSPs elicited in BNST are monosynaptic, exhibit paired pulse facilitation, and contain both an AMPA- and an N-methyl-d-aspartate (NMDA) receptor-mediated component. These data support the hypothesis that neurons of the dorsal and ventral BNST differentially integrate synaptic input, which is likely of behavioral significance. The data also suggest mechanisms by which information may flow through stress and reward circuits.

Synaptic plasticity in drug reward circuitry.

Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.

LTP in the mouse nucleus accumbens is developmentally regulated.

Glutamatergic transmission in the nucleus accumbens (NAc) has been shown to be important for behavioral adaptations in response to drugs of abuse. NMDA-receptor dependent long-term potentiation (LTP) of glutamatergic synaptic transmission has been hypothesized to underlie many lasting alterations in behavior. Thus, we examined LTP in NAc core and find that it is developmentally regulated. Specifically, tetanus-evoked, NMDA receptor-dependent LTP is observed in the NAc of "adolescent" (3-week-old) mice more frequently than in adult (6-20-week-old) mice. In contrast, cAMP-dependent enhancement of transmission is not developmentally regulated. Removal of extracellular Mg(2+) restores LTP in adult NAc core, suggesting developmental regulation of induction processes rather than maintenance mechanisms. These findings are discussed in the context of behavioral changes elicited in response to drugs of abuse, which differ in adolescent vs. adult rodents and humans.