The role of Ca2+‐dependent K+‐ channels at the rat corticostriatal synapses revealed by paired pulse stimulation

Potassium channels play an important role in modulating synaptic activity both at presynaptic and postsynaptic levels. We have shown before that presynaptically located K_V and K_IR channels modulate the strength of corticostriatal synapses in rat brain, but the role of other types of potassium channels at these synapses remains largely unknown. Here, we show that calcium‐dependent potassium channels BK‐type but not SK‐type channels are located presynaptically in corticostriatal synapses. We stimulated cortical neurons in rat brain slices and recorded postsynaptic excitatory potentials (EPSP) in medium spiny neurons (MSN) in dorsal neostriatum. By using a paired pulse protocol, we induced synaptic facilitation before applying either BK‐ or SK‐specific toxins. Thus, we found that blockage of BK_Ca with iberiotoxin (10 nM) reduces synaptic facilitation and increases the amplitude of the EPSP, while exposure to SK‐blocker apamin (100 nM) has no effect. Additionally, we induced train action potentials on striatal MSN by current injection before and after the exposure to K_Ca toxins. We found that the action potential becomes broader when the MSN is exposed to iberiotoxin, although it has no impact on frequency. In contrast, exposure to apamin results in loss of afterhyperpolarization phase and an increase of spike frequency. Therefore, we concluded that postsynaptic SK channels are involved in afterhyperpolarization and modulation of spike frequency while the BK channels are involved on the late repolarization phase of the action potential. Altogether, our results show that calcium‐dependent potassium channels modulate both input towards and output from the striatum.     

SK channels modulate the excitability and firing precision of projection neurons in the robust nucleus of the arcopallium in adult male zebra finches

Objective Motor control is encoded by neuronal activity. Small conductance Ca2+-activated K+ channels (SK channels) maintain the regularity and precision of firing by contributing to the afterhyperpolarization (AHP) of the action potential in mammals. However, it is not clear how SK channels regulate the output of the vocal motor system in songbirds. The premotor robust nucleus of the arcopallium (RA) in the zebra finch is responsible for the output of song information. The temporal pattern of spike bursts in RA projection neurons is associated with the timing of the acoustic features of birdsong. Methods The firing properties of RA projection neurons were analyzed using patch clamp whole-cell and cell-attached recording techniques. Results SK channel blockade by apamin decreased the AHP amplitude and increased the evoked firing rate in RA projection neurons. It also caused reductions in the regularity and precision of firing. RA projection neurons displayed regular spontaneous action potentials, while apamin caused irregular spontaneous firing but had no effect on the firing rate. In the absence of synaptic inputs, RA projection neurons still had spontaneous firing, and apamin had an evident effect on the firing rate, but caused no significant change in the firing regularity, compared with apamin application in the presence of synaptic inputs. Conclusion SK channels contribute to the maintenance of firing regularity in RA projection neurons which requires synaptic activity, and consequently ensures the precision of song encoding.     

SK channel blockade promotes burst firing in dorsal raphe serotonergic neurons

Previous in vivo studies have shown that blockade of small-conductance Ca(2+)-activated potassium (SK) channels enhances burst firing in dopaminergic neurons. As bursting has been found to be physiologically relevant for the synaptic release of serotonin (5-HT), we investigated the possible role of SK channels in the control of this firing pattern in 5-HT neurons of the dorsal raphe nucleus. In these cells, bursts are usually composed of doublets consisting of action potentials separated by a small interval (< 20 ms). Both in vivo and in vitro extracellular recordings were performed, using anesthetized rats and rat brain slices, respectively. In vivo, the specific SK blocker UCL 1684 (200 microm) iontophoresed onto presumed 5-HT neurons significantly increased the production of bursts in 13 out of 25 cells. Furthermore, the effect of UCL 1684 persisted in the presence of both the GABA(A) antagonist SR 95531 (10 mm) and the GABA(B) antagonist CGP 35348 (10 mm), whereas these agents by themselves did not significantly influence the neuronal firing pattern. In vitro, bath superfusion of the SK channel blocker apamin (300 nm) induced bursting in only three out of 18 neurons, although it increased the coefficient of variation of the interspike intervals in all the other cells. Our results suggest that SK channel blockade promotes bursting activity in 5-HT neurons via a direct action. An input which is present only in vivo seems to be important for the induction of this firing pattern in these cells.     

Apamin induces plastic changes in hippocampal neurons in senile Sprague-Dawley rats

Apamin is a neurotoxin extracted from honey bee venom and is a selective blocker of small‐conductance Ca²⁺‐activated K⁺ channels (SK). Several behavioral and electrophysiological studies indicate that SK‐blockade by apamin may enhance neuron excitability, synaptic plasticity, and long‐term potentiation in the CA1 hippocampal region, and, for that reason, apamin has been proposed as a therapeutic agent in Alzheimer's disease treatment. However, the dendritic morphological mechanisms implied in such enhancement are unknown. In the present work, Golgi–Cox stain protocol and Sholl analysis were used to study the effect of apamin on the dendritic morphology of pyramidal neurons from hippocampus and the prefrontal cortex as well as on the medium spiny neurons from the nucleus accumbens and granule cells from the dentate gyrus (DG) of the hippocampus. We found that only granule cells from the DG and pyramidal neurons from dorsal and ventral hippocampus were altered in senile rats injected with apamin. Our research suggests that apamin may increase the dendritic morphology in the hippocampus, which could be related to the neuronal excitability and synaptic plasticity enhancement induced by apamin. Synapse 2011. © 2011 Wiley‐Liss, Inc.     

Long‐term plasticity of glutamatergic input from the subthalamic nucleus to the entopeduncular nucleus

The hyperdirect pathway of the basal ganglia bypasses the striatum, and delivers cortical information directly to the subthalamic nucleus (STN). In rodents, the STN excites the two output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and the substantia nigra reticulata (SNr). Thus, during hyperdirect pathway activation, the STN drives EP firing inhibiting the thalamus. We hypothesized that STN activity could induce long‐term changes to the STN‐>EP synapse. To test this hypothesis, we recorded in the whole‐cell mode from neurons in the EP in acute brain slices from rats while electrically stimulating the STN. Repetitive pre‐synaptic stimulation generated modest long‐term depression (LTD) in the STN‐>EP synapse. However, pairing EP firing with STN stimulation generated robust LTD that manifested for pre‐before post‐as well as for post‐ before pre‐synaptic pairing. This LTD was highly sensitive to the time difference and was not detected at a time delay of 10 ms. To investigate whether post‐synaptic calcium levels were important for LTD induction, we made dendritic recordings from EP neurons that revealed action potential back‐propagation and dendritic calcium transients. Buffering the dendritic calcium concentration in the EP neurons with EGTA generated long term potentiation instead of LTD. Finally, mild LTD could be induced by post‐synaptic activity alone that was blocked by an endocannabinoid 1 (CB1) receptor blocker. These results thus suggest there may be an adaptive mechanism for buffering the impact of the hyperdirect pathway on basal ganglia output which could contribute to the de‐correlation of STN and EP firing.     

New rules governing synaptic plasticity in core nucleus accumbens medium spiny neurons

The nucleus accumbens is a forebrain region responsible for drug reward and goal‐directed behaviors. It has long been believed that drugs of abuse exert their addictive properties on behavior by altering the strength of synaptic communication over long periods of time. To date, attempts at understanding the relationship between drugs of abuse and synaptic plasticity have relied on the high‐frequency long‐term potentiation model of T.V. Bliss & T. Lømo [(1973) Journal of Physiology, 232, 331–356]. We examined synaptic plasticity using spike‐timing‐dependent plasticity, a stimulation paradigm that reflects more closely the in vivo firing patterns of mouse core nucleus accumbens medium spiny neurons and their afferents. In contrast to other brain regions, the same stimulation paradigm evoked bidirectional long‐term plasticity. The magnitude of spike‐timing‐dependent long‐term potentiation (tLTP) changed with the delay between action potentials and excitatory post‐synaptic potentials, and frequency, whereas that of spike‐timing‐dependent long‐term depression (tLTD) remained unchanged. We showed that tLTP depended on N‐methyl‐d ‐aspartate receptors, whereas tLTD relied on action potentials. Importantly, the intracellular calcium signaling pathways mobilised during tLTP and tLTD were different. Thus, calcium‐induced calcium release underlies tLTD but not tLTP. Finally, we found that the firing pattern of a subset of medium spiny neurons was strongly inhibited by dopamine receptor agonists. Surprisingly, these neurons were exclusively associated with tLTP but not with tLTD. Taken together, these data point to the existence of two subgroups of medium spiny neurons with distinct properties, each displaying unique abilities to undergo synaptic plasticity.     

Electrophysiological evidence of mediolateral functional dichotomy in the rat nucleus accumbens during cocaine self‐administration II: phasic firing patterns

In the cocaine self‐administering rat, individual nucleus accumbens (NAcc) neurons exhibit phasic changes in firing rate within minutes and/or seconds of lever presses (i.e. slow phasic and rapid phasic changes, respectively). To determine whether neurons that demonstrate these changes during self‐administration sessions are differentially distributed in the NAcc, rats were implanted with jugular catheters and microwire arrays in different NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell, or rostral pole). Neural recording sessions were typically conducted on days 13–17 of cocaine self‐administration (0.77 mg/kg per 0.2‐mL infusion; fixed‐ratio 1 schedule of reinforcement; 6‐h daily sessions). Pre‐press rapid phasic firing rate changes were greater in lateral accumbal (core and ventrolateral shell) than in medial accumbal (dorsal shell and rostral pole shell) subregions. Slow phasic pattern analysis revealed that reversal latencies of neurons that exhibited change + reversal patterns differed mediolaterally: medial NAcc neurons exhibited more early reversals and fewer progressive/late reversals than lateral NAcc neurons. Comparisons of firing patterns within individual neurons across time bases indicated that lateral NAcc pre‐press rapid phasic increases were correlated with tonic increases. Tonic decreases were correlated with slow phasic patterns in individual medial NAcc neurons, indicative of greater pharmacological sensitivity of neurons in this region. On the other hand, the bias of the lateral NAcc towards increased pre‐press rapid phasic activity, coupled with a greater prevalence of tonic increase firing, may reflect particular sensitivity of these neurons to excitatory afferent signaling and perhaps differential pharmacological influences on firing rates between regions.     

Cocaine self-administration differentially alters mRNA expression of striatal peptides.

The influence of cocaine self-administration on the expression of messenger RNAs for dynorphin, enkephalin and substance P was analyzed in the rat striatum with in situ hybridization histochemistry. Cocaine, an indirect dopamine agonist, was found to differentially affect the levels of mRNA encoding these neuropeptides in different subregions of the striatum. Following a 7 day period of variable free access to cocaine, dynorphin and substance P mRNA levels were elevated throughout the striatum, but the increases were substantially greater in the dorsal striatum than in the nucleus accumbens. Enkephalin mRNA was not significantly altered in the dorsal striatum but was slightly elevated in the nucleus accumbens. These results suggest that cocaine self-administration has differential effects on striatonigral and striatopallidal projection neurons, and that these effects vary in subregions of the striatum.     

Methamphetamine-induced structural plasticity in the dorsal striatum

Repeated exposure to psychostimulant drugs produces long-lasting changes in dendritic structure, presumably reflecting a reorganization in patterns of synaptic connectivity, in brain regions that mediate the psychomotor activating and incentive motivational effects of these drugs, including the nucleus accumbens and prefrontal cortex. However, repeated exposure to psychostimulant drugs also facilitates a transition in the control of some behaviors from action-outcome associations to behavior controlled by stimulus-response (S-R) habits. This latter effect is thought to be due to increasing engagement and control over behavior by the dorsolateral (but not dorsomedial) striatum. We hypothesized therefore that repeated exposure to methamphetamine would differentially alter the density of dendritic spines on medium spiny neurons (MSNs) in the dorsolateral vs. dorsomedial striatum. Rats were treated with repeated injections of methamphetamine, and 3 months later dendrites were visualized using Sindbis virus-mediated green fluorescent protein (GFP) expression in vivo. We report that prior exposure to methamphetamine produced a significant increase in mushroom and thin spines on MSNs in the dorsolateral striatum, but a significant decrease in mushroom spines in the dorsomedial striatum. This may be due to changes in the glutamatergic innervation of these two subregions of the dorsal striatum. Thus, we speculate that exposure to psychostimulant drugs may facilitate the development of S-R habits because this reorganizes patterns of synaptic connectivity in the dorsal striatum in a way that increases control over behavior by the dorsolateral striatum.     

Electrophysiological evidence of mediolateral functional dichotomy in the rat accumbens during cocaine self‐administration: tonic firing patterns

Given the increasing research emphasis on putative accumbal functional compartmentation, we sought to determine whether neurons that demonstrate changes in tonic firing rate during cocaine self‐administration are differentially distributed across subregions of the NAcc. Rats were implanted with jugular catheters and microwire arrays targeting NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell and rostral pole shell). Recordings were obtained after acquisition of stable cocaine self‐administration (0.77 mg/kg/0.2mL infusion; fixed‐ratio 1 schedule of reinforcement; 6‐h daily sessions). During the self‐administration phase of the experiment, neurons demonstrated either: (i) tonic suppression (or decrease); (ii) tonic activation (or increase); or (iii) no tonic change in firing rate with respect to rates of firing during pre‐ and post‐drug phases. Consistent with earlier observations, tonic decrease was the predominant firing pattern observed. Differences in the prevalence of tonic increase firing were observed between the core and the dorsal shell and dorsal shell–core border regions, with the latter two areas exhibiting a virtual absence of tonic increases. Tonic suppression was exhibited to a greater extent by the dorsal shell–core border region relative to the core. These differences could reflect distinct subregional afferent processing and/or differential sensitivity of subpopulations of NAcc neurons to cocaine. Ventrolateral shell firing topographies resembled those of core neurons. Taken together, these observations are consistent with an emerging body of literature that differentiates the accumbens mediolaterally and further advances the likelihood that distinct functions are subserved by NAcc subregions in appetitive processing.     

Beyond drug‐induced alteration of glutamate homeostasis,astrocytes may contribute to dopamine‐dependent intrastriatal functional shifts that underlie the development of drug addiction: A working hypothesis

The transition from recreational drug use to compulsive drug‐seeking habits, the hallmark of addiction, has been shown to depend on a shift in the locus of control over behaviour from the ventral to the dorsolateral striatum. This process has hitherto been considered to depend on the aberrant engagement of dopamine‐dependent plasticity processes within neuronal networks. However, exposure to drugs of abuse also triggers cellular and molecular adaptations in astrocytes within the striatum which could potentially contribute to the intrastriatal transitions observed during the development of drug addiction. Pharmacological interventions aiming to restore the astrocytic mechanisms responsible for maintaining homeostatic glutamate concentrations in the nucleus accumbens, that are altered by chronic exposure to addictive drugs, abolish the propensity to relapse in both preclinical and, to a lesser extent, clinical studies. Exposure to drugs of abuse also alters the function of astrocytes in the dorsolateral striatum, wherein dopaminergic mechanisms control drug‐seeking habits, associated compulsivity and relapse. This suggests that drug‐induced alterations in the glutamatergic homeostasis maintained by astrocytes throughout the entire striatum may interact with dopaminergic mechanisms to promote aberrant plasticity processes that contribute to the maintenance of maladaptive drug‐seeking habits. Capitalising on growing evidence that astrocytes play a fundamental regulatory role in glutamate and dopamine transmission in the striatum, we present an innovative model of a quadripartite synaptic microenvironment within which astrocytes channel functional interactions between the dopaminergic and glutamatergic systems that may represent the primary striatal functional unit that undergoes drug‐induced adaptations eventually leading to addiction.     

Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine‐induced addictive behavior

The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine‐induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter‐delivered cocaine exposure, ex vivo whole‐cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular‐ but not burst‐type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole‐sensitive persistent sodium currents, but not changes in Ca²⁺‐activated BK, SK or voltage‐dependent A‐type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine‐induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine‐induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine‐induced addictive behaviors.     

Differential roles of ventral pallidum subregions during cocaine self‐administration behaviors

The ventral pallidum (VP) is necessary for drug‐seeking behavior. VP contains ventromedial (VPvm) and dorsolateral (VPdl) subregions, which receive projections from the nucleus accumbens shell and core, respectively. To date no study has investigated the behavioral functions of the VPdl and VPvm subregions. To address this issue, we investigated whether changes in firing rate (FR) differed between VP subregions during four events: approaching toward, responding on, or retreating away from a cocaine‐reinforced operandum and a cocaine‐associated cue. Baseline FR and waveform characteristics did not differ between subregions. VPdl neurons exhibited a greater change in FR compared with VPvm neurons during approaches toward, as well as responses on, the cocaine‐reinforced operandum. VPdl neurons were more likely to exhibit a similar change in FR (direction and magnitude) during approach and response than VPvm neurons. In contrast, VPvm firing patterns were heterogeneous, changing FRs during approach or response alone, or both. VP neurons did not discriminate cued behaviors from uncued behaviors. No differences were found between subregions during the retreat, and no VP neurons exhibited patterned changes in FR in response to the cocaine‐associated cue. The stronger, sustained FR changes of VPdl neurons during approach and response may implicate VPdl in the processing of drug‐seeking and drug‐taking behavior via projections to subthalamic nucleus and substantia nigra pars reticulata. In contrast, the heterogeneous firing patterns of VPvm neurons may implicate VPvm in facilitating mesocortical structures with information related to the sequence of behaviors predicting cocaine self‐infusions via projections to mediodorsal thalamus and ventral tegmental area. J. Comp. Neurol. 521:558–588, 2013. © 2012 Wiley Periodicals, Inc.     

A novel mouse brain slice preparation of the hippocampo-accumbens pathway

The nucleus accumbens (NAc) is an important component of circuitry that underlies reward related behaviors and the rewarding properties of drugs of abuse. Glutamatergic afferents to the nucleus are critical for its normal function and for behaviors related to drug addiction. An angled, sagittal mouse brain slice preparation has been designed to facilitate concurrent stimulation of two major glutamatergic afferent pathways to the nucleus accumbens. Medium spiny neurons at the medial core/shell boundary of the accumbens were depolarized by stimulation of either hippocampal or limbic cortical afferents through activation of AMPA-type glutamate receptors. High frequency but not low frequency stimulation of hippocampal afferents depolarized medium spiny neurons to a membrane potential that resembled the up state observed upon high frequency stimulation in vivo. The magnitude of the membrane depolarization was positively correlated with the amplitude of the stimulus-evoked EPSP. Concurrent stimulation of hippocampal and limbic cortical afferents at theta frequency selectively induced a long-term depression (LTD) in the magnitude of stimulus-evoked EPSPs on the hippocampal afferent only. These data suggest that this brain slice preparation can be used to study mechanisms underlying synaptic plasticity at two of the critical glutamatergic afferent synapses in the nucleus accumbens as well as characterizing potential interactions between afferents. Additionally, LTD at hippocampo-accumbens synapses can be induced at a stimulus frequency known to support reinstatement of drug seeking behavior.     

Mechanism of the medium‐duration afterhyperpolarization in rat serotonergic neurons

Most serotonergic neurons display a prominent medium‐duration afterhyperpolarization (mAHP), which is mediated by small‐conductance Ca²⁺‐activated K⁺ (SK) channels. Recent ex vivo and in vivo experiments have suggested that SK channel blockade increases the firing rate and/or bursting in these neurons. The purpose of this study was therefore to characterize the source of Ca²⁺ which activates the mAHP channels in serotonergic neurons. In voltage‐clamp experiments, an outward current was recorded at ?60 mV after a depolarizing pulse to +100 mV. A supramaximal concentration of the SK channel blockers apamin or (‐)‐bicuculline methiodide blocked this outward current. This current was also sensitive to the broad Ca²⁺ channel blocker Co²⁺ and was partially blocked by both ω‐conotoxin and mibefradil, which are blockers of N‐type and T‐type Ca²⁺ channels, respectively. Neither blockers of other voltage‐gated Ca²⁺ channels nor DBHQ, an inhibitor of Ca²⁺‐induced Ca²⁺ release, had any effect on the SK current. In current‐clamp experiments, mAHPs following action potentials were only blocked by ω‐conotoxin and were unaffected by mibefradil. This was observed in slices from both juvenile and adult rats. Finally, when these neurons were induced to fire in an in vivo‐like pacemaker rate, only ω‐conotoxin was able to increase their firing rate (by ~30%), an effect identical to the one previously reported for apamin. Our results demonstrate that N‐type Ca²⁺ channels are the only source of Ca²⁺ which activates the SK channels underlying the mAHP. T‐type Ca²⁺ channels may also activate SK channels under different circumstances.     

Resting‐state functional connectivity of the human hypothalamus

The hypothalamus is of enormous importance for multiple bodily functions such as energy homeostasis. Especially, rodent studies have greatly contributed to our understanding how specific hypothalamic subregions integrate peripheral and central signals into the brain to control food intake. In humans, however, the neural circuitry of the hypothalamus, with its different subregions, has not been delineated. Hence, the aim of this study was to map the hypothalamus network using resting‐state functional connectivity (FC) analyses from the medial hypothalamus (MH) and lateral hypothalamus (LH) in healthy normal‐weight adults (n = 49). Furthermore, in a separate sample, we examined differences within the LH and MH networks between healthy normal‐weight (n = 25) versus overweight/obese adults (n = 23). FC patterns from the LH and MH revealed significant connections to the striatum, thalamus, brainstem, orbitofrontal cortex, middle and posterior cingulum and temporal brain regions. However, our analysis revealed subtler distinctions within hypothalamic subregions. The LH was functionally stronger connected to the dorsal striatum, anterior cingulum, and frontal operculum, while the MH showed stronger functional connections to the nucleus accumbens and medial orbitofrontal cortex. Furthermore, overweight/obese participants revealed heightened FC in the orbitofrontal cortex and nucleus accumbens within the MH network. Our results indicate that the MH and LH network are tapped into different parts of the dopaminergic circuitry of the brain, potentially modulating food reward based on the functional connections to the ventral and dorsal striatum, respectively. In obese adults, FC changes were observed in the MH network. Hum Brain Mapp 35:6088–6096, 2014. © 2014 Wiley Periodicals, Inc.     

A potent transient outward current regulates excitability of dorsal raphe neurons

Activity of neurons in the dorsal raphe nucleus of the rat was recorded intracellularly in a brainstem slice. The neurons had a high input resistance, a linear I-V curve in the hyperpolarizing direction and a long membrane time constant. Broad action potentials were followed by a large afterhyperpolarization (AHP). This AHP removes partial inactivation of a potent transient outward rectifier that is activated by a subsequent depolarization of the neuron; it clamps the cell membrane at a potential slightly below firing level and blocks generation of action potentials for up to 100 ms. The transient rectification was sensitive to 4-aminopyridine (4-AP) but not to tetraethylammonium (TEA). It appears to share similar properties with those of IA seen elsewhere and to function in the regulation of interspike intervals of dorsal raphe (DR) neurons in vitro.     

Synaptic Plasticity in an In Vitro Slice Preparation of the Rat Nucleus Accumbens

Extra- and intracellular recordings in slices were used to examine what types of synaptic plasticity can be found in the core of the nucleus accumbens, and how these forms of plasticity may be modulated by dopamine. Stimulus electrodes were placed at the rostral border of the nucleus accumbens in order to excite primarily infralimbic and prelimbic afferents, as was confirmed by injections of the retrograde tracer fluoro-gold. In extracellular recordings, tetanization induced long-term potentiation (LTP) of the population spike in 20 out of 53 slices. The presynaptic compound action potential did not change following LTP induction. For the intracellularly recorded excitatory postsynaptic potential, three types of synaptic plasticity were noted: long-term potentiation (16 out of 54 cells), decremental potentiation (eight cells) and long-term depression (LTD; six cells). No correlation was found between the occurrence of potentiation or depression and various parameters of the tetanic depolarization (e.g. peak voltage, integral under the curve). The N -methyl- d -aspartate receptor antagonist d (–)-2-amino-5-phosphonopentanoic acid (50 μM; d -AP5) reduced, but did not completely prevent, the induction of LTP. The incidence of LTD was not markedly affected by d -AP5. No difference in LTP was found when comparing slices bathed in dopamine (10 μM) and controls. Likewise, slices treated with a mixture of the D1 receptor antagonist Sch 23390 (1 μM) and the D2 antagonist S (–)-sulpiride (1 μM) generated a similar amount of LTP as controls. In conclusion, both LTP and LTD can be induced in a key structure of the limbic-innervated basal ganglia. LTP in the nucleus accumbens strongly depends on N -methyl- d -aspartate receptor activity, but is not significantly affected by dopamine.     

Functional properties of dopamine neurons and co‐expression of vasoactive intestinal polypeptide in the dorsal raphe nucleus and ventro‐lateral periaqueductal grey

The dorsal raphe nucleus (DRN) and ventrolateral periaqueductal grey (vlPAG) regions contain populations of dopamine neurons, often considered to be a dorsal caudal extension of the A10 group [mostly found in the ventral tegmental area (VTA)]. Recent studies suggest they are involved in promoting wakefulness and mediate some of the antinociceptive and rewarding properties of opiates. However, little is known about their electrophysiological properties. To address this, we used Pitx3‐GFP and tyrosine hydroxylase (TH)‐GFP mice to carry out targeted whole‐cell recordings from this population in acute brain slices. We found that DRN/vlPAG dopamine neurons have characteristics similar to most VTA dopamine neurons, but distinct from dorsal raphe serotonin neurons. They fire broad action potentials at a relatively slow, regular rate, exhibit a hyperpolarization‐activated inward current and delayed repolarization, and show spike‐frequency adaptation in response to prolonged depolarization. In addition, they receive fast excitatory and inhibitory synaptic inputs. Moreover, we found co‐expression of vasoactive intestinal polypeptide in small, periaqueductal dopamine neurons, but generally not in larger, more ventral dopamine neurons.