Cocaine self‐administration disrupts mesolimbic dopamine circuit function and attenuates dopaminergic responsiveness to cocaine

Dopaminergic projections from the ventral midbrain to the nucleus accumbens (NAc) have long been implicated in encoding associations between reward availability and environmental stimuli. As such, this circuit is instrumental in guiding behaviors towards obtaining maximal rewards based on previous experience. Cocaine acts on the dopamine system to exert its reinforcing effects and it is thought that cocaine‐induced dysregulation of dopamine neurotransmission contributes to the difficulty that cocaine addicts exhibit in selecting environmentally appropriate behaviors. Here we used cocaine self‐administration combined with in vivo fast scan cyclic voltammetry in anesthetised rats to examine the function of the ventral tegmental area to NAc projection neurons. Over 5 days of cocaine self‐administration (fixed‐ratio 1; 1.5 mg/kg/injection; 40 injections/day), animals increased their rate of intake. Following cocaine self‐administration, there was a marked reduction in ventral tegmental area‐stimulated NAc dopamine release. Additionally, there was a decreased augmentation of stimulated dopamine overflow in response to a cocaine challenge. These findings demonstrate that cocaine induces a hypodopaminergic state, which may contribute to the inflexible drug‐taking and drug‐seeking behaviors observed in cocaine abusers. Additionally, tolerance to the ability of cocaine to elevate dopamine may lead to increased cocaine intake in order to overcome decreased effects, another hallmark of cocaine abuse.     

Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat

The lateral habenula (LHb) is an epithalamic structure differentiated in a medial (LHbM) and a lateral division (LHbL). Together with the rostromedial tegmental nucleus (RMTg), the LHb has been implicated in the processing of aversive stimuli and inhibitory control of monoamine nuclei. The inhibitory LHb influence on midbrain dopamine neurons has been shown to be mainly mediated by the RMTg, a mostly GABAergic nucleus that receives a dominant input from the LHbL. Interestingly, the RMTg also projects to the dorsal raphe nucleus (DR), which also receives direct LHb projections. To compare the organization and transmitter phenotype of LHb projections to the DR, direct and indirect via the RMTg, we first placed injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the LHb or the RMTg. We then confirmed our findings by retrograde tracing and investigated a possible GABAergic phenotype of DR‐projecting RMTg neurons by combining retrograde tracing with in situ hybridization for GAD67. We found only moderate direct LHb projections to the DR, which mainly emerged from the LHbM and were predominantly directed to the serotonin‐rich caudal DR. In contrast, RMTg projections to the DR were more robust, emerged from RMTg neurons enriched in GAD67 mRNA, and were focally directed to a distinctive DR subdivision immunohistochemically characterized as poor in serotonin and enriched in presumptive glutamatergic neurons. Thus, besides its well‐acknowledged role as a GABAergic control center for the ventral tegmental area (VTA)–nigra complex, our findings indicate that the RMTg is also a major GABAergic relay between the LHb and the DR. J. Comp. Neurol. 522:1454–1484, 2014. © 2013 Wiley Periodicals, Inc.     

Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat

The mesopontine rostromedial tegmental nucleus (RMTg) is a mostly γ-aminobutyric acid (GABA)ergic structure believed to be a node for signaling aversive events to dopamine (DA) neurons in the ventral tegmental area (VTA). The RMTg receives glutamatergic inputs from the lateral habenula (LHb) and sends substantial GABAergic projections to the VTA, which also receives direct projections from the LHb. To further specify the topography of LHb projections to the RMTg and VTA, small focal injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin were aimed at different subdivisions of the LHb. The subnuclear origin of LHb inputs to the VTA and RMTg was then confirmed by injections of the retrograde tracer cholera toxin subunit b into the VTA or RMTg. Furthermore, we compared the topographic position of retrogradely labeled neurons in the RMTg resulting from VTA injections with that of anterogradely labeled axons emerging from the LHb. As revealed by anterograde and retrograde tracing, LHb projections were organized in a strikingly topographic manner, with inputs to the RMTg mostly arising from the lateral division of the LHb (LHbL), whereas inputs to the VTA mainly emerged from the medial division of the LHb (LHbM). In the RMTg, profusely branched LHb axons were found in close register with VTA projecting neurons and were frequently apposed to the latter. Overall, our findings demonstrate that LHb inputs to the RMTg and VTA arise from different divisions of the LHb and provide direct evidence for a disynaptic pathway that links the LHbL to the VTA via the RMTg.     

Anterior and posterior parts of the rat ventral tegmental area and the rostromedial tegmental nucleus receive topographically distinct afferents from the lateral habenular complex

That activation of the reward system involves increased activity of dopaminergic (DA) neurons in the ventral tegmental area (VTA) is widely accepted. In contrast, the lateral habenular complex (LHb), which is known as the center of the anti‐reward system, directly and indirectly inhibits DA neurons in the VTA. The VTA, however, is not a homogenous entity. Instead, it displays major functional differences between its anterior (aVTA) and posterior (pVTA) regions. It is not precisely known, whether habenular input to the aVTA, pVTA, and the newly recognized rostromedial tegmental nucleus (RMTg) are similarly or differently organized. Consequently, the present investigation addressed the connections between LHb and aVTA, pVTA, and RMTg using retrograde and anterograde tracing techniques in the rat. Our experiments disclosed strictly reciprocal and conspicuously focal interconnections between LHbM (LHbMPc/LHbMC) and PN, as well as between RLi and LHbLO. In addition, we found that LHb inputs to the aVTA are dorsoventrally ordered. Dorsal parts of the aVTA receive afferents from LHbL and LHbM, whereas ventral parts of the aVTA are preferentially targeted by the LHbM. LHb afferents to the pVTA are distinct from those to the RMTg, given that the RMTg is primarily innervated from the LHbL, whereas pVTA receives afferents from LHbM and LHbL. These data indicate the existence of two separate pathways from the LHb to the VTA, a direct and an indirect one, which may subserve distinct biological functions.     

Withdrawal from extended‐access cocaine self‐administration results in dysregulated functional activity and altered locomotor activity in rats

Much work has focused on determining the consequences of cocaine self‐administration on specific neurotransmitter systems, thus neglecting the global changes that occur. Previous imaging studies have focused on the effects of cocaine self‐administration in the presence of high blood levels of cocaine, but have not determined the functional effects of cocaine self‐administration after cocaine has cleared. Extended‐access cocaine self‐administration, where animals administer cocaine for 6 h each day, results in escalation in the rate of cocaine intake and is believed to model the transition from recreational use to addiction in humans. We aimed to determine the functional changes following acute (48 h) withdrawal from an extended‐access, defined‐intake self‐administration paradigm (5 days, 40 injections/day, 6 h/day), a time point when behavioral changes are present. Using the 2‐[¹⁴C]deoxyglucose method to measure rates of local cerebral glucose metabolism, an indicator of functional activity, we found reductions in circuits related to learning and memory, attention, sleep, and reward processing, which have important clinical implications for cocaine addiction. Additionally, lower levels of functional activity were found in the dorsal raphe and locus coeruleus, suggesting that cocaine self‐administration may have broader effects on brain function than previously noted. These widespread neurochemical reductions were concomitant with substantial behavioral differences in these animals, highlighted by increased vertical activity and decreased stereotypy. These data demonstrate that behavioral and neurochemical impairments following cocaine self‐administration are present in the absence of drug and persist after cocaine has been cleared.     

Differential projections from subfields in the lateral preoptic area to the lateral habenular complex of the rat

The lateral habenular complex (LHb) constitutes an important link in the dorsal diencephalic conduction system conveying information from limbic forebrain structures to regulatory midbrain nuclei. In line with the considerable number of biological functions in which the habenula is thought to be involved, a complex subnuclear organization of the LHb has been suggested. However, the precise connectivity of habenular subnuclei remains to be identified. We hypothesize that axons from the lateral preoptic area (LPOA) project to distinct subnuclei of the LHb. As a result of an unexpected heterogeneity within the LPOA, we first examined its subregional morphology. Based on the analysis of several coronal series of sections, seven subfields were identified within the LPOA. Retrograde tracing experiments revealed that neurons projecting to the LHb were concentrated in the dorsal, ventral, and ventromedial subfields of the rostral LPOA and in the caudal LPOA. Anterograde tracing experiments confirmed that all LPOA subfields containing retrogradely labelled cells project to the LHb. Neurons in rostral subfields of the LPOA target predominantly the lateral area of the LHb, whereas caudal LPOA fibers innervate the medial LHb. Afferent labelling is most prominent within the magnocellular subnucleus in the LHbM, and only few fibers can be observed in the parvocellular subnucleus of the LHbM. The superior subnucleus of the LHbM and the oval subnucleus of the LHbL do not receive any fibers from the LPOA at all. This is the first comprehensive study so far to show that projections from LPOA subfields individually target subnuclei in the lateral habenular complex.     

Cocaine withdrawal reduces GABABR transmission at entopeduncular nucleus – lateral habenula synapses

Lateral habenula (LHb) hyperactivity plays a pivotal role in the emergence of negative emotional states, including those occurring during withdrawal from addictive drugs. We have previously implicated cocaine‐driven adaptations at synapses from the entopeduncular nucleus (EPN) to the LHb in this process. Specifically, ionotropic GABA_A receptor (R)‐mediated neurotransmission at EPN‐to‐LHb synapses is reduced during cocaine withdrawal, due to impaired vesicle filling. Recent studies have shown that metabotropic GABA_BR signaling also controls LHb activity, although its role at EPN‐to‐LHb synapses during drug withdrawal is unknown. Here, we predicted that cocaine treatment would reduce GABA_BR‐mediated neurotransmission at EPN‐to‐LHb synapses. We chronically treated mice with saline or cocaine, prepared brain slices after two days of withdrawal and performed voltage‐clamp recordings from LHb neurons whilst optogenetically stimulating EPN terminals. Compared with controls, mice in cocaine withdrawal exhibited reduced GABA_AR‐mediated input to LHb neurons, and a reduced occurrence of GABA_BR‐signaling at EPN‐to‐LHb synapses. We then assessed the underlying mechanism of this decrease. Application of GABA_BR agonist baclofen evoked similar postsynaptic responses in EPN‐innervated LHb neurons in saline‐ and cocaine‐treated mice. Release probability at EPN‐to‐LHb GABAergic synapses was also comparable between groups. However, incubating brain slices in glutamine to facilitate GABA vesicle filling, normalized GABA_BR‐currents at EPN‐to‐LHb synapses in cocaine‐treated mice. Overall, we show that during cocaine withdrawal, together with reduced GABA_AR transmission, also GABA_BR‐mediated inhibitory signaling is diminished at EPN‐to‐LHb synapses, likely via the same presynaptic deficit. In concert, these alterations are predicted to contribute to the emergence of drug withdrawal symptoms, facilitating drug relapse.     

Paradoxical tolerance to cocaine after initial supersensitivity in drug‐use‐prone animals

There is great interest in outlining biological factors and behavioral characteristics that either predispose or predict vulnerability to substance use disorders. Response to an inescapable novel environment has been shown to predict a “drug‐use‐prone” phenotype that is defined by rapid acquisition of cocaine self‐administration. Here, we showed that response to novelty can also predict the neurochemical and behavioral effects of acute and repeated cocaine in rats. We used cocaine self‐administration under a fixed‐ratio 1 schedule followed by fast‐scan cyclic voltammetry in brain slices to measure subsecond dopamine (DA) release and uptake parameters in drug‐use‐prone and ‐resistant phenotypes. Despite no significant differences in stimulated release and uptake, animals with high responses to a novel environment had DA transporters that were more sensitive to cocaine‐induced uptake inhibition, which corresponded to greater locomotor activating effects of cocaine. These animals also acquired cocaine self‐administration more rapidly and, after 5 days of extended access cocaine self‐administration, high‐responding animals showed robust tolerance to DA uptake inhibition by cocaine. The effects of cocaine remained unchanged in animals with low novelty responses. Similarly, the rate of acquisition was negatively correlated with DA uptake inhibition by cocaine after self‐administration. Thus, we showed that tolerance to the cocaine‐induced inhibition of DA uptake coexists with a behavioral phenotype that is defined by increased preoccupation with cocaine as measured by rapid acquisition and early high intake.     

Modulation of striatal dopamine dynamics by cocaine self‐administration and amphetamine treatment in female rats

Despite decades of research into the neurobiological basis of cocaine abuse, pharmacotherapeutic treatments for cocaine addiction have been largely ineffective. Converging evidence from preclinical research and from outpatient clinical trials suggest that treatment with amphetamine is efficacious in reducing cocaine intake. Although it has been suggested that amphetamine treatment reduces cocaine intake as an agonist replacement therapy, we have shown recently that multiple aspects of dopamine signaling are altered by cocaine self‐administration and returned to pre‐cocaine function by amphetamine treatment in the nucleus accumbens of male rats. Here, we sought to determine if these effects were also evident in female subjects, and across regions of the striatum. Female rats performed 5 days of cocaine self‐administration (1.5 mg kg^?1 inj^?1, 40 inj/day) and were treated with a single amphetamine (0.56 mg/kg) or saline infusion 1 hr prior to killing. We then used ex vivo fast‐scan cyclic voltammetry in the nucleus accumbens core or dorsolateral caudate‐putamen to examine dopamine signaling and cocaine potency. We found that in the nucleus accumbens core, cocaine self‐administration decreased dopamine uptake rate and cocaine potency, and both alterations were restored by amphetamine treatment. In the dorsolateral caudate‐putamen, neither cocaine self‐administration nor amphetamine treatment altered dopamine uptake; however, cocaine potency was decreased by self‐administration and returned to control levels by amphetamine. Together, these findings support a role for amphetamine treatment for cocaine addiction outside of agonist replacement therapy, and suggest that the development of cocaine tolerance is similar across sexes.     

Fluorescent Visualisation of the Hypothalamic Oxytocin Neurones Activated by Cholecystokinin‐8 in Rats Expressing c‐fos‐Enhanced Green Fluorescent Protein and Oxytocin‐Monomeric Red Fluorescent Protein 1 Fusion Transgenes

The up‐regulation of c‐fos gene expression is widely used as a marker of neuronal activation elicited by various stimuli. Anatomically precise observation of c‐fos gene products can be achieved at the RNA level by in situ hybridisation or at the protein level by immunocytochemistry. Both of these methods are time and labour intensive. We have developed a novel transgenic rat system that enables the trivial visualisation of c‐fos expression using an enhanced green fluorescent protein (eGFP) tag. These rats express a transgene consisting of c‐fos gene regulatory sequences that drive the expression of a c‐fos‐eGFP fusion protein. In c‐fos‐eGFP transgenic rats, robust nuclear eGFP fluorescence was observed in osmosensitive brain regions 90 min after i.p. administration of hypertonic saline. Nuclear eGFP fluorescence was also observed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) 90 min after i.p. administration of cholecystokinin (CCK)‐8, which selectively activates oxytocin (OXT)‐secreting neurones in the hypothalamus. In double transgenic rats that express c‐fos‐eGFP and an OXT‐monomeric red fluorescent protein 1 (mRFP1) fusion gene, almost all mRFP1‐positive neurones in the SON and PVN expressed nuclear eGFP fluorescence 90 min after i.p. administration of CCK‐8. It is possible that not only a plane image, but also three‐dimensional reconstruction image may identify cytoplasmic vesicles in an activated neurone at the same time.     

High‐frequency stimulation of the subthalamic nucleus modulates neuronal activity in the lateral habenula nucleus

High‐frequency stimulation (HFS) of the subthalamic nucleus (STN) is often used to treat movement disability in advanced Parkinson's disease, but some patients experience debilitating psychiatric effects including depression. Interestingly, HFS of the STN modulates 5‐HT neurons in the dorsal raphe nucleus (DRN) which are linked to depression, but the neural substrate of this effect is unknown. Here, we tested the effect of STN stimulation on neuronal activity in the lateral habenula nucleus (LHb), an important source of input to DRN 5‐HT neurons and also a key controller of emotive behaviours. LHb neurons were monitored in anaesthetized rats using single‐unit extracellular recording, and localization within the LHb was confirmed by juxtacellular labelling. HFS of the STN (130 Hz) evoked rapid changes in the firing rate of the majority of LHb neurons tested (38 of 68). Some LHb neurons (19/68) were activated by HFS, while others (19/68), distinguished by a higher basal firing rate, were inhibited. LHb neurons that project to the DRN were identified using antidromic activation and collision testing (n = 17 neurons). Some of these neurons (5/17) were also excited by HFS of the STN, and others (7/17) were inhibited although this was only a statistical trend. In summary, HFS of the STN modulated the firing of LHb neurons, including those projecting to the DRN. The data identify that the STN impacts on the LHb‐DRN pathway. Moreover, this pathway may be part of the circuitry mediating the psychiatric effects of STN stimulation experienced by patients with Parkinson's disease.     

Neonatal maternal separation opposes the facilitatory effect of castration on the respiratory response to hypercapnia of the adult male rat: Evidence for the involvement of the medial amygdala

Respiratory manifestations of panic disorder (PD) include a greater respiratory instability and enhanced responsiveness to CO₂ compared to normal individuals. Although the prevalence of PD is approximately three times greater in women compared to men, the origins of this sexual dimorphism remain poorly understood. Similar to PD patients, adult female rats previously subjected to neonatal maternal separation (NMS) show an increase in their ventilatory response to CO₂. Because this effect of NMS is not observed in males, we hypothesised that testosterone prevents NMS‐induced hyper‐responsiveness to CO₂. Pups subjected to NMS were placed in an incubator for 3 h d^‐1 from postnatal days 3‐12. Control pups remained undisturbed. At adulthood (8‐10 weeks of age), rats were then subjected either to sham surgery or castration. Fourteen days later, breathing was measured at rest (room air) and during acute exposure to hypercapnia (5 and 10% CO₂ for 10 minutes each) using plethysmography. To gain insight into the mechanisms involved, c‐fos expression was used as an indicator of neuronal activation. Brains were collected following air or CO₂ exposure for quantification of c‐fos positive cells by immunohistochemistry in selected regions, including the paraventricular nucleus of the hypothalamus, the dorsomedial hypothalamus and the amygdalar complex. Castration produced a 100% increase of hyperventilatory response to 10% CO₂ in control rats. Unexpectedly, castration had no effect on the hyperventilatory response of NMS rats. The intensity of the hypercapnic response was inversely correlated with c‐fos expression in the medial amygdala. We conclude that testosterone prevents the hyper‐responsiveness to CO₂, whereas NMS attenuates sensitivity to hormone withdrawal. We propose that an inhibitory influence from the medial amygdala contributes to this effect.     

Neurones in the Preoptic Area of the Male Goldfish are Activated by a Sex Pheromone 17α,20β‐Dihydroxy‐4‐Pregnen‐3‐One

Pheromones are interesting molecules given their ability to evoke changes in the endocrine state and behaviours of animals. In goldfish, a sex pheromone, 17α,20β‐dihydroxy‐4‐pregnen‐3‐one (17,20β‐P), which is released by preovulatory females, is known to trigger the elevation of luteinising hormone (LH) levels, as well as reproductive behaviour in males. Interestingly, when 11‐ketotestosterone (11‐KT) is implanted into adult female fish, LH levels increase in response to the pheromone at any time of the day, which is normally a male‐specific response. However, the neural mechanisms underlying the male‐specific information processing of 17,20β‐P and its androgen dependence are yet unknown. In the present study, we focused on the preoptic area (POA), which plays important roles in the regulation of reproduction and reproductive behaviours. We mapped activity in the POA evoked by 17,20β‐P exposure using the immediate‐early gene c‐fos. We found that a population of ventral POA neurones close to kisspeptin2 (kiss2) neurones that appear to have important roles in reproduction was activated by 17,20β‐P exposure, suggesting that these activated neurones are important for the 17,20β‐P response. Next, we investigated the distribution of androgen receptor (ar) in the POA and its relationship with 17,20β‐P‐responsive and kiss2 neurones. We found that ar is widely expressed in the ventral POA, whereas it is only expressed in approximately 10% of 17,20β‐P‐activated neurones. On the other hand, it is expressed in almost 90% of the kiss2 neurones. Taken together, it is possible that ar expressing neurones in the ventral POA, most of which were not labelled by c‐fos in the present study, may at least partly account for androgen effects on responses to primer pheromones; the ar‐positive kiss2 neurones in the ventral POA may be a candidate. These results offer a novel insight into the mechanisms underlying male‐specific information processing of 17,20β‐P in goldfish.     

Inhibitory effects of heterotopic noxious counter‐stimulation on perception and brain activity related to Aβ‐fibre activation

Heterotopic noxious counter‐stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non‐nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter‐balanced sessions, including non‐nociceptive (selective Aβ‐fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20‐min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0–100 scale, where 0 is no pain and 100 the worst pain imaginable). Non‐nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII‐reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non‐nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak‐to‐peak amplitude at Cz was significantly decreased by HNCS for non‐nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aβ‐fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide‐dynamic‐range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.     

Prelimbic cortex is a common brain area activated during cue‐induced reinstatement of cocaine and heroin seeking in a polydrug self‐administration rat model

Many preclinical studies examined cue‐induced relapse to heroin and cocaine seeking in animal models, but most of these studies examined only one drug at a time. In human addicts, however, polydrug use of cocaine and heroin is common. We used a polydrug self‐administration relapse model in rats to determine similarities and differences in brain areas activated during cue‐induced reinstatement of heroin and cocaine seeking. We trained rats to lever press for cocaine (1.0 mg/kg per infusion, 3‐hr/day, 18 day) or heroin (0.03 mg/kg per infusion) on alternating days (9 day for each drug); drug infusions were paired with either intermittent or continuous light cue. Next, the rats underwent extinction training followed by tests for cue‐induced reinstatement where they were exposed to either heroin‐ or cocaine‐associated cues. We observed cue‐selective reinstatement of drug seeking: the heroin cue selectively reinstated heroin seeking and the cocaine cue selectively reinstated cocaine seeking. We used Fos immunohistochemistry to assess cue‐induced neuronal activation in different subregions of the medial prefrontal cortex, dorsal striatum, nucleus accumbens, and amygdala. Fos expression results indicated that only the prelimbic cortex (PL) was activated by both heroin and cocaine cues; in contrast, no significant cue‐induced neuronal activation was observed in other brain areas. RNA in situ hybridization indicated that the proportion of glutamatergic and GABAergic markers in PL Fos‐expressing cells was similar for the heroin and cocaine cue‐activated neurons. Overall, the results indicate that PL may be a common brain area involved in both heroin and cocaine seeking during polydrug use.     

Effects of environmental enrichment on ERK1/2 phosphorylation in the rat prefrontal cortex following nicotine‐induced sensitization or nicotine self‐administration

Rats raised in an enriched condition (EC) exhibit alterations in the neurobiological and behavioral response to nicotine compared with rats reared in an impoverished condition (IC) or a standard condition (SC). The current study determined whether environmental enrichment differentially regulates extracellular signal‐regulated kinase1/2 (ERK1/2) activity in the prefrontal cortex in rats following nicotine sensitization or nicotine self‐administration. Under the saline control condition, EC rats displayed diminished baseline activity and greater sensitization to repeated administration of nicotine compared with IC and SC rats. After repeated saline injections, the basal levels of phosphorylated ERK1/2 (pERK1/2) were higher in EC compared with IC and SC rats, which was negatively correlated with their respective baseline activities. Repeated nicotine (0.35 mg/kg) injections induced pERK1/2 to similar levels in SC and IC rats; however, the induction of pERK1/2 in EC rats by nicotine was not significantly different from saline controls, owing to their high baseline. In the self‐administration paradigm, EC rats self‐administered less nicotine (0.03 mg/kg/infusion) relative to IC or SC rats on a fixed ratio‐1 schedule of reinforcement. Accordingly, no differences in pERK1/2 were found between EC and IC rats self‐administering saline, whereas nicotine self‐administration resulted in an increase in pERK1/2 in IC rats but not in EC rats. Furthermore, the levels of pERK1/2 in EC and IC rats were positively correlated with their respective total number of nicotine infusions. Thus, these findings suggest that environmental enrichment alters the basal and nicotine‐mediated pERK1/2, which may contribute to enrichment‐induced behavioral alterations in response to nicotine.     

Electrophysiological evidence of alterations to the nucleus accumbens and dorsolateral striatum during chronic cocaine self‐administration

As drug use becomes chronic, aberrant striatal processing contributes to the development of perseverative drug‐taking behaviors. Two particular portions of the striatum, the nucleus accumbens (NAc) and the dorsolateral striatum (DLS), are known to undergo neurobiological changes from acute to chronic drug use. However, little is known about the exact progression of changes in functional striatal processing as drug intake persists. We sampled single‐unit activity in the NAc and DLS throughout 24 daily sessions of chronic long‐access cocaine self‐administration, and longitudinally tracked firing rates (FR) specifically during the operant response, an upward vertical head movement. A total of 103 neurons were held longitudinally and immunohistochemically localised to either NAc Medial Shell (n = 29), NAc Core (n = 30), or DLS (n = 54). We modeled changes representative of each category as a whole. Results demonstrated that FRs of DLS Head Movement neurons were significantly increased relative to baseline during all sessions, while FRs of DLS Uncategorised neurons were significantly reduced relative to baseline during all sessions. NAc Shell neurons' FRs were also significantly decreased relative to baseline during all sessions while FRs of NAc Core neurons were reduced relative to baseline only during training days 1–18 but were not significantly reduced on the remaining sessions (19–24). The data suggest that all striatal subregions show changes in FR during the operant response relative to baseline, but longitudinal changes in response firing patterns were observed only in the NAc Core, suggesting that this region is particularly susceptible to plastic changes induced by abused drugs.     

Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self‐administration

Competitive dopamine receptor antagonists increase the rate of cocaine self‐administration. As the rate of self‐administration at a particular unit dose is determined by the satiety threshold and the elimination half‐life (t_1/2) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters in rats. The plasma cocaine concentration at the time of each self‐administration was constant during a session demonstrating that this satiety threshold concentration represents an equiactive cocaine concentration. The plasma cocaine concentration at the time of self‐administration was increased by SCH23390, consistent with pharmacological theory. In rats trained to reliably self‐administer cocaine, SCH23390 had no effect on the plasma steady‐state cocaine concentration produced by constant infusions of cocaine. Therefore, this antagonist had no effect on cocaine t_1/2 at a dose that accelerated cocaine self‐administration. A constant cocaine infusion at a rate that maintained steady state concentrations above the satiety threshold stopped self‐administration. SCH23390, or the D₂ dopamine receptor antagonist (?)eticlopride, reinstated self‐administration in the presence of the constant cocaine infusion. This is consistent with SCH23390 and eticlopride raising the satiety threshold above the steady state level produced by the constant cocaine infusion. It is concluded that the antagonist‐induced acceleration of cocaine self‐administration is the result of a pharmacokinetic/pharmacodynamic interaction whereby the rate of cocaine elimination is faster at the higher concentrations, as dictated by first‐order kinetics, so that cocaine levels decline more rapidly to the elevated satiety threshold. This results in the decreased interinjection intervals. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

Subthreshold delta‐frequency resonance in thalamic reticular neurons

The thalamic reticular nucleus (nRt) is an assembly of GABAergic projection neurons that participate in the generation of brain rhythms during synchronous sleep and absence epilepsy. NRt cells receive inhibitory and excitatory synaptic inputs, and are endowed with an intricate set of intrinsic conductances. However, little is known about how intrinsic and synaptic properties interact to generate rhythmic discharges in these neurons. In order to better understand this interaction, I studied the subthreshold responses of nRt cells to time‐varying inputs. Patch‐clamp recordings were performed in acute slices of rat thalamus (postnatal days 12–21). Sinusoidal current waveforms of linearly changing frequencies were injected into the soma, and the resulting voltage oscillations were recorded. At the resting membrane potential, the impedance profile showed a characteristic resonance at 1.7 Hz. The relative strength of the resonance was 1.2, and increased with membrane hyperpolarization. Small suprathreshold current injections led to preferred spike generation at the resonance frequency. Bath application of ZD7288 or Cs⁺, inhibitors of the hyperpolarization‐activated cation current (I_h), transformed the resonance into low‐pass behaviour, whereas the T‐channel blockers mibefradil and Ni²⁺ decreased the strength of the resonance. It is concluded that nRt cells have an I_h‐mediated intrinsic frequency preference in the subthreshold voltage range that favours action potential generation in the delta‐frequency band.