Effects of orbitofrontal cortex lesions on cocaine self-administration

Previous research has implicated limbic and prefrontal cortical areas in the control of drug-seeking behavior. The present study examined the effects of orbitofrontal-cortex (OFC) lesions on acquisition, dose-dependence, within-session patterning, and reinstatement of cocaine self-administration. Rats received OFC or sham lesions before or after acquisition (0.3 mg/kg/injection, paired with a visual stimulus), then were tested with a range of doses (0, 0.03, 0.1, 0.3 and 1). Compared to controls, rats lesioned before acquisition acquired the behavior sooner, responded more at low doses, and responded more on the first day of extinction. Rats that were lesioned after acquisition showed an even larger increase in responding (∼250%) at the lowest dose, and they also showed increased timeout responding and drug “loading” at low doses. Pre-acquisition lesions were tested and found to have no effect on cocaine-induced reinstatement. In parallel experiments examining effects of pre-acquisition OFC lesions on food-reinforced responding, lesions did not alter acquisition, maintenance, or reinstatement, but accelerated the course of extinction. The increased cocaine self-administration seen in OFC-lesioned rats did not resemble the dysregulated drug intake observed in long-access models of addiction but might be due to impaired response inhibition or impaired tracking of the reward value of drug-related cues.     

Long-term gender behavioral vulnerability after nociceptive neonatal formalin stimulation in rats

d-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine recognition site on the N-methyl-d-aspartate (NMDA) receptor complex, has been shown to facilitate the extinction and prevent the relapse of cocaine-induced conditioned place preference (CPP) when administered before or after each extinction trail. However, some studies have suggested that DCS does not influence or even enhance relapse of seeking behavior on cocaine self-administration (SA) in rats or cocaine-dependent individuals undergoing clinical exposure treatment. Furthermore, there are no reports on the effects of DCS and the extinction of morphine-conditioned behaviors in mice. The present study investigated the effects of DCS on extinction by exposing mice to drug-paired cues and the subsequent reinstatement of morphine-primed CPP. Our results showed that DCS at doses of 7.5, 15, and 30 mg/kg did not induce conditioned appetitive or aversive effects and DCS combined with morphine conditioning failed to affect the acquisition of morphine-induced CPP. Moreover, pretreatment with DCS (7.5, 15, and 30 mg/kg, i.p.) prior to extinction training had no significant effects on the extinction and subsequent morphine-primed reinstatement of morphine-induced CPP. These results suggested that DCS may not be a powerful adjunct for cue exposure therapy of opioid addiction. In view of differing outcomes in both preclinical and clinical studies, the potential of DCS in exposure treatment of drug-seeking behaviors should be carefully evaluated.     

D-serine treatment reduces cocaine-primed reinstatement in rats following extended access to cocaine self-administration

The most intractable feature of drug addiction is the high rate of relapse, even following extended periods of abstinence from drug-taking. Evidence suggests that allowing rats extended access to cocaine self-administration leads to behavioral characteristics in these animals that are consistent with the development of addiction in humans. In the current study, rats were allowed to self-administer cocaine over a total of 22 daily sessions, the final seven of which were long-access (LgA) sessions of 6 h duration. Assessments of reinstatement of drug-seeking behavior were made following reintroduction to the drug-taking environment and noncontingent priming with either conditioned stimulus (CS) or cocaine in both extinguished and abstinent subject groups. Three separate groups of rats were treated with either saline or d-serine (100 mg/kg i.p.) administered 2 h prior to, or immediately following, each extinction training session. Saline-treated LgA rats were resistant to the effects of extinction training to reduce noncontingent priming of reinstatement of drug-seeking behavior with either CS or cocaine. In contrast, treatment with d-serine either before or immediately following the sessions resulted in a significant enhancement in the ability of extinction training to reduce cocaine-primed reinstatement of drug-seeking behavior. These results suggest that d-serine can act to enhance the consolidation of extinction learning in LgA rats, and is therefore a promising adjunctive agent along with behavioral therapy for the treatment of cocaine addiction.     

Manipulation of dopamine d1-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior

These studies examined the ability of the dopamine D1-like agonist SKF 81297 and D1-like antagonist SCH 23390 in the medial prefrontal cortex to alter the reinstatement of cocaine-induced conditioned place preference behavior. Male Sprague-Dawley rats were fitted with bilateral cannulae over the medial prefrontal cortex and subsequently trained in a conditioned place preference task. Animals were trained in this task using four pairings of cocaine (12 mg/kg, i.p.). Conditioned place preference was demonstrated in all animals, and this behavior was then extinguished over a 5-10-day period before testing for reinstatement. Just prior to reinstatement by immobilization stress or a cocaine priming injection (5 mg/kg, i.p.), a microinjection of the D1-like receptor antagonist SCH 23390 (0.01, 0.1 or 1.0 microg/side), or the D1-like receptor agonist SKF 81297 (0.1, 0.3 or 1.0 microg/side) was given into the medial prefrontal cortex. SCH 23390 blocked both stress- and cocaine-induced reinstatement of conditioned place preference after the two higher doses were administered into the medial prefrontal cortex. The highest dose of SKF 81297 (1.0 microg/side) prevented immobilization stress- but not cocaine-induced reinstatement. The highest dose of these drugs given in the absence of stress or cocaine did not produce reinstatement. The results indicate that immobilization stress given within the place-preference chamber is capable of producing reinstatement of cocaine-seeking behavior. The microinjection studies suggest that D1-like receptor antagonism within the prefrontal cortex is sufficient to block reinstatement by stress and cocaine. Furthermore, the results from D1-like receptor activation in the medial prefrontal cortex point to utilization of different neural pathways for stress- and cocaine-induced reinstatement.     

Cocaine-taking and cocaine-seeking behaviors in rats remain stable after systemic administration of GYKI 52466: a non-competitive AMPA receptor antagonist

Given the posited role of enhanced AMPA-mediated synaptic transmission in relapse to drug seeking, we investigated whether systemic administration of the AMPA receptor antagonist GYKI 52466 inhibits cocaine-taking and cocaine-seeking behavior in rats. Rats were trained to self-administer cocaine until stable self-administration was achieved. Effects of GYKI 52466 (1, 3, or 10 mg/kg, i.v.) on cocaine self-administration were assessed. Animals were allowed to re-establish stable cocaine self-administration and were then behaviorally extinguished from drug taking. The effects of GYKI 52466 (3, 10 mg/kg, i.v.) on cocaine-induced reinstatement of drug-seeking behavior were assessed. We found that GYKI 52466 failed to inhibit cocaine-taking and cocaine-seeking in both the self-administration and reinstatement paradigms. We suggest that although AMPA receptors may be involved in cocaine reward and addiction, the AMPA receptor antagonist GYKI 52466 has low therapeutic potential for cocaine addiction treatment.     

18-Methoxycoronaridine blocks acquisition but enhances reinstatement of a cocaine place preference

The iboga alkaloid congener, 18-methoxycoronaridine (18-MC), decreases self-administration of multiple drugs of abuse. Here, in a biased procedure, we investigated whether 18-MC would have a similar effect on the acquisition, expression and reinstatement of a cocaine conditioned place preference (CPP) in male Sprague-Dawley rats. While 18-MC attenuated acquisition of a cocaine CPP, it had no effect on CPP expression, and enhanced the reinstatement of cocaine CPP following extinction. Our results are consistent with those obtained using ibogaine, but reinforce the notion that acquisition, expression and reinstatement of a CPP likely involve separate mechanisms.     

Muscarinic receptor antagonism in the basolateral amygdala blocks acquisition of cocaine-stimulus association in a model of relapse to cocaine-seeking behavior in rats

Recent evidence has demonstrated a critical role for the basolateral amygdala complex in the reinstatement of extinguished drug-seeking behavior produced by drug-paired cues. In the current study, we utilized a model of the acquisition and expression of cocaine-stimulus associative pairing in order to study the role of cholinergic input to the basolateral amygdala in mediating conditioned-cued reinstatement. Male, Sprague-Dawley rats were first trained daily to self-administer i.v. cocaine on a fixed ratio 1 schedule of reinforcement. The muscarinic acetylcholine receptor antagonist, scopolamine, was directly infused into the basolateral amygdala prior to: a) classically conditioned pairing of a tone+light stimulus with cocaine infusions (acquisition), or b) testing of conditioned-cued reinstatement following a period of withdrawal from cocaine and extinction of cocaine-paired lever responding. Infusion of scopolamine just prior to the classical conditioning trial produced a dose-dependent disruption of cocaine-seeking behavior maintained by cocaine-paired cues during the reinstatement test. In contrast, infusion of scopolamine prior to the reinstatement test had no effect on conditioned-cued reinstatement of cocaine-seeking behavior.These results indicate a crucial role for cholinergic innervation of muscarinic acetylcholine receptors in the basolateral amygdala during the formation, but not the expression, of stimulus-reward associations that mediate cue-induced cocaine-seeking behavior.     

Involvement of brain catalase activity in the acquisition of ethanol-induced conditioned place preference

It has been suggested that some of the behavioral effects produced by ethanol are mediated by its first metabolite, acetaldehyde. The present research addressed the hypothesis that catalase-dependent metabolism of ethanol to acetaldehyde in the brain is an important step in the production of ethanol-related affective properties. Firstly, we investigated the contribution of brain catalase in the acquisition of ethanol-induced conditioned place preference (CPP). Secondly, the specificity of the catalase inhibitor 3-amino-1,2,4-triazole (AT) was evaluated with morphine- and cocaine-induced CPP. Finally, to investigate the role of catalase in the process of relapse to ethanol seeking caused by re-exposure to ethanol, after an initial conditioning and extinction, mice were primed with saline and ethanol or AT and ethanol and tested for reinstatement of CPP. Conditioned place preference was blocked in animals treated with AT and ethanol. Morphine and cocaine CPP were unaffected by AT treatment. However, the reinstatement of place preference was not modified by catalase inhibition. Taken together, the results of the present study indicate that the brain catalase-H(2)O(2) system contributes to the acquisition of affective-dependent learning induced by ethanol, and support the involvement of centrally-formed acetaldehyde in the formation of positive affective memories produced by ethanol.     

Prefrontal cortex lesions differentially disrupt cocaine-reinforced conditioned place preference but not conditioned taste aversion

The reinforcing efficacy of cocaine is thought to involve, at least in part, mesocortical dopaminergic (DA) neurons. Rats will self-administer cocaine applied directly into the medial prefrontal cortex but not into nucleus accumbens or the ventral tegmental area (Goeders & Smith, 1983). The present experiments were conducted to assess whether lesions of prefrontal cortex (mesocortical DA target regions) attenuate the reinforcing properties of systemically administered cocaine. Male Sprague-Dawley rats were anesthetized, and one of three subfields (medial, orbital, or precentral) of the prefrontal cortex was removed by aspiration or no brain injury was done (sham operates). In four experiments the rats were tested on conditioned place preference (CPP), conditioned taste aversion (saccharin conditioned stimulus, cocaine unconditioned stimulus), general activity in the running wheel and open field, and food-reinforced spatial alternation in the T-maze. Sham operates demonstrated a cocaine-induced place preference, rats with medial frontal lesions showed a cocaine-induced place aversion, and other operates showed neither a conditioned place preference nor an aversion. The results of this experiment suggest that lesions of the DA projection fields of the prefrontal cortex in the rat reduce the positive reinforcing properties of systemically injected cocaine. In the second experiment, all subjects showed a conditioned taste aversion of equal magnitude. This suggests that whereas the positive reinforcing properties were affected differentially by prefrontal cortex lesions, the aversive properties were not affected. In Experiment 3 there were no lesion-induced differences in activity in either the running wheel or the open field. Therefore, changes in motor activity cannot account for the CPP data. In the final experiment, the medial frontal operates were impaired relative to the precentral and sham operates on learning to alternate choices in the T-maze, but the orbital frontal operates' performance was not different from that of any other group. This suggests that a general disruption of all reinforcement mechanisms did not occur following these lesions. Instead, these results indicate that mesocortical DA projection regions are involved with mediating the reinforcing properties of cocaine and that there is a separate system mediating the aversive properties of cocaine.     

The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse

Reinstatement of extinguished drug-seeking has been utilized in the study of the neural substrates of relapse to drugs of abuse, particularly cocaine. However, limited studies have examined the circuitry that drives the reinstatement of heroin-seeking behavior in the presence of conditioned cues, or by heroin itself. In order to test the hypothesis that the circuitry underlying reinstatement in heroin-experienced animals would show overlapping, yet distinct differences from cocaine-experienced animals, we used transient inhibition of several cortical, striatal, and limbic brain regions during reinstatement of heroin-seeking produced by heroin-paired cues, or by a single priming dose of heroin. Rats lever pressed for i.v. heroin discretely paired with a conditioned stimulus (CS) during daily 3-h sessions for a period of 2 weeks, followed by daily extinction of lever responding. Subsequent reinstatement of heroin-seeking was measured as lever responding in the absence of heroin reinforcement. The first set of reinstatement tests involved response-contingent CS presentations following bilateral intracranial infusion of either a combination of GABA receptor agonists (baclofen-muscimol, B/M) or vehicle (saline) into one of 13 different brain regions. The second set of reinstatement tests involved a single heroin injection (0.25 mg/kg, s.c.) following either B/M or vehicle infusions. Our results showed that vehicle-infused animals reinstated to both CS presentations and a priming injection of heroin, while B/M inactivation of several areas known to be important for the reinstatement of cocaine-seeking also attenuated heroin-seeking in response to CS presentations and/or a priming dose of heroin. However, as predicted, inactivation of areas previously shown to not affect cocaine-seeking significantly attenuated heroin-seeking, supporting the hypothesis that the circuitry underlying the reinstatement of heroin-seeking is more diffusely distributed than that for cocaine.     

Influence of ethanol withdrawal on fear memory: Effect of D-cycloserine

Animals made dependent via an ethanol (ETOH) -containing liquid diet (6% v/v) for 14 days were subjected to a contextual fear conditioning paradigm 3 days after the last consumption day. After conditioning, rats were subjected to four extinction trials by exposing the animals to the conditioned context and their freezing was evaluated for each trial. Immediately after the first extinction trial, animals were injected with D-cycloserine (DCS) 5 mg/kg i.p., a dose that did not influence the extinction in control rats. Spontaneous recovery of learned fear was tested seven days after the last extinction trial. The following day, animals were subjected to a reacquisition or a reinstatement procedure and their freezing responses evaluated 24 h later. The present study shows that: 1. discontinuation from chronic ETOH administration facilitated the formation of a new fear memory concomitant with a marked resistance to being extinguished, 2. administration of DCS (5 mg/kg) facilitated the extinction process only in ETOH withdrawn rats, 3. both reinstatement and reacquisition procedures restored the increased freezing in ETOH withdrawn animals after extinction, 4. DCS administered immediately after the first extinction trial prevented the increase in freezing following both reacquisition and reinstatement. The enhanced sensitivity to the facilitatory effect of DCS in ETOH withdrawn animals may be mediated by adaptive changes in N-methyl-D-aspartate (NMDA) receptor provoked by ETOH dependence.     

Optogenetic inhibition of cortical afferents in the nucleus accumbens simultaneously prevents cue-induced transient synaptic potentiation and cocaine-seeking behavior

Animal models of relapse reveal that the motivation to seek drug is regulated by enduring morphological and physiological changes in the nucleus accumbens, as well as transient synaptic potentiation in the accumbens core (NAcore) that parallels drug-seeking behavior. The current study sought to examine the link between the behavioral and synaptic consequences of cue-induced cocaine seeking by optically silencing glutamatergic afferents to the NAcore from the prelimbic cortex (PL). Adeno-associated virus coding for the inhibitory opsin archaerhodopsin was microinjected into PL, and optical fibers were targeted to NAcore. Animals were trained to self-administer cocaine followed by extinction training, and then underwent cue-induced reinstatement in the presence or absence of 15 min of optically induced inhibition of PL fibers in NAcore. Inhibiting the PL-to-NAcore projection blocked reinstated behavior and was paralleled by decreased dendritic spine head diameter and AMPA/NMDA ratio relative to sham-laser control rats. Interestingly, while spine density was elevated after extinction training, no further effects were observed by cued reinstatement or optical inhibition. These findings validate the critical role for PL afferents to the NAcore in simultaneously regulating both reinstated behavior and the associated transient synaptic potentiation.     

Obesity-resistant S5B rats showed greater cocaine conditioned place preference than the obesity-prone OM rats

Background

Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and conditioned responses to food and drug rewards. Osborne-Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, we then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains.

Methods

OM and S5B/P rats were conditioned with cocaine (5 or 10 mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20 mg/kg) on cocaine preference were then assessed in subsequent test sessions.

Results

OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5 mg/kg cocaine and in OM rats treated with 10 mg/kg cocaine.

Conclusion

Our results indicated that obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.     

The extinction of morphine-induced conditioned place preference by histone deacetylase inhibition

Recent evidence suggests that epigenetic mechanisms have an important role in the development of addictive behavior. However, little is known about the role of epigenetic mechanisms in the extinction of morphine-induced behavioral changes. In this study, we will examine the effect of histone deacetylase (HDAC) inhibitors on extinction of morphine-induced conditioned place preference (CPP). To facilitate extinction, rats will be administered an HDAC inhibitor (HDACi) following nonreinforced exposure to the conditioned context. To measure persistence, rats were subject to a reinstatement test using 3 mg/kg dose of morphine. To exclude the effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session, rats received injection of either NaBut or vehicle for 8 days. We found that HDAC inhibition during nonconfined extinction or confined extinction consolidation can facilitate extinction of morphine-induced CPP. We also showed that the extinction of drug seeking via HDAC inhibition modulates extinction learning such that reinstatement behavior is significantly attenuated. There is no effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session. In conclusion, our results extend earlier reports on the ability of HDACi to modify the behavioral effects of drugs of abuse. Our increasing understanding of these epigenetic mechanisms will provide key answers to basic processes in drug addiction and hopefully provide insight into designing improved treatments for drug addiction.     

Social and physical environment alter cocaine conditioned place preference and dopaminergic markers in adolescent male rats

This study was done to determine whether social and environmental factors alter cocaine reward and proteins implicated in mediating drug reward in rats during early adolescence. On postnatal day (PND) 23, rats were housed under conditions where both social (number of rats per cage) and environmental (availability of toys) factors were manipulated. Socially isolated rats were housed alone impoverished with no toys (II) or enriched with toys (IE). Social rats were housed two rats/cage with no toys (SI2) or with toys (SE2), or three/cage with (SE3) or without (SI3) toys. On PND 43, cocaine conditioned place preference (CPP) sessions began with the post-test done on PND 47. Cocaine CPP was established in response to 5 or 10 mg/kg cocaine in II rats, and CPP was decreased with the addition of cage mates or toys. No CPP was seen to any dose in SI3 or SE3 rats. Enriched housing (SE3) increased dopamine transporter (DAT) protein in the nucleus accumbens compared to II. There also were differential effects of cocaine on tyrosine hydroxylase and DAT depending on housing, with both increased by cocaine in II but not SE3 rats. DARPP-32 was unchanged by housing or cocaine, while phospho-Thr³⁴-DARPP-32 was increased by cocaine treatment across conditions. Thus, both social and environmental enrichment decrease cocaine CPP during adolescence and different housing alters proteins that regulate dopaminergic neurotransmission in a manner that may account for the observed differences in cocaine-induced reward.     

Dopamine D1 or D2 receptor antagonism within the basolateral amygdala differentially alters the acquisition of cocaine-cue associations necessary for cue-induced reinstatement of cocaine-seeking

The basolateral amygdala complex has been implicated in the formation and utilization of cocaine-cue associations in rat models of cue-induced reinstatement to cocaine-seeking behavior. We have previously demonstrated the importance of dopamine inputs to the basolateral amygdala complex in the reinstatement of cocaine-seeking behavior following chronic cocaine self-administration. Here we show that selective blockade of amygdalar dopamine D1 and D2 receptors during acquisition of cocaine-cue associations has distinctive effects on subsequent conditioned-cued cocaine-seeking behavior. Male, Sprague-Dawley rats were first trained to self-administer i.v. cocaine on a fixed ratio 1 schedule for 5 days. Subjects then received bilateral, intra-basolateral amygdala complex infusions of a dopamine D1 receptor antagonist (SCH23390, 0.25-2.0 microg/side; experiment 1), a dopamine D2 receptor antagonist (raclopride, 0.625-5.0 microg/side; experiment 2), or vehicle just prior to a single classical conditioning session, during which a light+tone cue was discretely paired with passive infusions of cocaine in the absence of lever responding. Following five additional days of cocaine self-administration and 7-10 days of extinction training, animals underwent multiple tests for cue-induced reinstatement. SCH23390 (2.0 microg/side), administered at the time of cocaine-cue association only, produced an attenuation of reinstatement to cue-induced cocaine-seeking behavior. In contrast, low doses of raclopride potentiated, while a higher dose of raclopride attenuated cue-induced reinstatement. These results demonstrate unique contributions of D1 vs. D2 receptors in mediating dopamine inputs within the basolateral amygdala complex during the formation of cocaine-stimulus associations that are critical for cue-induced reinstatement.     

Postnatal manganese exposure alters dopamine transporter function in adult rats: Potential impact on nonassociative and associative processes

In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 microg/day) on postnatal days (PD) 1-21. On PD 90, dopamine transporter (DAT) immunoreactivity and [3H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaine-induced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [3H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mn-induced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior.     

Neuroadaptations in the cellular and postsynaptic group 1 metabotropic glutamate receptor mGluR5 and Homer proteins following extinction of cocaine self-administration

This study examined the role of group1 metabotropic glutamate receptor mGluR5 and associated postsynaptic scaffolding protein Homer1b/c in behavioral plasticity after three withdrawal treatments from cocaine self-administration. Rats self-administered cocaine or saline for 14 days followed by a withdrawal period during which rats underwent extinction training, remained in their home cages, or were placed in the self-administration chambers in the absence of extinction. Subsequently, the tissue level and distribution of proteins in the synaptosomal fraction associated with the postsynaptic density were examined. Cocaine self-administration followed by home cage exposure reduced the mGluR5 protein in nucleus accumbens (NA) shell and dorsolateral striatum. While extinction training reduced mGluR5 protein in NAshell, NAcore and dorsolateral striatum did not display any change. The scaffolding protein PSD95 increased in NAcore of the extinguished animals. Extinction of drug seeking was associated with a significant decrease in the synaptosomal mGluR5 protein in NAshell and an increase in dorsolateral striatum, while that of NAcore was not modified. Interestingly, both Homer1b/c and PSD95 scaffolding proteins were decreased in the synaptosomal fraction after extinction training in NAshell but not NAcore. Extinguished drug-seeking behavior was also associated with an increase in the synaptosomal actin proteins in dorsolateral striatum. Therefore, extinction of cocaine seeking is associated with neuroadaptations in mGluR5 expression and distribution that are region-specific and consist of extinction-induced reversal of cocaine-induced adaptations as well as emergent extinction-induced alterations. Concurrent plasticity in the scaffolding proteins further suggests that mGluR5 receptor neuroadaptations may have implications for synaptic function.     

Early adolescents show enhanced acute cocaine-induced locomotor activity in comparison to late adolescent and adult rats

Initiation of drug use during adolescence is associated with an increased probability to develop a drug addiction. The present study examined dose-response effects of cocaine (0, 5, 10, or 20 mg/kg, i.p.) on locomotor activity in early adolescent (postnatal day (PND) 35), late adolescent (PND 45), and young adults (PND 60) by measuring total distance moved (TDM) and frequency of start-stops. In response to 20 mg/kg cocaine, early adolescents showed the greatest cocaine-induced increase in TDM in comparison to late adolescent and adult rats. At this same dose, early adolescents showed the greatest cocaine-induced attenuation of start-stops relative to older rats. Results suggest that early adolescents engage in more cocaine-induced locomotor activity and less stationary behavior indicating that early adolescents are more sensitive to locomotor activating effects of high dose cocaine than older rats.     

Phase preference for the display of activity is associated with the phase of extra-suprachiasmatic nucleus oscillators within and between species

Many features of the suprachiasmatic nucleus (SCN) are the same in diurnal and nocturnal animals, suggesting that differences in phase preference are determined by mechanisms downstream from the SCN. Here, we examined this hypothesis by characterizing rhythmic expression of Period 1 (PER1) and Period 2 (PER2) in several extra-SCN areas in the brains of a diurnal murid rodent, Arvicanthis niloticus (grass rats). In the shell of the nucleus accumbens, dorsal striatum, piriform cortex, and CA1 of the hippocampus, both PER1 and PER2 were rhythmic, with peak expression occurring at ZT10. PER1 in the dentate gyrus also peaked at ZT10, but PER2 was arrhythmic in this region. In general, these patterns are 180° out of phase with those reported for nocturnal species. In a second study, we examined inter-individual differences in the multioscillator system of grass rats. Here, we housed grass rats in cages with running wheels, under which conditions some individuals spontaneously adopt a day active (DA) and others a night active (NA) phase preference. In the majority of the extra-SCN regions sampled, the patterns of PER1 and PER2 expression of NA grass rats resembled those of nocturnal species, while those of DA grass rats were similar to the ones seen in grass without access to running wheels. In contrast, the rhythmic expression of both PER proteins was identical in the SCN and ventral subparaventricular zone (vSPZ) of DA and NA animals. Differences in the phase of oscillators downstream from the SCN, and perhaps the vSPZ, appear to determine the phase preference of particular species, as well as that of members of a diurnal species that show voluntary phase reversals. The latter observation has important implications for the understanding of health problems associated with human shift work.