Place Aversion In Rats Research Articles

Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects.

Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated-in laboratory rats-the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.

Oral Binge-Like Ethanol Pre-Exposure During Juvenile/Adolescent Period Attenuates Ethanol-Induced Conditioned Place Aversion in Rats.

To determine if oral ethanol self-administration produces a conditioned place preference (CPP) and to determine if ethanol pre-exposure conditions during the juvenile/adolescent period alter the conditioned effects of ethanol and subsequent ethanol self-administration. Modified conditioned place preference paradigm allowed rats to orally self-administer ethanol followed by short duration exposure to conditioning chambers. Ethanol produced a conditioned place aversion even though rats self-administered ethanol following the final conditioning test. Juvenile/adolescent pre-exposure to ethanol decreased the place aversion but did not produce place preference. Juvenile/adolescent rats consumed sweetened 5% ethanol in the home-cage either during continuous access or intermittent access with water restriction that promoted binge-like consumption. A control group had water access during the 4-week period. Adult rats were conditioned using a modified CPP paradigm wherein rats were water-restricted overnight before being placed in operant chambers to respond for 5% ethanol for 7 min. Following the operant session, rats were placed in the conditioning chamber for 8 min. After the conditioning post-test, rats self-administered ethanol during daily operant sessions. Ethanol produced a conditioned place aversion in water access rats and the continuous access rats. Binge-like ethanol consumption induced by intermittent access with water restriction abolished the place aversion, but did not allow place preference to develop. After conditioning, continuous access rats self-administered ethanol above ~0.6 g/kg which was similar to rats with binge-like experience via intermittent access. Results suggest that oral ethanol self-administration elicits aversive properties in this model even though ethanol continues to maintain self-administration. Pre-exposure to ethanol during the juvenile/adolescent period may produce tolerance to ethanol's aversive properties only when consumed in a binge-like manner with water restriction. More exploration is needed to understand how behavioral history can influence sensitivity to ethanol's rewarding and aversive properties and subsequent ethanol consumption or self-administration.

Changes of protein kinase A expressions in shell of accumbens nucleus during the process of chronic morphine-induced conditioned place aversion in rats

Objective To explore neurobiological mechanisms of the withdrawal-induced aversion, the changes of protein kinase A(PKA) were measured in shell of accumbens nucleus (AcbSH) of CPA model rats. Methods 1.All 36 male SD rats were divided into three groups, model group (MN group), and control group (MS group and SN group). MN group was injected with morphine, 6.5 days, 10mg/kg, intraperitoneally (IP), twice per day, naloxone injection, 0.3 mg/kg, ip, along with conditioned place aversion training, to develop the CPA model.The MS group was administrated equivalent volume of morphine and saline.Also the SN group was injected with equivalent volume of saline and naloxone.2.During the development of CPA, the expression of protein kinase A was assayed with immunohistochemistry in the AcbSH. Results Before the development of CPA, PKA expressions were no significant differences among the three groups in the AcbSH (F=2.306, P=0.130). However, after development of CPA , PKA expressions showed significant differences among the three groups(F=36.516, P=0.000). The average gray intensity of MN group (109.50±4.661) was apparently higher than the MS group(126.50±3.697, P<0.01), than the SN group (133.50±6.364, P<0.01). Conclusions 1.Protein kinase A expression, leading to the aversion in the AcbSH probably is a key pathway contributing to the development of CPA.2.The neuroadaptation mediated by PKA may be one of important molecular underpinnings of CPA. Key words: Conditioned place aversion; Protein kinase A; Immunohistochemistry

The kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), decreases morphine withdrawal and the consequent conditioned place aversion in rats

Much data suggest that the binding of dynorphin-like peptides to kappa-opioid receptors (KORs) during the administration of and withdrawal from a variety of addictive drugs is aversive and serves to limit the reinforcing properties of those drugs and to enhance tolerance, withdrawal, and the probability of stress-induced relapse. In this study, we examined the role of KORs in mediating opioid withdrawal and its aversive consequences in rats. We found that selective blockade of KORs by i.p. administration of 20mg/kg nor-binaltorphimine (nor-BNI) 5h prior to naltrexone-precipitated withdrawal in morphine-dependent rats decreased feces excreted during a 30-min withdrawal session. More critically, this injection of nor-BNI decreased the subsequent conditioned place aversion (CPA) for the withdrawal chamber 2 days later. The subsequent finding that administration of nor-BNI 2h following withdrawal did not affect the CPA 2 days later suggested that nor-BNI reduced the CPA in the prior experiment because it reduced the aversive effects of withdrawal, not because it reduced the aversive/anxiogenic effects of the withdrawal chamber at the time of CPA testing. These data indicate that the binding of dynorphin-like peptides to KORs during opioid withdrawal serves to enhance withdrawal and its aversive consequences and suggest that selective KOR antagonists may be useful in reducing these aversive effects and consequent relapse.

Involvement of KOP-r in cocaine withdrawal-induced conditioned place aversion in rats

Devices) cell lines stably expressing either theOX1orOX2 receptor. Select compounds were assessed in a conditioned place preference assay. Results: A number of compounds showed low nanomolar potency at the OX1 receptor and excellent selectivity (>100-fold) over the OX2 receptor. Several structural features that are important for OX1 activity have been identified. For instance, as the size of substituents increases at the 7-position of the tetrahydroisoquinoline the OX1 potency also increases. When tested in vivo, a compound with good in vitro potency and OX1 selectivity alone did not have place conditioning effect but blocked the acquisition of conditioned place preference to methamphetamine in rats. Conclusions: Structure–activity relationship studies have resulted in several compounds that are potent and OX1 selective. One such compound showed promising effect against the rewarding effects of methamphetamine. These results will facilitate the development of potent and selective OX1 antagonists as medications for the treatment of drug addiction. Financial support: NIH grants DA032837 and DA026582.

Effects of inactivating the agranular or granular insular cortex on the acquisition of the morphine-induced conditioned place preference and naloxone-precipitated conditioned place aversion in rats

Recent studies have indicated that the insula underlies affective learning. Although affective learning is well-established in the development of opiate addiction, the role of insula in this context remains unclear. To elucidate the organization of opiate-related affective learning within the insular cortex, we reversibly inactivated each of two major subdivisions of the insula in rats and tested the effects of this inactivation on the acquisition of morphine-induced conditioned place preference (CPP) and conditioned place aversion (CPA) induced by naloxone-precipitated acute morphine withdrawal. Results showed that inactivation of the primary interoceptive posterior granular insula (GI), but not that of the high-order anterior agranular insula (AI), disrupted the acquisition of CPP and that both GI and AI inactivation impaired the acquisition of CPA. These data suggest that the insular cortex is involved in positive and negative affective learning related to opiate addiction. In particular, the GI appears to be critical for both forms of affective learning, whereas the AI is crucial for learning associated with negative affects induced by opiate withdrawal.

Effects of Exogenous Cholecystokinin Octapeptide on Acquisition of Naloxone Precipitated Withdrawal Induced Conditioned Place Aversion in Rats

Cholecystokinin octapeptide (CCK-8), a gut-brain peptide, regulates a variety of physiological behavioral processes. Previously, we reported that exogenous CCK-8 attenuated morphine-induced conditioned place preference, but the possible effects of CCK-8 on aversively motivated drug seeking remained unclear. To investigate the effects of endogenous and exogenous CCK on negative components of morphine withdrawal, we evaluated the effects of CCK receptor antagonists and CCK-8 on the naloxone-precipitated withdrawal-induced conditioned place aversion (CPA). The results showed that CCK2 receptor antagonist (LY-288,513, 10 µg, i.c.v.), but not CCK1 receptor antagonist (L-364,718, 10 µg, i.c.v.), inhibited the acquisition of CPA when given prior to naloxone (0.3 mg/kg) administration in morphine-dependent rats. Similarly, CCK-8 (0.1–1 µg, i.c.v.) significantly attenuated naloxone-precipitated withdrawal-induced CPA, and this inhibitory function was blocked by co-injection with L-364,718. Microinjection of L-364,718, LY-288,513 or CCK-8 to saline pretreated rats produced neither a conditioned preference nor aversion, and the induction of CPA by CCK-8 itself after morphine pretreatments was not significant. Our study identifies a different role of CCK1 and CCK2 receptors in negative affective components of morphine abstinence and an inhibitory effect of exogenous CCK-8 on naloxone-precipitated withdrawal-induced CPA via CCK1 receptor.

Effects of calcium channel antagonists on the motivational effects of nicotine and morphine in conditioned place aversion paradigm

The motivational component of drug withdrawal may contribute to drug seeking and relapse through the negative reinforcement-related process; thus, it is important to understand the mechanisms that mediate affective withdrawal behaviors. The present study was undertaken to examine the calcium-dependent mechanism of negative motivational symptoms of nicotine and morphine withdrawal using the conditioned place aversion (CPA) paradigm. Rats were chronically treated with nicotine (1.168 mg/kg, free base, s.c., 11 days, three times daily) or morphine (10 mg/kg, s.c., 11 days, twice daily). Then, during conditioning, rats pre-treated with nicotine or morphine received a nicotinic receptor antagonist mecamylamine (3.5 mg/kg) or an opioid receptor antagonist naloxone (1 mg/kg) to precipitate withdrawal in their initially preferred compartment, or saline in their non-preferred compartment. Our results demonstrated that after three conditioning sessions, mecamylamine induced a clear place aversion in rats that had previously received nicotine injections, and naloxone induced a significant place aversion in rats that had previously received morphine injections. Further, the major findings showed that calcium channel antagonists, i.e., nimodipine, verapamil and flunarizine (5 and 10 mg/kg, i.p.), injected before the administration of mecamylamine or naloxone, attenuated nicotine or morphine place aversion. As an outcome, these findings support the hypothesis that similar calcium-dependent mechanisms are involved in aversive motivational component associated with nicotine a morphine withdrawal. We can suggest that calcium channel blockers have potential for alleviating nicotine and morphine addiction by selectively decreasing the incentive motivational properties of both drugs, and may be beneficial as smoking cessation or opioid dependence pharmacotherapies.

Contribution of limbic norepinephrine to cannabinoid-induced aversion

The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.

Roles of corticosterone in formalin-induced conditioned place aversion in rats

Glucocorticoid hormones have been shown to contribute to many cognitive functions, such as depressions, learning and memory, and abnormal glucocorticoid secretion results in functional changes in prefrontal cortex and amygdala. In the present study, we used the conditioned place aversion (CPA) paradigm to investigate the role of corticosterone (CORT) in the negative affective component of chemical somatic pain induced by intraplantar injection of formalin into male adult Long–Evan rats. Five percent of formalin produced acute biphasic nociceptive behaviors, including flinching and licking of hindpaw, and CPA. Intraplantar formalin induced CPA was abolished by bilateral adrenalectomy and the impairment of CPA can be restored by the CORT treatment. However, the adrenalectomy failed to affect the formalin-produced acute nociceptive behaviors. Therefore, data from the present study suggest that CORT secretion by the adrenal cortex may play a role in chemical somatic noxious stimuli-induced avoidance learning and aversive memory, but not sensory discrimination of noxious stimulation.

Forward conditioning with wheel running causes place aversion in rats

Backward pairings of a distinctive chamber as a conditioned stimulus and wheel running as an unconditioned stimulus (i.e., running-then-chamber) can produce a conditioned place preference in rats. The present study explored whether a forward conditioning procedure with these stimuli (i.e., chamber-then-running) would yield place preference or aversion. Confinement of a rat in one of two distinctive chambers was followed by a 20- or 60-min running opportunity, but confinement in the other was not. After four repetitions of this treatment (i.e., differential conditioning), a choice preference test was given in which the rat had free access to both chambers. This choice test showed that the rats given 60-min running opportunities spent less time in the running-paired chamber than in the unpaired chamber. Namely, a 60-min running opportunity after confinement in a distinctive chamber caused conditioned aversion to that chamber after four paired trials. This result was discussed with regard to the opponent-process theory of motivation.

ORIGINAL INVESTIGATIONS ON CPP: Development, extinction and reinstatement of morphine withdrawal‐induced conditioned place aversion in rats

The motivational component of drug withdrawal may contribute to drug seeking and relapse through the negative reinforcement-based process. Here, we used conditioned place aversion (CPA) induced by naloxone-precipitated morphine withdrawal to measure the aversive effects. Using an unbiased conditioning paradigm, we treated rats with morphine hydrochloride [(10 mg/kg intraperitoneally (i.p.)] twice per day (at 08:00 and 20:00) for 6.5 days (from day 1 to day 7 morning), while gave them naloxone (0.3 mg/kg i.p.) on day 6, a precipitated withdrawal paired with a compartment that caused CPA to the side. Then, the rats exhibited CPA were received 12 extinction trials from days 7 to 13, by daily exposed to the two compartments for free exploration. On day 13, the rats with extinguished CPA were treated with a priming injection of morphine (10 mg/kg i.p.) followed by naloxone (0.3 mg/kg i.p.) that reliably reinstated CPA. These results demonstrated that repeatedly morphine-treated rats showed the formation, extinction and reinstatement of CPA. The present CPA model induced by these procedures may be useful for studying the biological mechanisms underlying the aversive motivational component of opiate withdrawal.

Corticosterone fails to produce conditioned place preference or conditioned place aversion in rats

Rationale In some rats, the hormone corticosterone is reinforcing. High novelty-seeking rats (high responders, HR) self-administered corticosterone at a much higher rate than low novelty-seeking rats (low responders, LR) do [Piazza PV, Deroche V, Deminiere JM, Maccari S, Le Moal M, Simon H, Corticosterone in the range of stress-induced levels possesses reinforcing properties: implications for sensation-seeking behaviors, Proc Natl Acad Sci USA 1993;90:11738–42]. While previous studies demonstrated that corticosterone reinforces nose poking in a self-administration paradigm, no studies to date have examined whether corticosterone is rewarding. Objective Using the conditioned place preference (CPP) paradigm, we examined the rewarding effects of corticosterone in HR and LR rats. Methods Male Sprague–Dawley rats were classified into HR and LR groups based on their locomotor activity in a novel environment. Subsequently, independent groups of HR and LR rats underwent CPP for corticosterone (0, 2.5 or 10 mg/kg; i.p.) or cocaine (12 mg/kg; i.p). CPP for cocaine was used as a positive control. Results While cocaine produced a strong CPP in both HR and LR rats, corticosterone failed to produce either preference or aversion in both phenotypes. Conclusion Corticosterone is neither rewarding nor aversive in either behavioral phenotype.

Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats.

Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague-Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone. Animals were subjected to three pairings of a low dose of naloxone (15 microg/kg, s.c.) to one arm of a three-chambered place conditioning apparatus. Buprenorphine administered prior to each pairing dose-dependently blocked the place aversion produced by precipitated opiate withdrawal. A corticotropin-releasing factor-1 (CRF1) receptor antagonist (antalarmin) also reversed the place aversion produced by precipitated opiate withdrawal. Antalarmin did not produce a place preference or place aversion by itself in morphine-dependent rats. No effect was observed with pretreatment of the dopamine partial agonist terguride or the selective serotonin reuptake inhibitor fluoxetine. Also, chronic pretreatment with acamprosate (a glutamate receptor modulator used to prevent relapse in alcohol dependence) did not alter naloxone-induced place aversion. Buprenorphine by itself in dependent rats produced a mild place preference at low doses and a mild place aversion at higher doses. These results suggest that buprenorphine blocks the aversive stimulus effects of precipitated opiate withdrawal in rats and provides some validity for the use of place conditioning as a measure that is sensitive to potential opiate-dependence medications. In addition, these results suggest that CRF1 antagonists can block the aversive stimulus effects of opiate withdrawal and may be potential therapeutic targets for opiate dependence.

Modulation of κ-opioidergic systems on mecamylamine-precipitated nicotine-withdrawal aversion in rats

The present study was designed to examine the modulation of the κ-opioidergic system on mecamylamine-precipitated nicotine-withdrawal aversion. The nicotinic receptor antagonist mecamylamine, which is known to pass the blood–brain barrier, produced a place aversion in rats chronically treated with nicotine using an osmotic mini-pump. This effect was significantly attenuated by pretreatment with κ-opioid receptor agonists U50,488H (1.0 mg/kg, s.c.) and TRK-820 (0.03 mg/kg, s.c.). The attenuation of mecamylamine-precipitated nicotine-withdrawal aversion by U50,488H was completely reversed by the combination with a selective κ-opioid receptor antagonist nor-binaltorphimine (10.0 mg/kg, i.p.). These results suggest that the activation of endogenous κ-opioidergic systems can suppress the mecamylamine-precipitated nicotine-withdrawal aversion.

Involvement of Glutamate Receptors Within the Central Nucleus of the Amygdala in Naloxone-Precipitated Morphine Withdrawal-Induced Conditioned Place Aversion in Rats

Chronic use of morphine leads to physical and psychological dependence. The amygdala is known to be involved in the expression of emotion such as anxiety and fear, and several studies have shown that the central nucleus of the amygdala (CeA) is involved in morphine dependence. In the present study, we investigated the role of glutamate receptors within the CeA in the negative affective component of morphine abstinence by evaluating naloxone-precipitated withdrawal-induced conditioned place aversion (CPA) in morphine-dependent rats. We found that microinjection of the AMPA/kainate-glutamate-receptor antagonist CNQX (30 nmol/side) into the bilateral CeA significantly attenuated the naloxone-precipitated withdrawal-induced CPA, as well as several somatic signs, in morphine-dependent rats, without preference or aversive effects by itself in non-dependent rats. Furthermore, microinjection of the non-competitive NMDA-receptor antagonist MK-801 (30 nmol/side) or competitive NMDA-receptor antagonist D-CPPene (0.01 and 0.1 nmol/side) into the CeA significantly attenuated the naloxone-precipitated morphine withdrawal-induced CPA, but not somatic withdrawal signs. These results suggest that the activation of AMPA /kainate and NMDA receptors within the CeA play a crucial role in the negative affective component of morphine abstinence.

Involvement of the serotonergic neuronal system in phencyclidine-induced place aversion in rats

The possible involvement of the serotonergic neuronal system in aversive motivation produced by phencyclidine [1-(1-phenylcyclohexyl)piperidine; PCP] was investigated using a place-conditioning paradigm in rats. PCP (4 mg/kg, i.p.) produced place aversion in this task as reported previously (Kitaichi K, Noda Y, Hasegawa T, Furukawa H, Nabeshima T. Acute phencyclidine induces aversion, but repeated phencyclidine induces preference in the place conditioning test in rats. Eur J Pharmacol 1996;318:7–9). The blockade of serotonin 2A (5-HT 2A) receptors using the antagonist ritanserin (3 and 10 mg/kg, p.o.) significantly attenuated this aversive property of PCP whereas lesions of serotonergic neurons using 5,7-dihydroxytryptamine (5,7-DHT, 100 μg/animal, i.c.v.) failed to affect it. Repeated PCP treatment (10 mg/kg, i.p. for 14 days), which is enough to diminish the stereotyped 5-HT 2A receptor-mediated head-twitch behavior, also decreased the place aversion. These results suggest that the serotonergic neuronal system, specifically the 5-HT 2A receptor, may play a critical role in producing PCP-induced place aversion.

Ethanol-Induced Conditioned Place Aversion in Rats: Effect of Interstimulus Interval

The purpose of this study was to examine the effect of interstimulus interval (ISI) on ethanol-induced place aversion in rats. Six groups of rats initially received four pairings of a distinctive floor stimulus (CS+) with ethanol (1 g/kg, IP) and four pairings of a different floor stimulus (CS−) with saline. Groups −30, −15, −10, −5, 0, and 5 were injected 30, 15, 10, 5, or 0 min before, or 5 min after exposure to the 5 min CS, respectively. After testing for place aversion, all groups were exposed to an additional set of conditioning trials using a higher dose of ethanol (1.5 g/kg). During the first test, only groups 0 and −15 exhibited conditioned place aversion. However, during the second test, all groups showed conditioned aversion except group −30. The results suggest that ethanol’s aversive effects dissipate by 30 min postinjection or that it is more difficult to associate those effects with short-duration external stimuli at long backward intervals. In contrast to recent findings with mice, the direction of ethanol-induced place conditioning was not altered in rats exposed to different ISIs.

5,7-Dihydroxytryptamine lesion does not affect ethanol-induced conditioned taste and place aversion in rats

The effect of the lesion of central serotonergic neurons by 5,7-dihydroxytryptamine (5,7-DHT), on ethanol-induced taste and place aversion conditioning was studied in male Wistar rats. Control biochemical analysis revealed that 5,7-DHT (250 μg per rat, free base, ICV) produced marked and selective depletion of serotonin (5-HT) in the hippocampal formation and the limbic forebrain complex. Ethanol-induced (1.5 g/kg, IP) conditioned taste aversion (CTA) to saccharin solution was unaffected by the lesion of central serotonergic neurons. The 5,7-DHT-lesioned and sham-lesioned rats showed comparable ethanol-induced CTA even 30 days after the last ethanol injection. Similarly, ethanol-induced (1.5 g/kg, IP) conditioned place aversion (CPA) was unaffected by 5,7-DHT administration. These results suggest that central serotonergic pathways are not primarily involved in the aversive effects of high ethanol doses in rats.

P1-226 - Decrease of intensity in phencyclidine-induced place aversion in rats treated with subacute phencyclidine

P1-226 - Decrease of intensity in phencyclidine-induced place aversion in rats treated with subacute phencyclidine