Brain Stimulation Reward Thresholds Research Articles

Central leptin signaling transmits positive valence

Hunger resulting from food deprivation is associated with negative affect. This is supported by recent evidence showing that hunger-sensitive neurons drive feeding through a negative valence teaching signal. However, the complementary hypothesis that hormonal signals of energy surfeit counteract this negative valence, or even transmit positive valence, has received less attention. The adipose-derived hormone leptin signals in proportion to fat mass, is an indicator of energy surplus, and reduces food intake. Here, we showed that centrally-delivered leptin reduced food intake and conditioned a place preference in food-restricted as well as ad libitum fed rats. In contrast, leptin did not reduce food intake nor condition a place preference in obese rats, likely due to leptin resistance. Despite a well-known role for hindbrain leptin receptor signaling in energy balance control, hindbrain leptin delivery did not condition a place preference in food-restricted rats, suggesting that leptin acting in midbrain or forebrain sites mediates place preference conditioning. Supporting the hypothesis that leptin signaling induces a positive affective state, leptin also decreased the threshold for ventral tegmental area brain stimulation reward. Together, these data suggest that leptin signaling is intrinsically preferred, and support the view that signals of energy surfeit are associated with positive affect. Harnessing the positive valence of signals such as leptin may attenuate the negative affect associated with hunger, providing a compelling new approach for weight loss maintenance.

Orexin A role in mechanisms of reinforcement in the bed nucleus of stria terminalis

The orexin family of hypothalamic neuropeptides has been implicated in reinforcement mechanisms relevant to both food and drug reward. Previous behavioral studies with antagonists at the orexin A-selective receptor OX(1), have demonstrated its involvement in behavioral sensitization, conditioned place-preference, self-administration and reinstatement of drugs abuse. There are dense concentrations of hypocretin receptors, in brain regions implicated in drug reinforcement processes, such as the nucleus accumbens, ventral tegmental area and bed nucleus of the stria terminalis Adult male Wistar rats were implanted the stimulating electrodes to the lateral hypothalamus. Simultaneously, the microcanules were implanted into the BNST to inject the OX(1) receptor antagonist. Rats were trained to perform intracranial self-stimulation. The effects of the OX(1)-selective antagonist SB-408124 on brain stimulation-reward (BSR) were measured. SB-408124 injected into the BNST (1µg/1 µl in volume for each injection.) alone had no effect on self-stimulation of lateral hypothalamus. Amphetamine (1 mg/kg i.p.) potentiated BSR, measured as lowering of BSR threshold and enhancing of BSR frequency. Amphetamine-induced stimulatory effects on intracranial self-stimulation was blocked by injections of SB-408124 into BNST. These data demonstrate that OX(1) play an important role in regulating the reinforcing and reward-enhancing properties of amphetamine and suggest that orexin transmission is likely essential for establishing and maintaining the amphetamine habit in human addicts. However, the observations that OX1 antagonism reduce brain reward and block stress- and cue-induced reinstatement of drug-seeking suggests that this class of compounds may be useful additions to stress-reduction and other behavioral therapies in the treatment of substance abuse disorders.

A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice

BackgroundIt has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles. Here, we used this model system to examine the role of OPRM1 A118G variation for opioid antagonist effects on alcohol responses. MethodsEffects of naltrexone on alcohol reward were examined using intracranial self-stimulation. Effects of naltrexone or nalmefene on alcohol intake were examined in continuous access home cage two-bottle free-choice drinking and operant alcohol self-administration paradigms. ResultsAlcohol lowered brain stimulation reward thresholds in 118GG mice in a manner characteristic of rewarding drugs, and this effect was blocked by naltrexone. Brain stimulation reward thresholds were unchanged by alcohol or naltrexone in 118AA mice. In the home cage, increased alcohol intake emerged in 118GG mice with increasing alcohol concentrations and was 33% higher at 17% alcohol. At this concentration, naltrexone selectively suppressed alcohol intake in 118GG animals to a level virtually identical to that of 118AA mice. No effect of naltrexone was found in the latter group. Similarly, both naltrexone and nalmefene were more effective in suppressing operant alcohol self-administration in 118GG mice. ConclusionsIn a model that allows close experimental control, OPRM1 A118G variation robustly moderates effects of opioid antagonism on alcohol reward and consumption. These findings strongly support a personalized medicine approach to alcoholism treatment that takes into account OPRM1 genotype.

Different contributions of dopamine D1 and D2 receptor activity to alcohol potentiation of brain stimulation reward in C57BL/6J and DBA/2J mice.

C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (±-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1-0.56 mg/kg) and antagonist SCH 23390 (+-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003-0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1-3.0 mg/kg) and antagonist raclopride (0.01-0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6-2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains.

Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J mice.

The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration. To examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine. Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward (BSR)). Mice received cocaine (n = 11, 3.0-30.0 mg/kg, intraperitoneal (i.p.)) or the neuroactive steroid allopregnanolone (n = 11, 3.0-17.0 mg/kg, i.p.). BSR thresholds (θ 0) and maximum (MAX) operant response rates after drug treatments were compared to those after vehicle injections. Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 min following the 30 mg/kg dose, while allopregnanolone was maximally effective (30 % reduction) 15-45 min after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates. The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol, suggesting that positive modulation of GABAA receptors can facilitate reward-related behaviors in C57BL/6J mice.

Tolerance to cocaine in brain stimulation reward following continuous cocaine infusions

This study examined tolerance to cocaine's threshold-lowering effect in brain stimulation reward (BSR) following continuous cocaine infusions and secondly, used the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) to determine NO's involvement in the development of cocaine tolerance. Animals were continuously infused with saline or cocaine (30mg/kg per day) via osmotic minipump for 14days and injected daily with saline or L-NAME (30mg/kg, i.p.) following BSR testing. Saline-treated animals continuously infused with saline showed stable BSR thresholds across the 14-day infusion period. Saline-treated animals continuously infused with cocaine showed markedly lowered BSR thresholds on Day 1 followed by a progressive increase in BSR thresholds across the infusion period – indicating the development of tolerance. L-NAME-treated animals continuously infused with cocaine showed stimulation thresholds that were not significantly different from saline-treated animals continuously infused with cocaine.A cocaine challenge injection (10mg/kg, i.p.) administered 3 and again at 10days following minipump removal revealed that saline-treated animals continuously infused with saline showed lowered BSR thresholds. Saline-treated animals continuously infused with cocaine displayed lowered BSR thresholds that were not significantly different from saline-infused animals. L-NAME treated animals continuously infused with cocaine showed higher BSR thresholds to a challenge 3days following pump removal. However, stimulation thresholds for this group failed to reach statistical significance on both days (i.e., Days 3 and 10) following pump removal.Results showed that animals continuously infused with cocaine develop robust tolerance to cocaine's threshold-lowering effect during the 14-day infusion period. Tolerance to cocaine's threshold-lowering effect was short-lived and dissipated soon after minipump removal. L-NAME treatment failed to significantly alter the development of tolerance to cocaine's threshold-lowering suggesting that NO does not have a primary role in the development of cocaine tolerance.

Blockade of D3 receptors by YQA14 inhibits cocaine's rewarding effects and relapse to drug-seeking behavior in rats

Preclinical studies suggest that dopamine D3 receptor (D3R) antagonists are promising for the treatment of drug abuse and addiction. However, few D3R antagonists have potential to be tested in humans due to short half-life, toxicity or limited preclinical research into pharmacotherapeutic efficacy. Here, we report on a novel D3R antagonist YQA14, which has improved half-life and pharmacokinetic profile and which displays potent pharmacotherapeutic efficacy in attenuating cocaine reward and relapse to drug-seeking behavior. Electrical brain-stimulation reward (BSR) in laboratory animals is a highly sensitive experimental approach to evaluate a drug's rewarding effects. We found that cocaine (2 mg/kg) significantly enhanced electrical BSR in rats (i.e., decreased stimulation threshold for BSR), while YQA14 alone had no effect on BSR. Pretreatment with YQA14 significantly and dose-dependently attenuated cocaine-enhanced BSR. YQA14 also facilitated extinction from drug-seeking behavior in rats during early behavioral extinction, and attenuated cocaine- or contextual cue-induced relapse to drug-seeking behavior. YQA14 alone did not maintain self-administration in either naïve rats or in rats experienced at cocaine self-administration. YQA14 also inhibited expression of repeated cocaine-induced behavioral sensitization. These findings suggest that YQA14 may have pharmacotherapeutic potential in attenuating cocaine-taking and cocaine-seeking behavior. Thus, YQA14 deserves further investigation as a promising agent for treatment of cocaine addiction.

Levetiracetam Has Opposite Effects on Alcohol- and Cocaine-Related Behaviors in C57BL/6J Mice

The antiepileptic drug levetiracetam (LEV) is a potential treatment for alcohol use disorders, yet few preclinical studies exist on its effects in animal models relevant to drug or alcohol abuse. We investigated the effects of LEV on locomotor stimulation following acute and repeated administration of alcohol or cocaine and on alcohol- and cocaine-mediated changes in responding for brain stimulation reward (BSR) in C57BL/6J mice. LEV alone (10.0-100.0 mg/kg intraperitoneally) had no significant effect on locomotor activity or intracranial self-stimulation. Pretreatment with LEV reduced acute locomotor stimulation by 2.0 g/kg alcohol, attenuated the development of locomotor sensitization to alcohol with repeated exposure, and produced a shift in the dose-response curve for alcohol on BSR threshold without affecting maximum operant response rate (MAX). Conversely, LEV pretreatment enhanced both acute locomotor stimulation by 15 mg/kg cocaine and development of locomotor sensitization following repeated exposure and produced a leftward shift in the dose-response curve for cocaine on BSR threshold without affecting MAX. Electrophysiological recordings in vitro showed that LEV reduced excitatory currents in both ventral tegmental area (VTA) dopamine neurons and nucleus accumbens (NAc) medium spiny neurons, consistent with a presynaptic effect. The opposite effects of LEV pretreatment on alcohol- and cocaine-related behaviors may predict its clinical utility in the treatment of patients with alcohol, but not psychostimulant abuse disorders.

Neural processing of a cocaine-associated odor cue revealed by functional MRI in awake rats

Using an olfactory conditioning procedure, brain stimulation reward threshold measurements, and functional magnetic resonance imaging (fMRI), we investigated brain stimulation reward threshold change and fMRI neural activation in response to a cocaine-associated odor cue. In the first brain stimulation experiment, over 10 days of rate–frequency curve-shift testing, rats were administered intravenous cocaine (1.0mg/kg) paired with a contextual cue of peppermint odor previously placed in the operant chamber or they were given vehicle treatment (no cocaine) in the presence of no olfactory cue. Following a 14-day drug-free rest period, rats were again given the rate–frequency curve-shift threshold test with or without the odor cue. In a second experiment, rats were similarly conditioned with a peppermint odor but with intraperitoneally delivered cocaine (10mg/kg). After a 14 day rest period, rats were imaged on a 7-T MRI for their blood oxygen level dependent (BOLD) in response to the cocaine-paired peppermint odor versus an unpaired neutral lemon odor. In the brain stimulation experiment, expected significant reward threshold shifts were produced by cocaine and, importantly, about half that level of shift was produced by the paired contextual olfactory cue. In the fMRI experiment, the insular cortex showed a significantly greater BOLD activation in cocaine-treated versus saline-treated animals to the olfactory cue, but not with the unpaired lemon scent. These data are in agreement with previous studies suggesting a role of the insular cortex in attributing reward value (positive or negative) to conditioned odor stimuli.

Fibrillation atriale

An animal model can be viewed as an experimental paradigm developed for the purpose of studying a given phenomenon found in humans. Although there are no complete animal models of depression, anxiety, schizophrenia, or addiction, animal models do exist for many elements of the syndrome. Animal models for antidepressant medications include a number of tests with good predictive validity, but limited construct validity, and include the forced swim test, modified swim test, learned helplessness, olfactory bulbectomy, differential reinforcement of low rates of responding, maternal deprivation, neonatal clomipramine treatment, social stress in shrews, chronic mild stress, agonistic behavior, and Flinders sensitive rats. Animal models of depression that have face validity and construct validity for a key element of depression are reward deficits measured by brain stimulation reward and progressive-ratio responding for a natural reward. Widely used animal models of generalized anxiety include the operant conflict test, elevated plus maze, defensive withdrawal, defensive burying, and social interaction, all of which have face and predictive validity. Animal models for individual types of anxiety disorder remain a challenge, with some advances in posttraumatic stress disorder, which includes models of repeated shock stressors, repeated social stressors, and a single prolonged stress paradigm. Animal models of schizophrenia are limited by the limited knowledge of the pathophysiology of the disease but include pharmacological, developmental, and genetic models combined with behavioral tests with some face and contruct validity, such as locomotor activity (positive symptoms), prepulse inhibition of the startle response (attention), latent inhibition (attention), social withdrawal (negative symptoms), and measures of executive function. Animal models of addiction can be organized within the stages of the addiction cycle, including: binge/intoxication (drug or alcohol self-administration, conditioned place preference, brain stimulation reward thresholds), withdrawal/negative affect (anxiety-like responses, conditioned place aversion, elevated reward thresholds, withdrawal-induced increases in drug self-administration), and preoccupation/anticipation (drug-induced reinstatement, cue-induced reinstatement, stress-induced reinstatement). These models have excellent face and construct validity and have led to major insights into the neurobiological mechanisms of addiction. Animal models remain a key heuristic approach to elucidation of the pathophysiology and treatment of psychiatric disorders.

Mephedrone (4-methylmethcathinone) and intracranial self-stimulation in C57BL/6J mice: Comparison to cocaine

The recreational use of cathinone-derived synthetic stimulants, also known as “bath salts”, has increased during the last five years. A commonly abused drug in this class is mephedrone (4-methylmethcathinone or “meow–meow”), which alters mood and produces euphoria in humans. Intracranial self-stimulation (ICSS) measures the behavioral effects of neuroactive compounds on brain reward circuitry. We used ICSS to investigate the ability of mephedrone and cocaine to alter responding for electrical stimulation of the medial forebrain bundle in C57BL/6J mice. Adult male C57BL/6J mice (n=6) implanted with unipolar stimulating electrodes at the level of the lateral hypothalamus responded for varying frequencies of brain stimulation reward (BSR). The frequency that supported half maximal responding (EF50), the BSR threshold (θ0), and the maximum response rate were determined before and after intraperitoneal administration of saline, mephedrone (1.0, 3.0, or 10.0mg/kg), or cocaine (1.0, 3.0, or 10.0mg/kg). Mephedrone dose-dependently decreased EF50 (max. effect=72.3% of baseline), θ0 (max. effect=59.6% of baseline), and the maximum response rate (max. effect=67.0% of baseline) beginning 15min after administration. Beginning immediately after administration, cocaine dose-dependently lowered EF50 (max. effect=66.4% of baseline) and θ0 (max. effect=60.1% of baseline) but did not affect maximum response rate. These results suggest that mephedrone, like cocaine, potentiates BSR, which may indicate its potential for abuse. Given the public health concern of stimulant abuse, future studies will be necessary to determine the cellular and behavioral effects of acute and chronic mephedrone use.

Orexin-1 receptor antagonism does not reduce the rewarding potency of cocaine in Swiss–Webster mice

The orexin family of hypothalamic neuropeptides has been implicated in reinforcement mechanisms relevant to both food and drug reward. Previous behavioral studies with antagonists at the orexin A-selective receptor, OX 1, have demonstrated its involvement in behavioral sensitization, conditioned place-preference, and self-administration of drugs of abuse. Adult male Swiss–Webster mice were implanted with stimulating electrodes to the lateral hypothalamus and trained to perform intracranial self-stimulation (ICSS). The effects of the OX 1-selective antagonist SB 334867 on brain stimulation-reward (BSR) and cocaine potentiation of BSR were measured. SB 334867 (10–30 mg/kg, i.p.) alone had no effect on ICSS performance or BSR threshold. Cocaine (1.0–30 mg/kg i.p.) dose-dependently potentiated BSR, measured as lowering of BSR threshold. This effect was not blocked by 30 mg/kg SB 334867 at any cocaine dose tested. In agreement with previous reports, SB 334867 resulted in a reduction of body weight 24 h after acute administration. Based on these data, it is concluded that orexins acting at OX 1 do not contribute to BSR; and are not involved in the reward-potentiating actions of cocaine on BSR. The data are discussed in the context of prior findings of SB 334867 effects on drug-seeking and drug-consuming behaviors.

Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism

The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists. This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method. Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline. Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX. The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.

Lipopolysaccharide induces anhedonia-like reward deficits, reflected by long-term increases in brain stimulation reward thresholds

Lipopolysaccharide induces anhedonia-like reward deficits, reflected by long-term increases in brain stimulation reward thresholds

Varenicline does not alter brain stimulation reward thresholds and reverses nicotine‐facilitated thresholds in rats

AbstractThe partial α4β2 nicotinic acetylcholine receptor (nAChR) agonist, varenicline, shares some but not all preclinical effects of nicotine. This unique profile may be crucial to its effectiveness as a therapeutic aid for smoking cessation. The present study evaluated the ability of varenicline to alter brain stimulation reward (BSR) and to alter nicotine facilitation of BSR in a rate‐independent intracranial self‐stimulation discrete trial procedure. Male Sprague‐Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation aimed at the medial forebrain bundle. Once stable thresholds were established, nicotine, varenicline, and mecamylamine were tested alone to determine their effects on BSR. Subsequently, challenge tests for nicotine facilitation of BSR with nonthreshold altering doses of varenicline and mecamylamine were conducted. This study demonstrated that nicotine dose‐ dependently facilitated BSR, whereas varenicline did not. Similarly to mecamylamine, varenicline reversed nicotine facilitation of BSR, suggesting that nAChRs mediate the effects of nicotine on BSR. Thus, specifically targeting α4β2 nAChRs inhibits the ability of nicotine to facilitate BSR. The efficacy of varenicline as a treatment for smoking cessation may be related to its unique ability to reduce the rewarding effects of nicotine while not producing rewarding effects alone, a critical consideration in effective drug replacement therapies. Drug Dev Res 72: 310–314, 2011. © 2010 Wiley‐Liss, Inc.

Effects of Δ9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress

Although cannabis derivatives produce clear subjective motivational responses in humans leading to drug-seeking behaviour, the reinforcing attributes of these subjective effects are difficult to define in experimental animals. The aim of this study was to examine how exposure to chronic unpredictable stress (CUS) will affect reward function and anxiety after acute administration of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in rats. Male rats were exposed to either 10 days of CUS or no stressor. Alterations in brain reward function were assessed with the intracranial self-stimulation (ICSS) paradigm, and anxiety responses were measured with the elevated plus maze. CUS did not affect baseline brain stimulation reward thresholds. Delta(9)-THC did not exhibit reinforcing actions in the ICSS paradigm neither in nonstressed nor in stressed animals. More importantly, in nonstressed animals, both the low and the high dose of Delta(9)-THC exerted anxiolytic-like effects. In stressed animals, however, only the high dose of THC induced an anxiolytic-like response, whereas the low dose induced anxiogenic effects. The present results provide clear evidence for an anxiolytic effect of Delta(9)-THC both in stressed and in nonstressed animals, and indicate that environmental conditions, such as stressful experiences, do not alter the behavioural effects of Delta( 9)-THC in the ICSS paradigm.

Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of α4β2 nicotinic receptors in rats

Varenicline, a partial α4β2 and full α7 nicotinic receptor agonist, has been shown to inhibit nicotine self-administration and nicotine-induced increases in extracellular dopamine in the nucleus accumbens. In the present study, we investigated whether varenicline inhibits nicotine-enhanced electrical brain-stimulation reward (BSR), and if so, which receptor subtypes are involved. Systemic administration of nicotine (0.25–1.0 mg/kg, i.p.) or varenicline (0.03–3 mg/kg, i.p.) produced biphasic effects, with low doses producing enhancement (e.g., decreased BSR threshold), and high doses inhibiting BSR. Pretreatment with low dose (0.03–1.0 mg/kg) varenicline dose-dependently attenuated nicotine (0.25 or 0.5 mg/kg)-enhanced BSR. The BSR-enhancing effect produced by varenicline was blocked by mecamylamine (a high affinity nicotinic receptor antagonist) or dihydro-β-erythroidine (a relatively selective nicotinic α4-containing receptor antagonist), but not methyllycaconitine (a selective α7 receptor antagonist), suggesting an effect mediated by activation of α4β2 receptors. This suggestion is supported by findings that the α4β2 receptor agonist SIB-1765F produced a dose-dependent enhancement of BSR, while pretreatment with SIB-1765F attenuated nicotine (0.5 mg/kg)-enhanced BSR. In contrast, the selective α7 receptor agonist ARR-17779, altered neither BSR itself nor nicotine-enhanced BSR, at any dose tested. These findings suggest that: 1) varenicline inhibits nicotine-enhanced BSR, supporting its use as a smoking cessation aid; and 2) varenicline-enhanced BSR by itself and varenicline's anti-nicotine effects are mediated by activation of α4β2, but not α7, receptors.

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats.

We have previously reported that selective antagonism of brain D3 receptors by SB-277011A or NGB 2904 significantly attenuates cocaine- or nicotine-enhanced brain stimulation reward (BSR). In the present study, we investigated whether the selective D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 agonist BP-897 similarly reduce methamphetamine (METH)-enhanced BSR. Rats were trained to respond for rewarding electrical self-stimulation of the medial forebrain bundle. To assess the degree of drug-induced changes in BSR, a rate-frequency curve shift paradigm was used to measure brain-reward threshold (theta 0). METH (0.1-0.65 mg/kg, i.p.) dose-dependently lowered ( approximately 10-50%) BSR thresholds, producing an enhancement of BSR. Pretreatment with SB-277011A (12 mg/kg, but not 24 mg/kg, i.p.) significantly attenuated METH-enhanced BSR. NGB 2904 (0.1-1.0 mg/kg, but not 10 mg/kg) also attenuated METH-enhanced BSR. SB-277011A or NGB 2904 alone, at the doses tested, had no effect on BSR. Pretreatment with BP-897 (0.1-5 mg/kg) dose-dependently attenuated METH-enhanced BSR. However, when the dose was increased to 10 mg/kg, BP-897 shifted the stimulation-response curve to the right (inhibited BSR itself) in the presence or absence of METH. Selective antagonism of D3 receptors by SB-277011A or NGB 2904 attenuates METH-enhanced BSR in rats, while the METH-enhanced BSR attenuation produced by BP-897 may involve both D3 and non-D3 receptors. These findings support a potential use of selective D3 receptor antagonists for the treatment of METH addiction.

Lack of evidence for appetitive effects of Δ9-tetrahydrocannabinol in the intracranial self-stimulation and conditioned place preference procedures in rodents

Data on the ability of Delta 9-tetrahydrocannabinol (THC) to modify reward processes in experimental animals are inconsistent. This study examined the effects of Delta 9-THC on brain reward function using the rate-frequency curve shift paradigm of intracranial self-stimulation (ICSS) and the conditioned place preference (CPP) paradigm. In ICSS tests, rats were implanted with electrodes into the medial forebrain bundle. After brain stimulation reward thresholds stabilized, rats received intraperitoneal injections of Delta 9-THC (0, 0.5, 1 and 2 mg/kg) or the CB1 receptor antagonist SR141716A (0, 0.02 mg/kg) and Delta 9-THC (0, 2 mg/kg). The two highest doses of Delta 9-THC significantly increased the threshold ICSS frequency. SR141716A reversed the action of Delta 9-THC (2 mg/kg), without affecting reward thresholds by itself. In the CPP test, mice received intraperitoneal injections of Delta 9-THC (0, 1 or 3 mg/kg). Delta 9-THC showed neither statistically significant preference nor aversion in either of the doses tested. These findings indicate that Delta 9-THC, in contrast to other drugs of abuse, does not facilitate ICSS or support CPP under the present experimental conditions, but rather has a dose-dependent inhibitory influence on ICSS.

Prenatal Exposure to Cocaine Increases the Rewarding Potency of Cocaine and Selective Dopaminergic Agonists in Adult Mice

Substance abuse during pregnancy results in persistent affective and behavioral deficits in drug-exposed children, and increased rates of substance abuse have been observed in young adults prenatally exposed to drugs of abuse. Animal models of prenatal cocaine exposure have yielded differing results depending on the behavioral method used to assess drug potency. The effects of cocaine, the dopamine D1 agonists SKF-81297 and SKF-82958, and the D2 agonist quinpirole on intracranial self-stimulation were measured in adult Swiss-Webster mice exposed to cocaine in utero (40 mg/kg/day) and vehicle controls with the curve-shift method of brain stimulation-reward (BSR) threshold determination. The reward-potentiating effects of cocaine (0.3-30 mg/kg IP) and SKF-82958 but not SKF-81297 on BSR were increased in adult male but not female mice after prenatal cocaine exposure. Quinpirole exerted biphasic effects on BSR, both elevating (0.1-0.3 mg/kg IP) and lowering (1.0-10 mg/kg IP) reward thresholds. Both effects of quinpirole were also enhanced in adult male mice after prenatal cocaine exposure. Prenatal cocaine exposure results in increased reward-potentiating potency of cocaine on BSR in adult mice in a sexually-dimorphic manner. This augmented rewarding effect of cocaine is also associated with increased sensitivity to both D1- and D2-selective agonists.