Brain Stimulation Reward Paradigm Research Articles

Cannabinoids reward sensitivity in a neurodevelopmental animal model of schizophrenia: A brain stimulation reward study

The comorbidity schizophrenia and cannabis has a high prevalence. The consumption of cannabis is ten times higher among schizophrenia patients, suggesting that these patients could be differentially sensitive to its motivational effects. To study this question, we investigated the motivational effects of cannabinoid agonists using the brain stimulation reward paradigm and a neurodevelopmental model of schizophrenia: neonatal ventral hippocampus lesions (NVHL). Using the curve-shift paradigm, we first compared the effect single dose (0.75mg/kg) of amphetamine in sham and NVHL rats on reward and operant responding. Then, in different groups of NVHL and sham rats, we studied the effect of delta-9-tetrahydrocannabinnol (THC, 0.5mg/kg, i.p.) and WIN55,212-2 (WIN, 1 and 3mg/kg, i.p.) Rats were initially trained to self-administer an electrical stimulation to the posterio-medial mesencephalon. Once responding was stable, reward threshold defined as the frequency required to induce a half maximum response rate was measured before and after injection of the drug or the vehicle. Results show that amphetamine enhanced reward in sham and NVHL rats, an effect that was shorter in duration in NVHL rats. THC produced a weak attenuation of reward in sham rats while WIN produced a dose-dependent attenuation in NVHL; the attenuation effect of WIN was blocked by the cannabinoid antagonist, AM251. WIN also produced an attenuation of performance in sham and NVHL rats, and this effect was partially prevented by AM251. These results provide the additional evidence that the motivational effect of cannabinoids is altered in animals with a schizophrenia-like phenotype.

The preferential dopamine D3 receptor antagonist S33138 inhibits cocaine reward and cocaine-triggered relapse to drug-seeking behavior in rats

We have previously reported that selective dopamine (DA) D3 receptor antagonists are effective in a number of animal models of drug addiction, but not in intravenous drug self-administration, suggesting a limited ability to modify drug reward. In the present study, we evaluated the actions of S33138, a novel partially selective D3 receptor antagonist, in animal models relevant to drug addiction. S33138, at doses of 0.156 or 0.625mg/kg (i.p.), attenuated cocaine-enhanced brain-stimulation reward (BSR), and the highest dose tested (2.5mg/kg) produced a significant aversive-like rightward shift in BSR rate-frequency reward functions. Further, S33138 produced biphasic effects on cocaine self-administration, i.e., a moderate dose (2.5mg/kg, p.o.) increased, while a higher dose (5mg/kg, p.o.) inhibited, cocaine self-administration. The increase in cocaine self-administration likely reflects a compensatory response to a partial reduction in drug reward after S33138. In addition, S33138 (0.156–2.5mg/kg, p.o.) also dose-dependently inhibited cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-enhanced BSR and cocaine-triggered reinstatement produced by lower effective doses (e.g., 0.156 or 0.625mg/kg) of S33138 is unlikely due to impaired locomotion, as lower effective doses of S33138 decreased neither Ymax levels in the BSR paradigm, rotarod performance, nor locomotion. However, the higher doses (2.5 or 5mg/kg) of S33138 also significantly inhibited sucrose self-administration and rotarod performance, suggesting non-D3 receptor-mediated effects on non-drug reward and locomotion. These data suggest that lower doses of S33138 interacting essentially with D3 receptors have pharmacotherapeutic potential in treatment of cocaine addiction, while higher doses occupying D2 receptors may influence locomotion and non-drug reward.

Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: Experiments with self-administration and brain-stimulation reward in rats

It was recently reported that levo-tetrahydropalmatine ( l-THP), a dopamine (DA) D 1 and D 2 receptor antagonist purified from the Chinese herb Stephanie, appears to be effective in attenuating cocaine self-administration, cocaine-triggered reinstatement and cocaine-induced conditioned place preference in preclinical animal models. The present study was designed to contrast l-THP's effects on cocaine self-administration under fixed-ratio (FR) and progressive-ratio (PR) reinforcement, and to study l-THP's effects on cocaine-enhanced brain stimulation reward (BSR). Systemic administration of l-THP produced dose-dependent, biphasic effects, i.e., low-to-moderate doses (1, 3, 10 mg/kg) increased, while a high dose (20 mg/kg) inhibited cocaine self-administration behavior under FR2 reinforcement. The increased cocaine self-administration is likely a compensatory response to a reduction in cocaine's rewarding effects, because the same low doses of l-THP dose-dependently attenuated cocaine self-administration under PR reinforcement and also attenuated cocaine-enhanced BSR. These attenuations of PR cocaine self-administration and cocaine-enhanced BSR are unlikely due to l-THP-induced sedation or locomotor inhibition, because only 10 mg/kg, but not 1–3 mg/kg, of l-THP inhibited locomotion, sucrose self-administration and asymptotic operant performance in the BSR paradigm. In vivo microdialysis demonstrated that l-THP slightly elevates extracellular nucleus accumbens DA by itself, but dose-dependently potentiates cocaine-augmented DA, suggesting that a postsynaptic, rather than presynaptic, DA receptor antagonism underlies l-THP's actions on cocaine reward. Together, the present data, combined with previous findings, support the potential use of l-THP for treatment of cocaine addiction.

Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction.

As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue-induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1-2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction.

ChemInform Abstract: An Enantioselective Synthesis and Biobehavioral Evaluation of 7-Fluoro-3-(p-fluorophenyl)-2-propyltropanes.

Abstract Optically pure 7-fluorotropanes 3a – c , were synthesized as structural probes of the dopamine transporter. The synthesis of these compounds was accomplished through the asymmetric 1,3-dipolar cycloaddition reaction of the oxidopyridinium betaine 4 with the chiral dipolarophile ( R )- p -tolyl vinyl sulfoxide. In the preliminary analysis, tropane 3a was found to reduce the rewarding effects of cocaine in the brain stimulation reward paradigm.

An enantioselective synthesis and biobehavioral evaluation of 7-fluoro-3-( p-fluorophenyl)-2-propyltropanes

Optically pure 7-fluorotropanes 3a– c, were synthesized as structural probes of the dopamine transporter. The synthesis of these compounds was accomplished through the asymmetric 1,3-dipolar cycloaddition reaction of the oxidopyridinium betaine 4 with the chiral dipolarophile ( R)- p-tolyl vinyl sulfoxide. In the preliminary analysis, tropane 3a was found to reduce the rewarding effects of cocaine in the brain stimulation reward paradigm.

Psychostimulant-like effect of central microinjection of neurotensin on brain stimulation reward

The curve shift method and the brain stimulation reward paradigm were used to dissociate reward and performance changes and determine whether unilateral ICV microinjection of neurotensin (3, 10, and 30 micrograms/10 microliters) produces neuroleptic- or psychostimulant-like effect on a dopamine-dependent behavior. At the highest dose tested, neurotensin potentiated brain stimulation reward, producing a significant time-dependent decrease in frequency threshold. Neurotensin also suppressed maximal rate of responding at every dose tested, suggesting that it was more effective at attenuating performance capability. These results suggest that a centrally acting neurotensin receptor agonist may specifically stimulate dopamine-dependent behaviors, producing psychostimulant-like effect that can be attenuated or masked by a suppression of performance capability.

Automating the generation and collection of rate-frequency functions in a curve-shift brain stimulation reward paradigm

The electrical self-stimulation paradigm has proven to be very useful in research aimed at delineating the neural substrates involved in reward-related learning. Of the procedures currently employed the curve-shift method is among the more useful since it distinguishes between treatment effects on reward and performance. This method involves generating and plotting rate-frequency functions and quantifying the effects of experimental manipulations on reward by measuring the degree of lateral shift in these functions. We have designed a computerized system that automatically generates and collects descending rate-frequency functions from self-stimulating rats. The 3 main units of this system consisted of a 6809 micro-controller, a programmable timer logic board and a constant current source. The micro-controller and programmable timer operated on custom written software that monitored lever pressing in the operant chambers and controlled stimulation parameters to generate and record rate-frequency functions. The present report describes this system and presents some typical data collected from rats self-stimulating on ventral tegmental electrodes before and after the administration of intra-accumbens vehicle (0.5 μml distilled H 2O), (+)-amphetamine (20.0 μg/0.5 μl), quinpirole (10.0 μ/0.5 μl) and systemic quinpirole (1.0 mg/kg), all dopamine agonists. Stimulation consisting of 300-ms trains of cathodal rectangular pulses (0.1 ms) was available in 50-s trials. The number of pulses per train was decreased logarithmically from a value that sustained maximal responding to one that would not sustain responding. Self-stimulation thresholds were obtained by fitting the Gompertz growth model to the data and calculating the point of maximal acceleration of the sigmoidal curve. It was found that the present system generated and collected rate-frequency functions similar to those that have been obtained manually in previous experiments. The data showed that the system was sensitive to both central and systemic pharmacological manipulations by producing lateral and vertical shifts of the rate-frequency functions, indications of reward and motor effects, respectively. It was concluded that the present design was useful in conducting entire self-stimulation sessions that required minimal monitoring by the experimenter.

Clozapine's functional mesolimbic selectivity is not duplicated by the addition of anticholinergic action to haloperidol: a brain stimulation study in the rat

This study examined whether the anticholinergic potency of the clinically superior antipsychotic drug clozapine contributes to clozapine's anatomically-selective functional inhibition of the mesolimbic dopamine (DA) system, using an electrical brain-stimulation reward (BSR) paradigm in rats that has been previously shown to be highly sensitive to clozapine's mesolimbic functional selectivity. Rats were chronically administered saline, clozapine, haloperidol, or haloperidol plus the anticholinergic compound trihexyphenidyl, and threshold sensitivity of the mesolimbic and nigrostriatal DA systems was assessed using the BSR paradigm, to infer degree of functional DA blockade produced by the chronic drug regimens. Chronic saline produced no change in either DA system. Congruent with previous findings, chronic clozapine powerfully inhibited the mesolimbic DA system but spared the nigrostriatal DA system. Also congruent with previous findings, chronic haloperidol powerfully inhibited both DA systems. Compared to chronic haloperidol alone, chronic haloperidol plus chronic trihexyphenidyl exerted diminished anti-DA action in both the mesolimbic and nigrostriatal DA systems. These results suggest that clozapine's anticholinergic potency is not an adequate explanation for its functional mesolimbic selectivity.

Effects of nucleus accumbens amphetamine on lateral hypothalamic brain stimulation reward

The effects of amphetamine were examined in a brain stimulation reward paradigm in which response rate was measured across a range of stimulation frequencies. Both low (0.0625 and 0.125 mg/kg) and high (1.0, 2.0 and 4.0 mg/kg) doses of systemic amphetamine decreased the stimulation frequency needed to sustain low rates of responding; high doses decreased the maximal response rates that were sustained by the highest stimulation frequencies. Ipsilateral microinjections (2.5, 5.0 and 10.0 μg/0.5 μl) of d-amphetamine sulfate into the nucleus accumbens also caused shifts to the left of the rate-frequency function; no central dose caused a change in the asymptotic response rate associated with high stimulation frequencies. Contralateral injections of d-amphetamine (10.0 μg) also shifted the rate-frequency functions to the left, but were much less potent. Ipsilateral injections of d-amphetamine into the caudate were also less potent, suggesting nucleus accumbens rather than more dorsal tissue as the site of this behavioral action. Also less potent were the effects of l-amphetamine, ruling out non-specific effects of pH, osmolarity and the like and also ruling out noradrenergic actions as explanations of the behavioral effects of the injections. These data suggest that nucleus accumbens is a site of amphetamine's reward-enhancing and threshold-lowering effects on brain stimulation reward.