Eliot L. Gardner

Δ9-Tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis

This study examined the effects of acute administration of delta-9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient in marijuana, on extracellular efflux of dopamine (DA) and its metabolites as measured by in vivo microdialysis in nucleus accumbens of conscious, freely-moving rats. Δ9-THC, at low doses (0.5–1.0 mg/kg), which significantly enhance brain stimulation reward (intracranial self-stimulation), significantly increased DA efflux in nucleus accumbens. Augmentation of DA efflux by Δ9-THC was abolished by removal of calcium (Ca++) ions from the perfusion fluid, indicating a Ca++-dependence of Δ9-THCs action. Augmentation of DA efflux by Δ9-THC was either totally blocked or significantly attenuated by doses of naloxone as low as 0.1 mg/kg. Given the postulated role of mesocorticolimbic DA circuits in mediating and/or modulating brain stimulation reward, the present data raise the possibility that marijuanas rewarding effects, and hence its euphorigenic effects and abuse potential, may be related to pharmacological augmentation of presynaptic DA mechanisms. Additionally, the DA mechanisms enhanced by marijuana appear to be modulated by an endogenous opioid peptide system.

Conditioned place preference induced by Δ9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward

The rewarding property of delta 9-tetrahydrocannabinol (THC), the psychoactive constituent of marijuana and hashish, was studied using the conditioned place preference paradigm, and compared to that of cocaine, morphine, and food reward. The results of Experiment 1 demonstrated that 2.0 and 4.0 mg/kg doses produced a reliable shift in preference for the THC-paired compartment. The THC place preference observed at 2.0 and 4.0 mg/kg was nearly equivalent to that produced by low doses of cocaine (5.0 mg/kg), morphine (4.0 mg/kg), and food in non food-deprived animals. The second experiment used a different conditioning procedure that included a washout period for THC. The results of Experiment 2 demonstrated that a THC place preference could be obtained using a lower dose of THC (1.0 mg/kg), and that this THC place preference was equivalent to that produced by 10 mg/kg cocaine. At higher doses (2.0 and 4.0 mg/kg), THC produced a dose-dependent place aversion. These results suggest that THCs action on brain reward substrates, previously demonstrated by electrical brain stimulation reward, in vivo brain microdialysis, and in vivo brain electrochemistry studies, reflects itself behaviorally in increased appetitive motivational value for environmental stimuli associated with ingestion of marijuana and hashish.

Facilitation of brain stimulation reward by delta 9-tetrahydrocannabinol.

The present experiment explored whetherΔ9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient in marijuana, shares with other drugs of abuse the ability to facilitate brain stimulation reward acutely, as measured by clectrical intracranial self-stimulation (ICSS). Laboratory rats were implanted with stimulation electrodes in the medial forebrain bundle, and trained to stable performance on a self-titrating threshold ICSS paradigm.Δ9-THC, at a dose believed pharmacologically relevant to moderate human use of marijuana, acutely lowered ICSS thresholds, suggesting that marijuana acts on similar CNS hedonic systems to most other drugs of abuse.

Activation of 5-HT3 receptor by 1-phenylbiguanide increases dopamine release in the rat nucleus accumbens

The serotonin-3 (5-HT3) agonist 1-phenylbiguanide (0.1-1.0 mM in perfusate) caused a robust, dose-dependent enhancement of extracellular dopamine content in nucleus accumbens as measured by in vivo microdialysis. This action was antagonized by co-perfusion of the 5-HT3 antagonists zacopride and GR38032F (1 mM in perfusate). Similar effects were observed in 5-HT-denervated rats. These findings suggest that there is a potent modulation of dopamine (DA) release in the nucleus accumbens mediated via 5-HT3 receptors, which appear to be located presynaptically on DA terminals of the mesolimbic DA pathway.

A novel strategy for the treatment of cocaine addiction

Cocaines addictive liability has been linked to its pharmacologic actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma‐aminobutyric acid (GABA). With this knowledge, we examined the utility of gamma vinylGABA (GVG), a selective and irreversible inhibitor of GABA‐transaminase (GABA‐T) known to potentiate GABAergic inhibition, to alter cocaines biochemical effects as well as its effects on behaviors associated with these biochemical changes. GVG significantly attenuated cocaine‐induced increases in neostriatal synaptic DA in the non‐human primate (baboon) brain as assessed by positron emission tomography (PET) and abolished both the expression and acquisition of cocaine‐induced conditioned place preference (CPP). It had no effect on CPP for a food reward, the delivery of cocaine to the brain or locomotor activity. These findings suggest the possible therapeutic utility in cocaine addiction of a pharmacologic strategy targeted at the GABAergic neurotransmitter system, a system distinct from but functionally linked to the DA mesotelencephalic reward/reinforcement system. However, rather than targeting the GABA receptor complex with a direct GABA agonist, this novel approach with GVG takes advantage of the prolonged effects of an irreversible enzyme inhibitor that raises endogenous GABA levels without the addictive liability associated with GABA agonists acting directly at the receptor itself. Human trials with GVG are currently being developed to directly examine the utility of this novel strategy for the treatment of cocaine addiction. Synapse 30:119–129, 1998.

A Pharmacologic Strategy for the Treatment of Nicotine Addiction

Like many psychostimulant drugs, nicotine elevates extracellular and synaptic dopamine (DA) concentrations in the nucleus accumbens (NAc). This elevation has been linked to its reinforcing properties. Dopaminergic transmission within the NAc is modulated by gamma‐aminobutyric acid (GABA). Therefore, we examined the utility of gamma vinyl‐GABA (GVG, Vigabatrin) for inhibiting nicotines biochemical effects on NAc DA as well as its effects on behaviors associated with these biochemical changes. Given 2.5 hours prior to nicotine, GVG (75 mg/kg) had no effect on nicotine‐induced increases in extracellular NAc DA. However, at 90 mg/kg, GVG significantly inhibited nicotine‐induced increases by approximately 50% while at 100 or 150 mg/kg, GVG completely abolished nicotine‐induced increases in both naïve and chronically nicotine‐treated animals. When given 12 or 24 hours prior to nicotine administration at a dose of 100 mg/kg, GVG‐induced inhibition was diminished or abolished, respectively. In addition, at a dose of 18.75 mg/kg GVG abolished the expression of nicotine‐induced conditioned place preference (CPP) while a dose of 75 mg/kg abolished the acquisition phase of CPP. Finally, using positron emission tomography (PET) and 11C‐raclopride in primates, GVG (100 mg/kg) abolished nicotine‐induced increases in synaptic DA while having no effect on the rate of metabolism of the radiotracer or its regional distribution. Together, these data suggest that GVG may be useful for the treatment of nicotine addiction and further support the strategy of targeting the GABAergic system with a suicide inhibitor of GABA‐transaminase for the treatment of drug addiction. Synapse 31:76–86, 1999.

Δ9-Tetrahydroeannabinol enhances presynaptic dopamine efflux In medial prefrontal cortex

Abstract Acute administration of 1.0–2.0 mg/kg Δ 9 -tetrahydrocannabinoI Δ 9 -THC) increased presynaptic dopamine (DA) efflux in the medial prefrontal cortex of rats, as measured by intracerebral microdialysis in awake, behaving rats. These data are congruent with suggestions that (1) marijuanas euphorigenic effects and abuse potential may be related to augmentation of presynaptic DA mechanisms, and (2) the medial prefrontal cortex may be an important site of action for drugs of abuse in general and for Δ 9 -THC in particular.

The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats.

Accumulating evidence indicates that dopamine (DA) D3 receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D3-selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of drug-seeking behavior in male Long–Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1–10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished drug-seeking behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-seeking behavior. Overall, these data show that the novel D3-selective antagonist NGB 2904 attenuates cocaines rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-seeking behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.

(-)-Nicotine produces conditioned place preference in Lewis, but not Fischer 344 rats.

In this study, we sought to determine if Fischer 344 (F344) and Lewis rats showed different conditioned place preference (CPP) responses to subcutaneously administered (—)‐nicotine. Lewis rats displayed a CPP response to (—)‐nicotine after five pairings, whereas F344 rats showed no preference for nicotine compared to vehicle. After 10 pairings, the F344 rats showed a conditioned place aversion to (—)‐nicotine, whereas the Lewis rats still displayed a significant CPP response. These results suggest that the differences in appetitiveness shown between Lewis and F344 rats to other drugs of abuse extend also to (—)‐nicotine. Synapse 26:93–94, 1997.

The effects of Δ9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study

The effect of systemically administered delta 9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, on the potassium-evoked release of dopamine (DA) was examined in the neostriatum of the chloral hydrate anesthetized rat. Both in vivo electrochemical and in vivo microdialysis techniques were employed. A low dose of THC (0.5 mg/kg, i.p.) increased the time course of potassium-evoked in vivo electrochemical signals corresponding to released extracellular DA. In vivo microdialysis showed an increase in potassium-evoked DA release following 0.5 and 2.0 mg/kg doses of THC. Potassium-evoked electrochemical signals corresponding to released extracellular DA were augmented in time course following i.p. administration (5.0 mg/kg) of nomifensine, a recognized and potent catecholaminergic reuptake blocker. In addition, in vivo brain microdialysis studies of nomifensine (5.0 mg/kg i.p.) on neostriatal potassium-evoked DA release showed that DA levels were augmented in magnitude over the time course of the microdialysis. Taken together, these studies indicate that THC has a potent presynaptic augmenting effect on at least the neostriatal portions of the mesotelencephalic DA system in the rat, although the possibility that this effect could be mediated transsynaptically cannot be ruled out. Given the previous extensive evidence for an involvement of portions of the mesotelencephalic DA system in mediating the reinforcing and euphorigenic properties of many classes of abused drugs, and in mediating direct electrical brain stimulation reward, we suggest that the presently demonstrated effects of THC on forebrain dopamine function may be related to marijuanas euphorigenic properties and, thus, to its abuse potential.