Behavioral pharmacology of local anesthetics: Reinforcing and discriminative stimulus effects

doi:10.1016/0091-3057(82)90458-0

Pharmacology Biochemistry and Behavior

Volume 16, Issue 3, March 1982, Pages 491-500

https://doi.org/10.1016/0091-3057(82)90458-0 Get rights and content

Abstract

The reinforcing properties of several short-acting esteratic local anesthetics were determined in rhesus monkeys experienced in the IV self-administration of cocaine. In addition, the discriminative stimulus properties of these and several other local anesthetics of both the ester and amide class were determined in rats trained to discriminate procaine from saline in a 2-lever operant task. IV delivery of chloroprocaine, dimethylprocaine or dimethocaine maintained responding above vehicle levels in most monkeys while propoxycaine, piperocaine and dimethylaminoethanol (Deanol) failed to maintain self-administration behavior. Thus some, but not all, short-acting esteratic local anesthetics are positive reinforcers in rhesus monkeys. In addition, it is unlikely that the reinforcing effects of dimethylprocaine are mediated by its metabolite dimethylaminoethanol. In rats, all local anesthetics tested except piperocaine and procainamide resulted in responding on the procaine-appropriate lever indicating procaine-like discriminative stimulus effects for these compounds. In addition, injections of d-amphetamine resulted in principally procaine lever responding. All local anesthetics that were self-administered by rhesus monkeys had discriminative stimulus effects in rats that were similar to those of procaine. However, not all local anesthetics that were procaine-like in rats were self-administered by rhesus monkeys. These data may represent a separation of these two stimulus properties for local anesthetics although other variables such as species differences may play a role.

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William L. Woolverton: A case history in unraveling the behavioral pharmacology of stimulants
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Clinical findings suggest that the most promising strategy for cocaine addiction is a combination of indirect-acting monoamine agonists with some form of behavioral intervention. This approach can be traced back to preclinical research, some of which was conducted by William L. Woolverton. The goal of this brief review is to provide readers with an appreciation for the experimental breadth involving both behavior and pharmacology that encompassed Woolverton's amazing career, from the evaluation of abuse liability of drugs to the use of complex behavioral contingencies to better model the human condition. We begin with Woolverton's research using simple and complex schedules of reinforcement to evaluate abuse liability and how that has impacted current animal models. We also discuss his use of cocaine vs. food choice schedules of reinforcement as a model to evaluate potential medications for treating cocaine use disorders. Woolverton concluded that drug taking behavior was not “impulsive” and “out of control” as has often been proposed, but rather directly determined by the environmental contingencies and the context of its availability, providing a nuanced understanding of drug–behavior interactions.
This article is part of the Special Issue entitled ‘CNS Stimulants’
Neural response to lidocaine in healthy subjects
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Citation Excerpt :
We have previously hypothesized that the attenuated rCBF response to procaine in cocaine-addicted subjects reflects a non-dopaminergic mechanism. However, while procaine's affinity for the DAT is low compared to cocaine, both preclinical and clinical studies suggest an overlap between the rewarding and stimulus effects of cocaine and procaine (Woolverton and Balster, 1979, 1982; Fischman et al., 1983b; Garza and Johanson, 1983; Jarbe, 1984; Silverman and Schultz, 1989; Adinoff et al., 1998; Wilcox et al., 2000; Tella and Goldberg, 2001). Studies demonstrating a direct effect of procaine upon dopamine efflux (Woodward et al., 1995) and a relationship between procaine's reinforcing effects and DAT occupancy (Wilcox et al., 2005) suggest that these cocaine-like effects of procaine may be mediated through the DAT.
Recent studies suggest that some of cocaine's central nervous system (CNS) effects may be mediated through its sodium channel inhibiting local anesthetic properties. Local anesthetics that lack cocaine's strong affinity for the dopamine transporter (DAT) also produce sensory and mood effects, further suggesting a role for this neural pathway. Due to an absence of affinity at the DAT, the local anesthetic lidocaine may offer the potential to assess sodium channel activity in vivo in humans. To assess the utility of lidocaine as a CNS probe, we determined regional cerebral blood flow (rCBF) with single photon emission computed tomography (SPECT) following the intravenous administration of lidocaine (0.5 mg/kg) and compared this response to procaine (0.5 mg/kg and 1.0 mg/kg), a local anesthetic with partial affinity for the DAT, and saline. Infusions were administered in nine healthy female controls over a 10-day period with at least 2 days between each scan. Increased rCBF was observed following lidocaine, relative to saline, in the insula, caudate, thalamus, and posterior cingulate. Decreased rCBF was detected in a different region of the posterior cingulate. In general, increases in rCBF were more marked following lidocaine relative to procaine. Mood and sensory changes following lidocaine were limited and significantly less than those induced by either dose of procaine. There were no significant changes in blood pressure or heart rate following either medication. These findings suggest that lidocaine can be safely used to assess sodium channel function in persons with addictive and other psychiatric disorders.
Inhibition of serotonin transporters by cocaine and meprylcaine through 5-TH<inf>2C</inf> receptor stimulation facilitates their seizure activities
2005, Brain Research
Citation Excerpt :
However, it could be also possible that cocaine indirectly activates the neurons through cocaine-induced inhibition of Na+ current of inhibitory neurons innervating to 5-HT neurons. While synthetic local anesthetics are generally believed to lack the effect on monoamine transporters, certain local anesthetics have been shown to have cocaine-like reinforcing effects in animals [9,15,35,36]. We and others have recently demonstrated that some synthetic local anesthetics such as procaine and meprylcaine do inhibit monoamine transporters (MAT) in rat brain synaptosomes [36], in COS cells transfected with MAT cDNAs [25] and in SH-SY5Y human neuroblastoma cells [16], while lidocaine displays no inhibitory action [25,34].
The present study examined whether the inhibition of serotonin transporters (SERT) contributes to cocaine- and other local anesthetics-induced convulsions, and which subtypes of 5-HT receptor are involved in the convulsions. For this purpose, cocaine, meprylcaine and lidocaine, all of which have different effects on SERT, were used as convulsants and the effects of serotonin reuptake inhibitors (SSRIs), specific agonists and antagonists for 5-HT receptor subtypes were evaluated in mice. Administration of SSRI, zimelidine, citalopram and fluoxetine, 5-HT_2A,2C receptor agonist, R(−)-DOI and the 5-HT_2C receptor agonists, mCPP, and MK212 resulted in a marked increase in incidence of convulsions and a reduction in the threshold of lidocaine-induced convulsions, while the 5-HT_2B receptor agonist, BW723C86, had little influence. On the other hand, SSRI did not affect the measured parameters in meprylcaine- and cocaine-induced convulsions. R(−)-DOI, mCPP, and MK212 reduced the threshold of meprylcaine or cocaine with less extent than the reduction of lidocaine threshold. Incidence of cocaine- and meprylcaine-induced convulsions was significantly reduced by 5-HT_2A,2B,2C antagonist, LY-53857, and 5-HT_2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT_2A antagonists MDL 11,939 and ketanserin, and 5-HT_2B antagonist SB 204741 except at high doses had little effect on cocaine- and meprylcaine-induced convulsions. None of these antagonists altered the parameters of lidocaine-induced convulsions. Pretreatment with fluoxetine but not citalopram increased the plasma concentration of lidocaine. These results suggest that the increase of serotonergic neuronal activity through 5-HT_2C receptor stimulation was responsible for increased activity of local anesthetics-induced convulsions and support the involvement of this mechanism in cocaine- and meprylcaine- but not in lidocaine-induced convulsions through their direct inhibitory action on central SERT.
Regional cerebral blood flow in female cocaine-addicted subjects following limbic activation
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Background: Cocaine dependence follows a different disease course in men and women, possibly as a consequence of sex-specific neurobiologic responses to chronic cocaine use. We have previously reported that male cocaine-dependent subjects demonstrate a significantly different limbic response to the limbic-stimulus procaine, as measured by regional cerebral blood flow (rCBF), compared with male controls. In this study, we assessed the limbic rCBF response to procaine in female cocaine-addicted subjects (n=10) and female controls (n=10). Methods: Subjects were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Single photon emission computed tomography (SPECT) was used to compare the rCBF response to procaine. Results: Female cocaine-dependent subjects demonstrate a markedly muted, and distinctly different, limbic response to procaine compared with matched healthy controls. Conclusions: The rCBF response to procaine in female cocaine-dependent subjects suggests significant CNS differences compared with non-addicted female controls. Coupled with findings previously observed in male cocaine-dependent subjects, these biologic differences suggest that both male and female subjects experience alterations in limbic responsiveness following the chronic use of cocaine.
Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum
2003, Life Sciences
Citation Excerpt :
In these regions, a single dose of cocaine raises the extracellular concentration of DA, and the rise and decline of DA correspond closely to cocaine levels in the blood and brain (Madras et al., 1998). Also, behaviors such as motor excitation and hyperactivity are seen in individuals who administer psychostimulants (Woolverton and Balster, 1982). These clinical observations have generated considerable interest for the development of animal models for psychostimulant psychosis.
The mechanism of action of drugs of abuse like cocaine and amphetamines has been studied extensively in the dopamine terminal field areas of the caudate-putamen (CPu) and the nucleus accumbens (NAc) of the rodent brain. These brain regions contain several neuropeptides that must play important roles in the normal physiological functions of these brain regions. The study of neuropeptide physiology in the context of the neurobiological responses to drugs of abuse may shed some light on the intrinsic mechanism of action of neuropeptides of the CPu and the NAc. The neuropeptides substance P (SP) and cholecystokinin (CCK) are present in the striatum where they could play an important role regulating the effects of psychostimulants like cocaine and amphetamines (methamphetamine [METH] is a long acting derivative of d-amphetamine). These highly addictive agents induce the release of dopamine (DA) (and other catecholamines) from dopaminergic terminals of the striatum. The excessive release of DA in the striatum and the NAc has been implicated in the habit-forming properties of these drugs. In order to study the contribution of SP and CCK in the striatum during psychostimulant treatment, we employed selective non-peptide neurokinin-1 (NK-1) and cholecystokinin-2 (CCK-2) receptor antagonists that readily cross the blood brain barrier. We infused the neurokinin-1 receptor (NK-1R) antagonist, L-733,060, into the striatum of freely moving rats via a microdialysis probe in order to assess the effects of SP on cocaine-induced DA overflow in the striatum. Infusion of the NK-1R antagonist prior to a systemic injection of cocaine (10 mg/kg i.p.) significantly attenuated DA overflow in the striatum. Conversely, infusion of a CCK-2 receptor (CCK-2R) antagonist, L-369,293, through the microdialysis probe evoked DA overflow in the striatum in the absence of cocaine and potentiated DA overflow after a single injection of cocaine (10 mg/kg i.p.). Exposure to METH (10 mg/kg 4× at two-hour intervals) produced deficits of dopamine transporters (DAT) in mice striatum that are detectable three days after the treatment and are long lasting. Pre-treatment (i.p. injections) with the NK-1R antagonist, WIN-51,708 30 minutes before the 1st and 4th injections of METH prevented the loss of DAT in the striatum. Moreover, pre-treatment with the NK-1R antagonist prevents METH-induced cell death. Taken together, these results demonstrate that the NK-1R and the CCK-2R are important modulators of the actions of the psychostimulants cocaine and METH. Neuropeptide receptors represent an important control point mediating the effects of the neurotransmitter DA in the striatum of the rodent brain.

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^☆: Research supported by N.I.D.A. Grant DA-00490.

²: Postdoctoral Fellow Supported by N.I.D.A. Fellowship DA-05164. Present address: University of Chicago, Department of Pharmacological and Physiological Sciences, Chicago, IL 60637.

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Behavioral pharmacology of local anesthetics: Reinforcing and discriminative stimulus effects☆

Abstract

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Life Sci.

Pharmac. Biochem. Behav.

Mood alterations during deanol therapy

Psychopharmacology

Self-administration of psychoactive substances by the monkey: A measure of psychological dependence

Psychopharmacologia

Codeine- and cocaine-reinforced responding in rhesus monkeys: Effects of dose on response rates under a fixed-ratio schedule

J. Pharmac. exp. Ther.

The reinforcing properties of procaine and d-amphetamine compared in rhesus monkeys

J. Pharmac. exp. Ther.

Procaine as an acetylcholine agonist in snail neuron

J. Pharmac. exp. Ther.