Psychostimulant Properties Research Articles

Mechanism of action and therapeutic uses of psychostimulants.

1. Kevin F Foley, PhD MT(ASCP)[⇑][1] 1. is with the Department of Biomedical Technologies, University of Vermont, Burlington VT 1. Address for correspondence: Kevin F Foley PhD MT (ASCP), Assistant Professor, University of Vermont, Department of Medical Laboratory and Radiation Sciences, 302 Rowell Building, 106 Carrigan Drive, Burlington VT 05405. (802) 656-2506. kfoley{at}uvm.edu. The name stimulant can be given to any drug that increases the rate of a physiologic function. The term psychostimulant is more specific, referring to compounds that have direct neurological effects, typically: heightened alertness, increased energy, appetite suppression, and sometimes euphoria. Use of psychostimulants is widespread and occurs in both recreational and clinical settings. Therapeutic monitoring and screening for use and abuse of these drugs is common in clinical laboratories. Understanding the physiological effects and uses of stimulants will be of value to clinical and forensic laboratory scientists. EXAMPLES OF PSYCHOSTIMULANTS Table 1 lists several psychostimulants that are commonly prescribed, have widespread illicit use, or are well-known by the general public. Table 1 also identifies the control schedule of each compound. Many psychostimulants are listed as controlled substances under the Controlled Substances Act, Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. Schedules I through IV are assigned to compounds based on their abuse potential and their medical utility. Schedules II through V contain drugs which have known medical uses whereas Schedule I compounds have no current, sanctioned medical use. THERAPEUTIC USES OF PSYCHOSTIMULANTS Amphetamine has long been known to be a mental stimulant. Because of its psychostimulant properties, amphetamine has been used successfully by U.S. fighter pilots because it enhances cockpit performance by reducing the effects of fatigue.1 Since amphetamine heightens alertness it has found use in the treatment of narcolepsy and in attention-deficit hyperactivity disorder.2 The drug Adderall® for example, is used widely in… ABBREVIATIONS: ADHD = attention-deficit hyper-activity disorder; CNS = central nervous system; MDA = 3,4-methylenedioxyamphetamine; MDMA = 3,4-methylenedioxymethamphetamine; NC = not controlled; OTC = over the counter. [1]: #corresp-1

L-type Ca2+ channels mediate adaptation of extracellular signal-regulated kinase 1/2 phosphorylation in the ventral tegmental area after chronic amphetamine treatment.

L-type Ca2+ channels (LTCCs) play an important role in chronic psychostimulant-induced behaviors. However, the Ca2+ second messenger pathways activated by LTCCs after acute and recurrent psychostimulant administration that contribute to drug-induced molecular adaptations are poorly understood. Using a chronic amphetamine treatment paradigm in rats, we have examined the role of LTCCs in activating the mitogen-activated protein (MAP) kinase pathway in the ventral tegmental area (VTA), a primary target for the reinforcing properties of psychostimulants. Using immunoblot and immunohistochemical analyses, we find that in chronic saline-treated rats a challenge injection of amphetamine increases phosphorylation of MAP [extracellular signal-regulated kinase 1/2 (ERK1/2)] kinase in the VTA that is independent of LTCCs. However, in chronic amphetamine-treated rats there is no increase in amphetamine-mediated ERK1/2 phosphorylation unless LTCCs are blocked, in which case there is robust phosphorylation in VTA dopamine neurons. Examination of the expression of phosphatases reveals an increase in calcineurin [protein phosphatase 2B (PP2B)] and MAP kinase phosphatase-1 (MKP-1) in the VTA. Using in situ hybridization histochemistry and immunoblot analyses, we further examined the mRNA and protein expression of the LTCC subtypes Ca(v)1.2 and Ca(v)1.3 in VTA dopamine neurons in drug-naive animals and in rats after chronic amphetamine treatment. We found an increase in Ca(v)1.2 mRNA and protein levels, with no change in Ca(v)1.3. Together, our results suggest that one aspect of LTCC-induced changes in second messenger pathways after chronic amphetamine exposure involves activation of the MAP kinase phosphatase pathway by upregulation of Ca(v)1.2 in VTA dopaminergic neurons.

Acetyl-L-carnitine reduces impulsive behaviour in adolescent rats.

The attention deficit/hyperactivity disorder (ADHD) can affect human infants and adolescents. One important feature of this disorder is behavioural impulsivity. This study assessed the ability of chronic acetyl-L-carnitine (ALC, saline or 100 mg/kg SC, plus 50 mg/kg orally) to reduce impulsivity in a validated animal model for ADHD. Food-restricted rats were tested during adolescence (postnatal days, pnd, 30-45) in operant chambers with two nose-poking holes, one delivering one food pellet immediately, and the other five pellets after a delay. Delay length was increased over days (from 0 to 80 s). Individual differences in the preference-delay curve emerged, with the identification of two distinct subpopulations, i.e. one with a nearly horizontal curve and another with a very steep ("impulsive") slope. The impulsivity profile was slightly but consistently reduced by chronic ALC administration. Consistent results were also obtained with methylphenidate (MPH, saline or 3 mg/kg IP twice daily). Impulsive rats exhibited a lower metabolite/serotonin (5HIAA/5HT) ratio in the medial frontal cortex (MFC) and lower noradrenaline (NA) levels in the MFC and cingulate cortex (CC) when compared with the other subgroup. The ALC treatment increased NA levels in the CC and the 5HIAA/5HT ratio in both CC and MFC. Present data suggest that ALC, a drug devoid of psychostimulant properties, may have some beneficial effects in the treatment of ADHD children.

Ethological analyses of crayfish behavior: a new invertebrate system for measuring the rewarding properties of psychostimulants

Recent investigations in invertebrate neurobiology have opened up a new line of research into the basic behavioral, neurochemical and genomic alterations that accompany psychostimulant drug exposure. However, the extent to which such findings relate to changes in motivational and learning processes, such as those that typify drug addictions, remains unclear. The present study addressed this issue in the crayfish, Orconectes rusticus. The first set of experiments demonstrated that intramuscular injections of cocaine and amphetamine have robust and distinguishable effects on crayfish behavior. In the second part of the study, the reinforcing properties of psychostimulants were tested in a series of conditioned place preference experiments. Amphetamine and, to a lesser extent, cocaine were both found to serve as rewards when their intra-circulatory infusion was coupled to a distinct visual environment. The monoaminergic regulation of behavior has been extensively studied in decapod crustaceans and the present experiments demonstrated that (mammalian) drugs of abuse, capable of interfering with monoamine chemistry, are similarly rewarding to crayfish. Behavioral studies in crayfish can provide a complementary approach to using other invertebrate species in addiction research.

Reduced inhibitory action of a GABAB receptor agonist on [3H]-dopamine release from rat ventral tegmental area in vitro after chronic nicotine administration

BackgroundThe activation of GABAB receptors in the ventral tegmental area (VTA) has been suggested to attenuate the rewarding properties of psychostimulants, including nicotine. However, the neurochemical mechanism that underlie this effect remains unknown. Since GABAB receptors modulate the release of several neurotransmitters in the mammalian brain, we have characterised the effect of the GABAB receptor agonist baclofen on the release of [3H]-dopamine ([3H]-DA) from VTA slices of naïve rats and of rats pre-treated with nicotine.ResultsIn naïve rats, baclofen concentration-dependently inhibited the electrically evoked release of [3H]-DA from the isolated VTA (EC50 = 0.103 μM, 95% CI = 0.043–0.249), without affecting the basal [3H]-monoamine overflow. This effect was mediated by activation of GABAB receptors as it was blocked by the selective receptor antagonist CGP55845A. Chronic administration of nicotine (0.4 mg kg-1, s.c., for 14 days) affected neither the basal nor the electrically evoked release of [3H]-DA from VTA slices. However, the inhibitory effect of baclofen (10 μM) on the stimulated [3H]-monoamine overflow was abolished in rats pre-treated with nicotine as compared to saline-injected controls.ConclusionsOur results demonstrate that GABAB receptor activation reduces the release of DA from the rat VTA. In addition, a reduced sensitivity of VTA GABAB receptors appears to develop after chronic exposure to nicotine. The resulting disinhibition of VTA DA neurones might therefore contribute to the sensitised dopaminergic responses observed in the rat mesocorticolimbic system following repeated administration of nicotine.

Cocaine alters mu but not delta or kappa opioid receptor-stimulated in situ [35S]GTPgammaS binding in rat brain.

Chronic cocaine administration produces alterations in mu and kappa opioid receptor density as well as striatal and accumbens opioid-regulated adenylyl cyclase activity, suggesting a psychostimulant responsive interaction between opioidergic and dopaminergic systems. Stimulation of G-protein-coupled opioid receptors inhibits adenylyl cyclase production of cyclic AMP. The present study employed in situ [(35)S]GTPgammaS binding to measure opioid receptor-stimulated activation of G-proteins in response to acute and chronic cocaine exposure. Male Fischer rats received acute (1 or 3 days) or chronic (14 days) binge pattern cocaine administration. Three and 14 days of cocaine injections resulted in greater increases in the ability of the mu receptor agonist DAMGO to stimulate [(35)S]GTPgammaS binding in both the core and the shell of the nucleus accumbens, all regions of the caudate putamen and the cingulate cortex compared with saline-matched controls. The greatest increases in DAMGO-stimulated [(35)S]GTPgammaS binding were observed in the dorsal areas of the caudate putamen in animals that received 14 days of cocaine. No significant changes in delta (DPDPE), or kappa (dynorphin A(1-17)) receptor-stimulated [(35)S]GTPgammaS binding were found in any brain region in response to cocaine administration. These results demonstrate that binge pattern cocaine administration induce changes in mu but not delta or kappa opioid receptor-mediated G-protein activity. This study provides support for the hypothesis that the addictive properties of both psychostimulants and opiates may share common neurochemical signaling substrates.

Isatin β‐Ethyleneketals as Psychotropics.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Brain-derived neurotrophic factor expression is increased in the rat amygdala, piriform cortex and hypothalamus following repeated amphetamine administration

The amygdala plays an important role in the regulation of motivational states, especially those associated with addiction. The amygdala also expresses high levels of brain-derived neurotrophic factor (BDNF), an activity-dependent neurotrophin that can influence the reinforcing and locomotor activating properties of psychostimulants. In the present study, we examined the effects of acute and repeated amphetamine administration on the expression and production of this factor in the forebrain of rats. Animals given a single, acute injection (5 mg/kg, i.p.) of d-amphetamine developed hyperactivity followed by stereotypical behavior but showed no change in the basal expression of BDNF mRNA or its immunocytochemical profile in any region except the piriform cortex. Repeated injections (5 days) of 5 mg/kg amphetamine were accompanied by an enhanced onset of stereotypical behavior and elevated BDNF mRNA in the basolateral amygdala, rostral piriform cortex and paraventricular nucleus of the hypothalamus. Repeated treatment also increased BDNF immunoreactivity in perikarya of these same regions. In addition, increased BDNF immunoreactivity was found in fibers of many projection targets of the basolateral amygdala—the central extended amygdala, olfactory tubercle, medial nucleus accumbens, and in small zones resembling striosomes in the dorsal medial striatum. These results suggest that the upregulation of BDNF expression and protein in the basolateral nucleus of the amygdala and its targets could be an important part of the neuroadaptive response to psychostimulants.

Pharmacokinetic differences of morphine and morphine-glucuronides are reflected in locomotor activity

The main metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), have been considered to participate in some of the effects of morphine. There is limited knowledge of the pharmacokinetics and dynamics of morphine and the main metabolites in mice, but mice are widely used to study both the analgesic effects and the psychomotor effects of morphine. The present study aimed to explore pharmacokinetic differences between morphine and morphine-glucuronides in mice after different routes of administration, and to investigate how possible differences were reflected in locomotor activity, a measure of psychostimulant properties. Mice were given morphine, M3G or M6G by different routes of administration. Serum concentrations versus time curves, pharmacokinetic parameters and locomotor activity were determined. Intraperitoneal administration of morphine reduced the bioavailability compared to intravenous and subcutaneous administration, but not so for morphine-glucuronides. The two morphine-glucuronides had similar pharmacokinetics, but morphine demonstrated higher volume of distribution and clearance than morphine-glucuronides. The present results demonstrated no locomotor effect of M3G, but a serum concentration effect relationship for morphine and M6G. When serum concentrations and effect changes were followed over time, there was some right hand shifts with respect to locomotor activity, especially during the declining phase of the concentration curve and particularly for M6G.

Evidence for opponent-process actions of intravenous cocaine and cocaethylene

The affective response to cocaine (COC) has been suggested to follow a time-course and pattern that adheres to the prediction of opponent-process models of drug actions. While the initial impact of the drug is positive, within a few minutes that effect wanes and is replaced by an aversive state characterized by anxiety and drug craving. We have demonstrated this phenomenon in animals by showing that rats prefer distinctive environments associated with the immediate effects of intravenous COC (1.0 mg/kg) but avoid environments associated with the state present 15-min postinjection. Human addicts have reported taking ethanol with their COC as a means of attenuating the negative aftereffects of COC administration. The combination of ethanol and COC results in the production of cocaethylene (CE), a metabolite of COC having psychostimulant properties. The current study was devised to assess whether the immediate and delayed affective responses to CE might account for the self-medication strategy of COC addicts pretreating themselves with ethanol. Rats developed conditioned place preferences for environments paired with the immediate effects of a 1.44-mg/kg intravenous dose of CE (equimolar to a 1.0-mg/kg dose of COC). While no aversive effects were observed at 0, 5, or 15 min postinjection, reliable place avoidance was detected for an environment paired with the internal state present 30-min post-CE. These data are consistent with the view that the development of CE may account for efficacy of ethanol to delay and weaken the aversive aftereffects of COC.

Stimulation of Endorphin Neurotransmission in the Nucleus Accumbens by Ethanol, Cocaine, and Amphetamine

Numerous studies have demonstrated that drugs of abuse activate the mesolimbic dopamine reward pathway, and it is widely held that this activation contributes to the motivational and positive reinforcing properties of these substances. However, there is evidence that endogenous opioid systems within this brain reward circuit also play a role in drug reinforcement and drug-seeking behavior. Using microdialysis in freely moving rats, we sought to determine whether various drugs of abuse (i.e., ethanol, cocaine, d-amphetamine, and nicotine) would increase neurotransmission of endogenous opioid peptides (i.e., endorphins) in the nucleus accumbens. Drugs were administered intraperitoneally twice at 3 h intervals, and the endorphin content of microdialysates was analyzed by a solid-phase radioimmunoassay. Acute administration of ethanol, cocaine, and d-amphetamine transiently elevated extracellular levels of endorphins in the nucleus accumbens, whereas nicotine and saline were without effect. We hypothesize that this drug-induced release of endorphins may contribute to the positive reinforcing and motivating properties of ethanol and psychostimulants.

A novel neurotensin analog blocks cocaine- and d-amphetamine-induced hyperactivity

Neurotensin is a tridecapeptide that exhibits selective anatomic and neurochemical interactions with dopaminergic systems. Since dopaminergic neurotransmission underlies many of the behavioral properties of psychostimulants, and since neurotensin has been implicated in modulating dopaminergic neurotransmitter systems, we tested the effect of our novel neurotensin analog, NT69L ( N-methyl-Arg 8, l-Lys 9, l- neo-Trp 11,tert-Leu 12]neurotensin-(8-13)), on hyperactivity caused by cocaine and d-amphetamine. Previously, we showed that NT69L reduces body temperature, blocks apomorphine-induced climbing, and haloperidol-induced catalepsy. In this study, NT69L blocked the hyperactivity induced by both cocaine and d-amphetamine administered at three different doses each, when this peptide was injected intraperitoneally. These results provide further evidence for the involvement of the neurotensin system in some of the behavioral properties of psychostimulants and suggest that NT69L may find clinical application in patients who abuse this class of compounds.

Differential effects of cocaine on local cerebral glucose utilization in the mouse and in the rat

The aim of the study was to determine whether cocaine causes a different pattern of functional changes in the rat as compared to the mouse. The [ 14C]2-deoxyglucose method, for measuring local cerebral metabolic rates for glucose, was carried out in Sprague–Dawley rats and in two strains of mice, C57BL/6 and DBA/2, following a single intravenous administration of cocaine. Cocaine, according to previous reports, increased glucose utilization in the nucleus accumbens of the rat, while the drug decreased metabolic rates in most of brain areas of both strains of mice. The post-hoc analysis, however, suggests that the pattern of metabolic changes differ in the two strains. In particular, the effect on the shell of the nucleus accumbens was present in the C57, but not in the DBA mice. As the C57 mice are more likely than DBA to initiate cocaine self-administration, the effect on the nucleus accumbens support the role of the mesolimbic pathway in mediating the motivational properties of psychostimulants.

Chronic dopaminergic signaling in the basal ganglia: a damage perspective on kinases and fos-related antigens

Abstract Specific protein phosphorylation pathways have been shown to play a role in cellular adaptation responses underlying addiction to psychostimulants such as methamphetamine and cocaine. Transcriptional regulation through fos-related antigens constitutes one element through which these dopaminergic agonists exert their persistent actions. In addition to their addictive properties, amphetamines are known to damage dopaminergic nerve terminals. Although not widely appreciated, protein phosphorylation cascades and fos-related antigens also may play a role in the neurotoxic actions of substituted amphetamines such as methamphetamine. Here we document the involvement of the dopaminoceptive phosphoprotein, DARPP-32, the fos-related antigen, FRA-2, and the growth associated protein kinase, MAP kinase, in the neurotoxic action of known dopaminergic neurotoxicants, including methamphetamine. The addictive and neurotoxic properties of psychostimulants may share some molecular signaling mechanisms.

The α 4 β 2 agonist SIB 1765F, but not the α 7 agonist AR-R 17779, cross-sensitises to the psychostimulant effects of nicotine

Repeated administration of nicotine leads to an augmentation of its locomotor activating effects. Although studies have begun to identify the nicotinic receptor subtype(s) mediating the psychostimulant properties of nicotine, none as yet have investigated the subtypes which contribute to the process of sensitisation. We therefore investigated cross-sensitisation to nicotine using subjects chronically treated with two nicotine subtype-selective agonists in an attempt to identify the relative contribution of each to the sensitisation process. Rats received ten daily injections of either vehicle, nicotine (0.4 mg/kg), the alpha7-agonist AR-R 17779 (20 mg/kg), or the alpha4beta2-agonist SIB 1765F (3 mg/kg), and their subsequent locomotor response to acute challenge with each of these compounds was assessed. Chronic administration of both nicotine and SIB 1765F, but not AR-R 17779, resulted in an enhanced locomotor response to acute challenge with either nicotine or SIB 1765F but not AR-R 17779. These data support a role for the alpha4beta2 receptor in both the initiation and expression of sensitisation to the psychomotor stimulant effects of nicotine.

Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat.

Modafinil is a newly discovered waking substance now being used in the treatment of hypersomnia and narcolepsy. We have shown previously in the cat that, unlike amphetamine, modafinil induces long-lasting wakefulness (W) without behavioral excitation and subsequent sleep rebound, and that its waking effect does not depend on endogenous catecholamines. To further characterize the awakening properties of modafinil and current psychostimulants in experimental models of hypersomnia, we examined the effect of oral administration of placebo, modafinil (5 mg kg-1) or amphetamine (1 mg kg-1) on the sleep/wake cycle and power spectral density (PSD) in cats after an 18-h water-tank sleep deprivation period. We found that the placebo had no effect on the dynamics of sleep recovery, while both modafinil and amphetamine induced suppression of cortical slow activity and a waking state lasting 6-8 h. After the amphetamine-induced waking period, both deep slow wave sleep (SWS2) and paradoxical sleep (PS) occurred in greater amounts than after placebo and the PSD during SWS was also increased. Thus, the cumulative time spent in W during a 48-h period was similar to that with placebo, indicating enhanced sleep rebound. In contrast, after the modafinil-induced W, the occurrence and evolution of SWS2 or PS, as well as the PSD during SWS, were similar to those seen with placebo during the same period, so that the total time spent in W in a 48-h period remained significantly higher than the control level, indicating no additional sleep rebound. These results indicate that modafinil is effective against somnolence and hypersomnia and does not produce a subsequent increase in sleep and suggest that the pharmacological profile of modafinil is different from that of amphetamine.

Interaction of benztropine and haloperidol actions on rat substantia nigra dopamine cell electrophysiological activity in vivo

Despite the known efficacy of antimuscarinic agents in treating dopamine-related movement disorders, their effects on dopamine cell activity have not been well studied. We investigated the effects of systemically administered benztropine, an antimuscarinic agent that also inhibits the dopamine transporter, on substantia nigra dopamine neuron electrophysiological activity. Benztropine caused a dose-dependent inhibition of the firing rate of dopamine neurons in control rats but exerted baseline-dependent changes in burst firing. In rats pretreated with haloperidol, which prevents the effects of dopamine transporter inhibitors on dopamine cell activity, benztropine either increased or decreased firing rate; however, it consistently increased burst firing. Thus, the antimuscarinic and psychostimulant properties of benztropine have differential effects on dopamine neuron firing rate and burst firing. The increase in burst firing seen in the presence of haloperidol may mediate some of the therapeutic effects of benztropine in the treatment of antipsychotic drug-induced movement disorders.

Differential sensitivity to alcohol reinforcement in groups of men at risk for distinct alcoholism subtypes.

The present study examines the relationship of familial and personality risk factors for alcoholism to individual differences in sensitivity to the positively and negatively reinforcing properties of alcohol. Sixteen sons of male alcoholics with multigenerational family histories of alcoholism (MFH) and 11 men who self-report heightened sensitivity to anxiety (HAS) were compared with 13 age-matched family history negative, low anxiety sensitive men (FH-LAS) on sober and alcohol-intoxicated response patterns. We were interested in the effects of alcohol on specific psychophysiological indices of "stimulus reactivity," anxiety, and incentive reward. Alcohol significantly dampened heart rate reactivity to aversive stimulation for the MFH and HAS men equally, yet did not for the FH-LAS group. HAS men evidenced idiosyncrasies with respect to alcohol-induced changes in electrodermal reactivity to aversive stimulation (an index of anxiety/fear-dampening), and MFH men demonstrated elevated alcohol-intoxicated resting heart rates (an index of psychostimulation) relative to the FH-LAS men. The results are interpreted as reflecting a sensitivity to the "stimulus reactivity-dampening" effects of alcohol in both high-risk groups, yet population-specific sensitivities to the fear-dampening and psychostimulant properties of alcohol in the HAS and MFH groups, respectively.

Mediation of the Discriminative Stimulus Properties of Cocaine by Mesocorticolimbic Dopamine Systems

This paper provides a brief review of the scientific evidence implicating the mesocorticolimbic dopamine (DA) system in modulating the discriminative stimulus properties of cocaine in rats. Briefly, systemic administration of DA releasers, reuptake inhibitors, and DA D1, D2, and putative D3 receptor agonists engendered partial to full substitution for the discriminative stimulus effects of cocaine. Dopamine D1 and D2 receptor antagonists attenuate this behavioral property of cocaine. Intracranial microinjection studies have indicated certain key limbic nuclei as loci of action for DA in mediating the discriminative stimulus effects of cocaine. Microinjections of cocaine into either DA cell body (i.e., ventral tegmental area, substantia nigra) or DA terminal regions (i.e., prefrontal cortex, central amygdala, caudate putamen) have failed to reproduce the systemic cocaine discriminative stimulus. Only infusion of cocaine into the nucleus accumbens has been demonstrated to substitute fully for the systemic effects of this psychostimulant. Interestingly, microinjections of the DA D1 receptor antagonist SCH 23390 into either the prefrontal cortex, nucleus accumbens, or central or basolateral amygdala have been demonstrated to block the discriminative stimulus properties of cocaine. Although a determination of the antagonism of the cocaine discriminative stimulus following intra-accumbens microinjection of DA D2 receptor antagonists has not been made, intra- accumbens administration of the DA D2 receptor antagonist sulpiride blocked the discriminative stimulus effects of another psychostimulant, amphetamine. 6-Hydroxydopamine lesions of DA terminals in the nucleus accumbens also attenuated the dose–effect curve for systemic administration of cocaine. Taken together, this intracranial evidence suggests that DA D1 and D2 receptors in the mesocorticolimbic system are involved in modulating the discriminative stimulus properties of psychostimulants and that the nigrostriatal DA system is not primarily involved.

DOES SELECTIVE BREEDING FOR COCAETHYLENE PREFERENCE PRODUCE DIFFERENT BEHAVIORS IN RATS?

In an attempt to understand polysubstance abuse, and because little research has been performed regarding cocaethylene and genetic traits, the overall goal of this study was to determine if the hepatically synthesized metabolite of concurrent cocaine and ethanol administration, cocaethylene (CE), would display a genetic predisposition in rodents to seek its rewarding effects. This overall goal was achieved by employing the behavioral paradigm of conditional place preference (CPP). Male rats who were shown to highly prefer the effect of cocaethylene were mated with preferring females; nonpreferring males were mated with nonpreferring females; and randomly selected rats from the lower ends of each group were also mated. Subjects were selectively bred based on their degree of place preference to cocaethylene administration. The rats were further tested for locomotor activation by the psychostimulant properties of cocaethylene and for discrimination of interoceptive cues by using the drug discrimination parad...