Individual differences and social influences on the neurobehavioral pharmacology of abused drugs.

The interaction of drugs with biologic targets is a critical area of research, particularly for the development of medications to treat substance use disorders. In addition to understanding these drug-target interactions, however, there is a need to understand more fully the psychosocial influences that moderate these interactions. The first section of this review introduces some examples from human behavioral pharmacology that illustrate the clinical importance of this research. The second section covers preclinical evidence to characterize some of the key individual differences that alter drug sensitivity and abuse vulnerability, related primarily to differences in response to novelty and impulsivity. Evidence is presented to indicate that critical neuropharmacological mechanisms associated with these individual differences involve integrated neurocircuits underlying stress, reward, and behavioral inhibitory processes. The third section covers social influences on drug abuse vulnerability, including effects experienced during infancy, adolescence, and young adulthood, such as maternal separation, housing conditions, and social interactions (defeat, play, and social rank). Some of the same neurocircuits involved in individual differences also are altered by social influences, although the precise neurochemical and cellular mechanisms involved remain to be elucidated fully. Finally, some speculation is offered about the implications of this research for the prevention and treatment of substance abuse.

Diet-induced obesity: dopamine transporter function, impulsivity and motivation.

OBJECTIVE: A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. DESIGN: To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. METHODS: Striatal D2-receptor density was determined by in vitro kinetic analysis of [(3)H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [(3)H]dopamine uptake, methamphetamine-evoked [(3)H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. RESULTS: Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [(3)H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. CONCLUSION: Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that motivation for high-fat food, but not impulsive behavior, predicts the development of obesity, whereas decreases in striatal DAT function are exhibited only after the development of obesity.

Effects of Social Isolation on Perineuronal Nets in the Amygdala Following a Reward Omission Task in Female Rats.

Negative urgency is a facet of impulsivity associated with negative affect and risky behavior that may involve the amygdala. The current study determined if social isolation during development alters negative urgency and c-Fos activity in the basolateral amygdala (BLA). Female Sprague-Dawley rats were raised in an isolated condition (IC), a standard social condition (SC), or an enriched condition (EC) and then were tested for locomotor activity, novelty place preference, and negative urgency using a reward omission task. Following performance on the reward omission task, the brains were analyzed for c-Fos expression in Ca2+/calmodulin kinase II (CaMKII) and calbindin (CB) neurons, as well as in parvalbumin (PV) neurons associated with perineuronal nets (PNNs) in BLA. IC rats exhibited enhanced locomotion compared with both SC and EC rats, as well as enhanced novelty place preference compared with EC rats; only IC rats showed increased responding following omission of an expected reward (negative urgency). Following completion of the reward omission task, IC rats also displayed increased percent of c-Fos neurons in BLA associated with CaMKII, CB, and PV neurons compared with SC and EC rats. In IC rats, c-Fos activation in BLA occurred following the omission of an expected reward. Finally, IC rats displayed reduced PNN intensity associated with PV neurons compared with EC rats, but the percent of these neurons co-expressing c-Fos was greater in IC rats; SC rats were intermediate between IC and EC rats. Negative urgency was observed in IC rats, but not SC or EC rats. While multiple mechanisms are likely involved, this behavioral effect was associated with an isolation-induced increase in activity of excitatory neurons in BLA, as well as decreased PNN intensity surrounding GABAergic neurons in the same region.

Effects of methamphetamine isomers on d-methamphetamine self-administration and food-maintained responding in male rats.

RATIONALE: Methamphetamine (METH) abuse is generally attributed to the d-isomer. Self-administration of l-METH has been examined only in rhesus monkeys with a history of cocaine self-administration or drug-naïve rats using high toxic doses. OBJECTIVES: In this study, the ability of l-METH and, for comparison, d-METH to engender self-administration in experimentally naïve rats, as well as to decrease d-METH self-administration and food-maintained responding, was examined. METHODS: Male Sprague-Dawley rats were used in 3 separate experiments. In experiment 1, the acquisition of l- or d-METH self-administration followed by dose-response determinations was studied. In experiment 2, rats were trained to self-administer d-METH (0.05 mg/kg/infusion) and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (30 mg/kg) also was examined. In experiment 3, rats were trained to respond for food reinforcement and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (3 mg/kg) also was examined. RESULTS: Reliable acquisition of l- and d-METH self-administration was obtained at unit doses of 0.5 and 0.05 mg/kg/infusion respectively. The dose-response function for l-METH self-administration was flattened and shifted rightward compared with d-METH self-administration, with peak responding for l- and d-METH occurring at unit doses of 0.17 and 0.025 respectively. l-METH also was approximately 10-fold less potent than d-METH in decreasing d-METH self-administration and 2-fold lower in decreasing food-maintained responding. Tolerance did not occur to repeated l-METH pretreatments on either measure. CONCLUSIONS: As a potential pharmacotherapeutic, l-METH has less abuse liability than d-METH and its efficacy in decreasing d-METH self-administration and food-maintained responding is sustained with repeated treatment.

Region-specific effects of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide on nicotine-induced increase in extracellular dopamine in vivo.

BACKGROUND AND PURPOSE: Systemic administration of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), an antagonist of nicotinic acetylcholine receptors (nAChRs) attenuated the nicotine-induced increase in dopamine levels in nucleus accumbens (NAcc). EXPERIMENTAL APPROACH: Using in vivo microdialysis, we investigated the effects of local perfusion of the novel nAChR antagonist bPiDDB into the NAcc or ventral tegmental area (VTA) on increased extracellular dopamine in NAcc, induced by systemic nicotine. We also examined the concentration-dependent effects of bPiDDB on the acetylcholine (ACh)-evoked response of specific recombinant neuronal nAChR subtypes expressed in Xenopus oocytes, using electrophysiological methods. KEY RESULTS: Nicotine (0.4 mg kg(-1), s.c.) increased extracellular dopamine in NAcc, which was attenuated by intra-VTA perfusion of mecamylamine (100 microM). Intra-VTA perfusion of bPiDDB (1 and 10 microM) reduced nicotine-induced increases in extracellular dopamine in NAcc. In contrast, intra-NAcc perfusion of bPiDDB (1 or 10 microM) failed to alter the nicotine-induced increase in dopamine in NAcc. Intra-VTA perfusion of bPiDDB alone did not alter basal dopamine levels, compared to control, nor the increased dopamine in NAcc following amphetamine (0.5 mg kg(-1), s.c.). Using Xenopus oocytes, bPiDDB (0.01-100 microM) inhibited the response to ACh on specific combinations of rat neuronal nAChR subunits, with highest potency at alpha3beta4beta3 and lowest potency at alpha6/3beta2beta3. CONCLUSIONS AND IMPLICATIONS: bPiDDB-Sensitive nAChRs involved in regulating nicotine-induced dopamine release are located in the VTA, rather than in the NAcc. As bPiDDB has properties different from the prototypical nAChR antagonist mecamylamine, further development may lead to novel nAChR antagonists for the treatment of tobacco dependence.

Effects of nornicotine enantiomers on intravenous S(-)-nicotine self-administration and cardiovascular function in rats.

RATIONALE: Previous neurochemical evidence indicates that R(+)-nornicotine is more potent than S(-)-nornicotine in evoking dopamine release in rat nucleus accumbens slices. OBJECTIVE: The current study tested the hypothesis that R(+)-nornicotine is also more potent than S(-)-nornicotine in selectively decreasing intravenous S(-)-nicotine self-administration in rats. RESULTS: After acute pretreatment (1-10 mg/kg for each enantiomer), R(+)-nornicotine was more potent than S(-)-nornicotine in decreasing S(-)-nicotine self-administration; in contrast, within the same dose range, the nornicotine enantiomers were equipotent in decreasing sucrose-maintained responding. This enantioselectivity does not likely reflect a difference in bioavailability, since similar levels of nornicotine were recovered from the brain 60 min after injection (5.6 mg/kg for each enantiomer). With repeated pretreatment, tolerance did not develop to the rate-decreasing effect of either nornicotine enantiomer (3 or 5.6 mg/kg) with respect to the decrease in S(-)-nicotine self-administration, although the enantioselectivity dissipated across repeated pretreatments. While both enantiomers acutely produced a similar increase in blood pressure and heart rate, tolerance developed to the blood pressure effects of R(+)-nornicotine, but not to the effects of S(-)-nornicotine, across repeated treatments. CONCLUSION: Both R(+)- and S(-)-nornicotine may have potential utility as a novel tobacco use cessation agent.

Age and sex differences in the locomotor effect of repeated methylphenidate in rats classified as high or low novelty responders.

RATIONALE: Rats displaying high levels of activity in an inescapable novel environment (high responders; HR) are more sensitive to the locomotor effect of stimulant drugs than rats displaying low levels of activity (low responders; LR). OBJECTIVE: The current study determined the age- and sex-dependent locomotor effects of repeated methylphenidate in HR and LR rats. MATERIALS AND METHODS: Periadolescent and adult male and female Sprague-Dawley rats were first classified as HR or LR; rats were also classified as high or low novelty seekers based on free-choice preference for a novel environment. Locomotor activity was subsequently assessed after ten daily injections of methylphenidate (3 or 10 mg/kg s.c.) or saline. Fifteen days later, rats were challenged with saline and methylphenidate (10 mg/kg) over 2 days. RESULTS: During the repeated methylphenidate treatment phase, adult females showed greater methylphenidate-induced hyperactivity than adult males; there was no reliable difference in methylphenidate-induced hyperactivity between HR and LR rats of either age or sex. However, periadolescent male HR rats given repeated methylphenidate showed greater conditioned hyperactivity after the saline challenge than periadolescent male LR rats. Further, adult female HR rats given repeated methylphenidate showed greater conditioned hyperactivity and sensitization than adult female LR rats. In contrast, although free-choice novelty preference was greater among periadolescents than adults, individual differences in this variable did not predict the effect of repeated methylphenidate during any phase of the experiment. CONCLUSION: Although individual differences in response to inescapable novelty predict methylphenidate-induced conditioned hyperactivity and sensitization, this relationship is moderated by age and sex.

Effect of a novel nicotinic receptor antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide, on nicotine self-administration and hyperactivity in rats.

RATIONALE AND OBJECTIVE: Recent work has shown that the novel compound N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) may selectively block nicotinic acetylcholine receptors involved in regulating dopamine release. The current experiments examined the acute effect of bPiDDB on nicotine self-administration, sucrose-maintained responding, and nicotine-induced changes in acute and sensitized locomotor activity. METHODS: Rats were first trained to respond for either nicotine (i.v.) or sucrose pellets using a standard two-lever operant conditioning procedure using a fixed ratio 5 schedule of reinforcement and were then pretreated with bPiDDB (0, 0.3, 1, or 3 mg kg(-1)) 15 min prior to the session. In separate experiments, rats were assessed for nicotine-induced changes in locomotor activity following pretreatment with bPiDDB (1 or 3 mg kg(-1)) or mecamylamine (1 mg kg(-1)); pretreatments were assessed with both acute and repeated nicotine (0.4 mg kg(-1)) treatment. RESULTS: Results showed that bPiDDB dose-dependently decreased nicotine self-administration, but not sucrose-maintained responding. In the locomotor experiments, bPiDDB attenuated the hyperactivity produced by acute and repeated nicotine; however, this effect was not robust compared to mecamylamine. In contrast to mecamylamine, bPiDDB did not block the initial hypoactivity produced by acute nicotine. CONCLUSION: Since bPiDDB decreased nicotine self-administration specifically, this novel nicotinic receptor antagonist may constitute a lead for the development of a clinically useful treatment for tobacco dependence.

Contribution of dihydro-beta-erythroidine sensitive nicotinic acetylcholine receptors in the ventral tegmental area to cocaine-induced behavioral sensitization in rats.

Nicotinic acetylcholine receptors (nAChRs) are known to play a role in several aspects of cocaine addiction. Recently, systemic administration of the nicotinic receptor antagonist mecamylamine was shown to block the induction of long-term locomotor sensitization to cocaine. Behavioral sensitization being a model of long-term neuroadaptations to chronic cocaine exposure, the goal of the current study was to identify the anatomical localization, as well as the nature, of the nicotinic receptors involved. Male Sprague-Dawley rats were stereotaxically implanted with bilateral cannula into either the ventral tegmental area (VTA) or the nucleus accumbens (Nacc). On each of the six consecutive days, rats were microinjected bilaterally with the selective nicotinic antagonists dihydro-beta-erythroidine (DHbetaE), methyllycaconitine (MLA) or saline, followed by an intra-peritoneal injection of cocaine (15 mg/kg, i.p.) or saline. Following a 2-week withdrawal period, rats received a final injection of cocaine in the absence of nicotinic antagonist to test for sensitization. When microinjected into the VTA, DHbetaE, but not MLA, prevented the induction of behavioral sensitization to cocaine. In contrast, behavioral sensitization was present in rats receiving DHbetaE microinjections into the Nacc. Neither antagonist, whether injected into the VTA or the Nacc had any significant effect on the acute locomotor response to cocaine. Given the subtype selectivity of the nicotinic antagonists employed, heteromeric beta2-containing (beta2*) nAChRs, but not homomeric alpha7* nAChRs, in the VTA may be involved in the neuroadaptive changes underlying cocaine sensitization.

Effect of amphetamine on response inhibition in rats showing high or low response to novelty.

Previous work has shown that rats categorized as either high responder (HR) or low responder (LR) based on the amount of activity assessed in a novel environment show a differential response to stimulant reward, with HR rats self-administering more amphetamine and cocaine than LR rats. The current study assessed behavioral inhibitory processes in HR and LR rats using either fixed consecutive number (FCN) or differential reinforcement of low rate of responding (DRL) tasks. Individual differences in free-choice preference for a novel environment or novel object were also assessed to determine if these measures were predictive of performance on these inhibitory tasks. Results showed that, regardless of the test used to characterize individual differences in response to novelty, groups showed a similar ability to learn the FCN and DRL tasks. When subsequently pretreated with amphetamine, there was no significant difference between groups in performance efficiency (accuracy) on either the FCN or DRL task; however, based on activity in inescapable novelty, HR rats were less sensitive than LR rats to amphetamine-disrupted responding on the reinforcement lever in the FCN task. Although a deficit in inhibition is generally thought to play a role in drug abuse behavior, the differential rate of stimulant self-administration described previously between HR and LR rats more likely reflects an incentive motivational effect that is independent of response inhibition.

Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD.

Impulsivity and hyperactivity are two facets of attention deficit/hyperactivity disorder (ADHD). Impulsivity is expressed as reduced response inhibition capacity, an executive control mechanism that prevents premature execution of an intermittently reinforced behavior. During methylphenidate treatment, impulsivity and hyperactivity are decreased in adolescents with ADHD, but there is little information concerning levels of impulsivity and hyperactivity in adulthood after adolescent methylphenidate treatment is discontinued. The current study evaluated impulsivity, hyperactivity as well as cocaine sensitization during adulthood after adolescent methylphenidate treatment was discontinued in the Spontaneously Hypertensive Rat (SHR) model of ADHD. Treatments consisted of oral methylphenidate (1.5mg/kg) or water vehicle provided Monday-Friday from postnatal days 28-55. During adulthood, impulsivity was measured in SHR and control strains (Wistar Kyoto and Wistar rats) using differential reinforcement of low rate (DRL) schedules. Locomotor activity and cocaine sensitization were measured using the open-field assay. Adult SHR exhibited decreased efficiency of reinforcement under the DRL30 schedule and greater levels of locomotor activity and cocaine sensitization compared to control strains. Compared to vehicle, methylphenidate treatment during adolescence reduced hyperactivity in adult SHR, maintained the lower efficiency of reinforcement, and increased burst responding under DRL30. Cocaine sensitization was not altered following adolescent methylphenidate in adult SHR. In conclusion, adolescent treatment with methylphenidate followed by discontinuation in adulthood had a positive benefit by reducing hyperactivity in adult SHR rats; however, increased burst responding under DRL compared to SHR given vehicle, i.e., elevated impulsivity, constituted an adverse consequence associated with increased risk for cocaine abuse liability.

Individual differences in impulsive action and dopamine transporter function in rat orbitofrontal cortex.

Impulsivity, which can be subdivided into impulsive action and impulsive choice, is implicated as a factor underlying drug abuse vulnerability. Although previous research has shown that dopamine (DA) systems in prefrontal cortex are involved in impulsivity and substance abuse, it is not known if inherent variation in DA transporter (DAT) function contributes to impulsivity. The current study determined if individual differences in either impulsive action or impulsive choice are related to DAT function in orbitofrontal (OFC) and/or medial prefrontal cortex (mPFC). Rats were first tested both for impulsive action in a cued go/no-go task and for impulsive choice in a delay-discounting task. Following behavioral evaluation, in vitro [(3)H]DA uptake assays were performed in OFC and mPFC isolated from individual rats. Vmax in OFC, but not mPFC, was correlated with performance in the cued go/no-go task, with decreased OFC DAT function being associated with high impulsive action. In contrast, Vmax in OFC and mPFC was not correlated with performance in the delay-discounting task. The current results demonstrate that impulsive behavior in cued go/no-go performance is associated with decreased DAT function in OFC, suggesting that hyperdopaminergic tone in this prefrontal subregion mediates, at least in part, increased impulsive action.

Critical needs in drug discovery for cessation of alcohol and nicotine polysubstance abuse.

Polysubstance abuse of alcohol and nicotine has been overlooked in our understanding of the neurobiology of addiction and especially in the development of novel therapeutics for its treatment. Estimates show that as many as 92% of people with alcohol use disorders also smoke tobacco. The health risks associated with both excessive alcohol consumption and tobacco smoking create an urgent biomedical need for the discovery of effective cessation treatments, as opposed to current approaches that attempt to independently treat each abused agent. The lack of treatment approaches for alcohol and nicotine abuse/dependence mirrors a similar lack of research in the neurobiology of polysubstance abuse. This review discusses three critical needs in medications development for alcohol and nicotine co-abuse: (1) the need for a better understanding of the clinical condition (i.e. alcohol and nicotine polysubstance abuse), (2) the need to better understand how these drugs interact in order to identify new targets for therapeutic development and (3) the need for animal models that better mimic this human condition. Current and emerging treatments available for the cessation of each drug and their mechanisms of action are discussed within this context followed by what is known about the pharmacological interactions of alcohol and nicotine. Much has been and will continue to be gained from studying comorbid alcohol and nicotine exposure.

Conditioned place preference using opiate and stimulant drugs: a meta-analysis.

A meta-analysis was conducted on the data obtained from published articles that have used the conditioned place preference (CPP) paradigm to assess the rewarding effects of morphine, heroin, amphetamine and cocaine in rats. Using a histogram analysis of the data, significant dose-effect curves were evident with all of the drugs examined, except for cocaine. Analysis of the data also revealed that several methodological variables moderated the effect size for CPP, at least with some of the drugs examined. In particular, the following methodological variables significantly moderated CPP effect size: strain of rat used; housing condition (single or group cages); type of apparatus (2 or 3 compartments); preconditioning test (present or absent); route of drug administration; intervening saline trials (present or absent); conditioning trial duration; and drug compartment (nonpreferred, counterbalanced or white). No significant effect size differences were evident using sex, number of drug trials, or test duration as moderator variables in the analyses. These meta-analytic results may be useful to investigators for maximizing the effect size of drug-induced CPP.

Impaired supersensitivity to morphine following chronic naltrexone treatment in senescent rats.

Chronic administration of opiate antagonists produces an increase in the density of opiate receptors, as well as an enhanced sensitivity to the analgesic and locomotor depressant effects of morphine. The present study assessed whether aging alters these regulatory processes. Young (3-4 months), middle-aged (10-11 months), and senescent (25-30 months) rats were implanted subdermally with slow-release naltrexone pellets or were given sham surgery. The pellets were removed 10 days later. Twenty-four hours after pellet removal, morphine-induced (5 mg/kg, SC) analgesia and locomotor activity were assessed. Young and middle-aged rats treated with naltrexone showed enhanced sensitivity to the analgesic and locomotor activity depressant effects of morphine relative to age-matched controls. In contrast, senescent rats treated with naltrexone did not differ from age-matched controls in their response to morphine. The density of opiate receptors labeled with 3H-naloxone was measured in the anterior striatum. Both young and senescent rats treated with naltrexone exhibited an increase in opiate receptor density relative to age-matched controls. The results indicate that senescent rats are capable of up-regulating opiate receptors following chronic naltrexone treatment but do not exhibit the corresponding functional supersensitivity to morphine.

Up-regulation of opiate receptors following chronic naloxone treatment in aged rats.

The present study assessed whether there are age-dependent differences in up-regulation of opiate receptors following chronic naloxone treatment in mature (3 months) and aged (27 months) male Wistar rats. Half of each age group were implanted subdermally with slow-release naloxone pellets for 10 days, and half were given sham surgery. Twenty-four hours after pellet removal, the rats were decapitated and various CNS areas including spinal cord, hindbrain, midbrain, diencephalon, hippocampus, striatum, olfactory tubercles/nucleus accumbens and prefrontal cortex were dissected and assayed for [3H]naloxone binding. The results indicated that aged rats had fewer opiate receptors in the spinal cord, midbrain, striatum, and olfactory tubercle/nucleus accumbens. Despite this age-related decline in opiate receptors, aged rats showed an up-regulation response similar to mature rats in all areas except the hippocampus of the left hemisphere, where they showed enhanced up-regulation relative to mature rats. The maintained plasticity of the opioid system contrasts with findings in other receptors systems where age-related impairments of antagonist-induced up-regulation have been reported.

Ontogenetic changes in dopaminergic pre and postsynaptic elements in rat brain: effects of quinpirole and sulpiride.

The effects of quinpirole and sulpiride on dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and accumulation of dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase were determined for the striatum and tegmentum of 11- and 17-day-old rat pups. In both 11- and 17-day-olds, sulpiride enhanced striatal DOPAC and DOPA accumulation; whereas, quinpirole decreased DOPAC levels and increased DA levels. In the tegmentum, sulpiride enhanced DOPA accumulation in the 11-day-olds only. 3H-spiroperidol binding sites were also measured in the striatum, nucleus accumbens, tegmentum, medial frontal cortex, and the hippocampo-entorhinal area of 11- and 17-day-old pups. Age-dependent increases in binding site density were found in the striatum and nucleus accumbens.

The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release.

In two separate experiments, rats were raised in either an enriched condition (EC) or impoverished condition (IC) from 21 to 60 days of age. Experiment 1 assessed amphetamine-stimulated locomotor activity and in vivo dopamine (DA) synthesis and metabolism in the nucleus accumbens (NA) and striatum (Str). In Experiment 2, amphetamine-stimulated DA release in the NA and Str was assessed in vitro. The results showed that EC rats have lower basal levels of locomotor activity than IC rats. However, in the presence of amphetamine, EC rats showed a greater increase in locomotion over IC when compared to their own controls. Concomitant with this behavioral difference, EC rats also showed an enhanced neurochemical response to amphetamine in vivo. That is, relative to IC rats, amphetamine produced a greater synthesis of DA in the Str of EC rats, as well as a greater metabolism of DA in the NA of EC rats. In the in vitro DA release experiment, EC rats had a lower concentration of tissue DA than IC. However, in contrast to the in vivo experiment, there were no significant differences between EC and IC rats in amphetamine-stimulated release of DA in vitro in either the Str or NA. The failure of amphetamine to produce differential neurochemical effects in EC and IC rats in vitro may be because this experiment eliminated either pharmacokinetic effects or neurochemical differences in brain regions outside the NA and Str.

Effects of EEDQ on the synthesis and metabolism of dopamine in preweanling and adult rats.

Ontogenetic differences in dopamine (DA) synthesis and metabolism were assessed in 17- and 90-day-old rats injected i.p. with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) 24 hr prior to sacrifice. DA synthesis was determined by measuring DOPA accumulation after NSD-1015 induced inhibition of DOPA decarboxylase; whereas, DA turnover was estimated by measuring DA accumulation and DOPAC efflux after pargyline induced inhibition of monoamine oxidase. In addition, some of the rats were pretreated with the competitive D1 and D2 antagonists SCH 23390 (1.0 mg/kg) and sulpiride (100 mg/kg) in order to protect these receptor subtypes from EEDQ-induced inactivation. The latter procedure was used to determine whether EEDQ's presynaptic effects were mediated by D1 and D2 receptors or were nonspecific. The results showed that 7.5 mg/kg EEDQ increased the striatal DA synthesis of both preweanling and adult rats: effects eliminated if D1 and D2 receptors were protected by pretreatment with SCH 23390 and sulpiride. Striatal DA levels of both age groups were depressed by EEDQ treatment, while DA accumulation was unaffected. Age-dependent effects were apparent however, as 7.5 mg/kg EEDQ increased the DOPAC turnover of adult, but not 17-day-old rats. The inability of EEDQ to affect the DOPAC turnover of the younger rats was apparently not dose related, as 15 mg/kg EEDQ did not affect the striatal DOPAC turnover of 17-day-olds. In adult rats, the EEDQ-induced increase in DOPAC turnover was not mediated by DA receptors, as pretreatment with SCH 23390 and sulpiride did not block EEDQ's effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurochemical and behavioral effects of acute and chronic treatment with apomorphine in rats.

In three experiments, rats were injected once daily with 5.0 mg/kg apomorphine or vehicle and tested for locomotor activity for 10-14 days. In each experiment, apomorphine produced behavioral sensitization, characterized by a progressively greater increase in locomotor activity with each succeeding injection. On day 11 of testing, in an experiment designed to assess the synthesis of dopamine (DA), rats were injected with 5.0 mg/kg apomorphine or vehicle, followed by 100 mg/kg NSD-1015, an inhibitor of the enzyme l-aromatic amino acid decarboxylase. After administration of NSD-1015, concentrations of dihydroxyphenylalanine (DOPA) were determined in striatal and mesolimbic tissues by high performance liquid chromatography (HPLC) with electrochemical detection. The results revealed a significant decrease in accumulation of DOPA in both striatal and mesolimbic tissue after acute treatment with apomorphine. More important, chronic treatment with apomorphine produced a significant increase in accumulation of DOPA in both areas. In subsequent experiments, rats on day 14 of testing were sacrificed for determination of levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) or specific binding of [3H]spiperone in the striatum and mesolimbic region. Although levels of DOPAC were significantly reduced in the regions of the brain after an acute injection of apomorphine, chronic treatment with apomorphine did not significantly affect levels of DA, DOPAC or specific binding of [3H]spiperone. These findings suggest that the development of behavioral sensitization to apomorphine may be related to an alteration in the synthesis of DA.