Methamphetamine Reinforcement Research Articles

Effects of the kappa-opioid receptor antagonist nor-binaltorphimine on methamphetamine-vs-food choice in male rhesus monkeys

BackgroundKappa-opioid receptors (KOR) are hypothesized to be involved in mediating ongoing methamphetamine self-administration. Previous rat studies have demonstrated that treatment with the KOR antagonist nor-binaltorphimine (nor-BNI) decreases methamphetamine self-administration. However, KOR antagonist effects on methamphetamine self-administration in nonhuman primates are unknown. MethodsOperant behavior was maintained under a concurrent schedule of banana-flavored pellets (fixed-ratio 100 schedule) and intravenous methamphetamine injections (0–0.32mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined 7 days before and for up to 28 days following 10mg/kg, intramuscular nor-BNI treatment. ResultsUnder continuous saline treatment conditions, methamphetamine-maintained a dose-dependent increase in choice over the alternative food reinforcer. 10mg/kg nor-BNI failed to attenuate methamphetamine choice and trended towards increased methamphetamine choice. Methamphetamine choice returned to pre-nor-BNI treatment levels by 21 or 28 days in all 3 monkeys. ConclusionsThe present results do not support the hypothesis that the KOR/dynorphin system robustly modulates methamphetamine self-administration and that KOR antagonists should be considered as methamphetamine use disorder pharmacotherapies. In contrast, these results suggest KOR antagonism may increase methamphetamine reinforcement through blockade of methamphetamine-induced dynorphin release and consequent feedback inhibition.

Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.

Effects of systemic pretreatment with the NAALADase inhibitor 2-PMPA on oral methamphetamine reinforcement in C57BL/6J mice.

Repeated exposure to methamphetamine (MA) in laboratory rodents induces a sensitization of glutamate release within the corticoaccumbens pathway that drives both the rewarding and reinforcing properties of this highly addictive drug. Such findings argue the potential for pharmaceutical agents inhibiting glutamate release or its postsynaptic actions at glutamate receptors as treatment strategies for MA use disorder. One compound that may accomplish both of these pharmacological actions is the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA). 2-PMPA elevates brain levels of the endogenous agonist of glutamate mGluR3 autoreceptors, N-acetyl-aspartatylglutamate (NAAG), while potentially acting as an NMDA glutamate receptor antagonist. Of relevance to treating psychomotor stimulant use disorders, 2-PMPA is reported to reduce indices of both cocaine and synthetic cathinone reward, as well as cocaine reinforcement in preclinical rodent studies. Herein, we conducted three experiments to pilot the effects of systemic pretreatment with 2-PMPA (0-100 mg/kg, IP) on oral MA self-administration in C57BL/6J mice. The first experiment employed female mice with a prolonged history of MA exposure, while the mice in the second (females) and third (males and females) experiment were MA-naïve prior to study. In all experiments, mice were trained daily to nose-poke for delivery of unadulterated MA solutions until responding stabilized. Then, mice were pretreated with 2-PMPA prior to operant-conditioning sessions in which nose-poking behavior was reinforced by delivery of 120 mg/L or 200 mg/L MA (respectively, in Experiments 1 and 2/3). Contrary to our expectations, 30 mg/kg 2-PMPA pretreatment altered neither appetitive nor consummatory measures related to MA self-administration. In Experiment 3, 100 mg/kg 2-PMPA reduced responding in the MA-reinforced hole, as well as the number of reinforcers earned, but did not significantly lower drug intake. These results provide mixed evidenced related to the efficacy of this NAALADase inhibitor for reducing oral MA reinforcement in female mice.

Daily, limited access to methamphetamine self-administration during pregnancy leads to increased methamphetamine sensitivity in adult offspring.

Methamphetamine use by women, even throughout pregnancy, is common. But there is limited knowledge about the effects in prenatally methamphetamine-exposed children. This study investigated how prenatal methamphetamine exposure in rats, via maternal i.v. self-administration, affected the sensitivity of adult offspring to methamphetamine in comparison with controls. The offspring were generated from dams either self-administering methamphetamine daily under limited-access conditions prior to and throughout pregnancy, or their respective saline-yoked control dams. Spontaneous and methamphetamine-induced locomotor activity was assessed in male and female offspring of both exposure groups after a range of methamphetamine doses. In a separate group of offspring, acquisition of i.v. methamphetamine self-administration, responding under fixed and progressive ratio schedules of methamphetamine reinforcement, and reinstatement of extinguished drug-seeking behavior were assessed. Methamphetamine dose-dependently increased locomotor activity in both exposure groups. However, methamphetamine-exposed males showed significantly enhanced locomotor activity compared with controls at 1mg/kg, and methamphetamine-exposed females showed significantly enhanced locomotor activity compared with controls at 3.2mg/kg. Methamphetamine-exposed offspring of both sexes acquired methamphetamine self-administration faster and showed overall higher levels of methamphetamine-induced reinstatement compared with controls. Taken together, these results indicate that prenatal methamphetamine exposure to relatively low levels alters methamphetamine sensitivity in male and female adult offspring.

Selective Inhibition of PDE4B Reduces Methamphetamine Reinforcement in Two C57BL/6 Substrains.

Methamphetamine (MA) is a highly addictive psychostimulant drug, and the number of MA-related overdose deaths has reached epidemic proportions. Repeated MA exposure induces a robust and persistent neuroinflammatory response, and the evidence supports the potential utility of targeting neuroimmune function using non-selective phosphodiesterase 4 (PDE4) inhibitors as a therapeutic strategy for attenuating addiction-related behavior. Off-target, emetic effects associated with non-selective PDE4 blockade led to the development of isozyme-selective inhibitors, of which the PDE4B-selective inhibitor A33 was demonstrated recently to reduce binge drinking in two genetically related C57BL/6 (B6) substrains (C57BL/6NJ (B6NJ) and C57BL/6J (B6J)) that differ in their innate neuroimmune response. Herein, we determined the efficacy of A33 for reducing MA self-administration and MA-seeking behavior in these two B6 substrains. Female and male mice of both substrains were first trained to nose poke for a 100 mg/L MA solution followed by a characterization of the dose–response function for oral MA reinforcement (20 mg/L–3.2 g/L), the demand-response function for 400 mg/L MA, and cue-elicited MA seeking following a period of forced abstinence. During this substrain comparison of MA self-administration, we also determined the dose–response function for A33 pretreatment (0–1 mg/kg) on the maintenance of MA self-administration and cue-elicited MA seeking. Relative to B6NJ mice, B6J mice earned fewer reinforcers, consumed less MA, and took longer to reach acquisition criterion with males of both substrains exhibiting some signs of lower MA reinforcement than their female counterparts during the acquisition phase of the study. A33 pretreatment reduced MA reinforcement at all doses tested. These findings provide the first evidence that pretreatment with a selective PDE4B inhibitor effectively reduces MA self-administration in both male and female mice of two genetically distinct substrains but does not impact cue-elicited MA seeking following abstinence. If relevant to humans, these results posit the potential clinical utility of A33 or other selective PDE4B inhibitors for curbing active drug-taking in MA use disorder.

Age- and Sex-Dependent Nicotine Pretreatment Effects on the Enhancement of Methamphetamine Self-administration in Sprague-Dawley Rats

Initiation of tobacco products typically occurs in adolescence. Adolescence is a critical period in development where the maturation of brain neurocircuitry is vulnerable to nicotine. Nicotine-containing products and psychostimulants, such as methamphetamine (METH), are often coabused. Rodent studies have shown that nicotine exposure in early adolescence increases subsequent drug intake and reward. Given the exponential increase in e-cigarette use among adolescents, there is a pressing need to understand whether adolescent nicotine exposure impacts concurrent increased METH use. The objective of this study is to evaluate age, sex, and longitudinal effects of nicotine pretreatment on METH reinforcement. Male and female Sprague-Dawley rats were pretreated with a subchronic, low-dose nicotine (2×, 30 µg/kg/0.1 mL, intravenous) or saline during early adolescence (postnatal days [PN] 28-31) or adulthood (PN 86-89). Following nicotine pretreatment, on PN 32 or PN 90, animals underwent operant intravenous self-administration for METH (20 µg/kg/inf) over a 2-hour period for five consecutive days. Early adolescent nicotine exposure enhances intravenous METH self-administration in male, but not female adolescents. Male adult rats self-administer METH over the 5-day testing period, independent of nicotine exposure. In contrast, nicotine exposure increases METH self-administration in female adults during the later sessions of the 5-day testing period. Taken together, our data highlight age- and sex-dependent effects of low dose, subchronic nicotine pretreatment on subsequent intravenous METH self-administration. A majority of polysubstance users begin smoking before the age of 18. Mounting evidence highlights adolescent susceptibility to nicotine exposure on brain and behavior. With the escalation in nicotine-containing products and stimulant use among adolescents, it is important to identify the consequences from adolescent nicotine use, including polysubstance use. Our study provides evidence that adolescent nicotine exposure enhances subsequent METH use, with important sex- and age-dependent effects.

Reciprocal Substitution Between Methamphetamine and Heroin in Terms of Reinforcement Effects in Rats.

Heroin and methamphetamine are both popular illicit drugs in China. Previous clinical data showed that habitual users of either heroin or methamphetamine abuse the other drug for substitution in case of unavailability of their preferred drug. The present study aimed to observe whether heroin can substitute the methamphetamine reinforcement effect in rats, and vice versa. Rats were trained to self-administer heroin or methamphetamine (both 50 μg/kg/infusion) under an FR1 reinforcing schedule for 10 days. After having extracted the dose–effect curve of the two drugs, we administered methamphetamine at different doses (12.5–200 μg/kg/infusion) to replace heroin during the period of self-administration, and vice versa. The heroin dose–effect curve showed an inverted U-shaped trend, and the total intake dose of heroin significantly increased when the training dose increased from 50 to 100 or 200 μg/kg/infusion. Following replacement with methamphetamine, the total dose–effect curve shifted leftwards and upwards. By contrast, although the dose–effect curve of methamphetamine also showed an inverted U-shaped trend, the total dose of methamphetamine significantly decreased when the training dose decreased from 50 to 25 μg/kg/infusion; conversely, when the methamphetamine training dose increased, the total dose did not change significantly. The total dose–effect curve shifted rightwards after heroin was substituted with methamphetamine. Although heroin and methamphetamine had their own independent reward effects, low doses of methamphetamine can replace the heroin reward effect, while high doses of heroin can replace the methamphetamine reward effect. These results demonstrated that heroin and methamphetamine can substitute each other in terms of reinforcement effects in rats.

A Mutation in Hnrnph1 That Decreases Methamphetamine-Induced Reinforcement, Reward, and Dopamine Release and Increases Synaptosomal hnRNP H and Mitochondrial Proteins.

Individual variation in the addiction liability of amphetamines has a heritable genetic component. We previously identified Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) as a quantitative trait gene underlying decreased methamphetamine-induced locomotor activity in mice. Here, we showed that mice (both females and males) with a heterozygous mutation in the first coding exon of Hnrnph1 (H1+/-) showed reduced methamphetamine reinforcement and intake and dose-dependent changes in methamphetamine reward as measured via conditioned place preference. Furthermore, H1+/- mice showed a robust decrease in methamphetamine-induced dopamine release in the NAc with no change in baseline extracellular dopamine, striatal whole-tissue dopamine, dopamine transporter protein, dopamine uptake, or striatal methamphetamine and amphetamine metabolite levels. Immunohistochemical and immunoblot staining of midbrain dopaminergic neurons and their forebrain projections for TH did not reveal any major changes in staining intensity, cell number, or forebrain puncta counts. Surprisingly, there was a twofold increase in hnRNP H protein in the striatal synaptosome of H1+/- mice with no change in whole-tissue levels. To gain insight into the mechanisms linking increased synaptic hnRNP H with decreased methamphetamine-induced dopamine release and behaviors, synaptosomal proteomic analysis identified an increased baseline abundance of several mitochondrial complex I and V proteins that rapidly decreased at 30 min after methamphetamine administration in H1+/- mice. In contrast, the much lower level of basal synaptosomal mitochondrial proteins in WT mice showed a rapid increase. We conclude that H1+/- decreases methamphetamine-induced dopamine release, reward, and reinforcement and induces dynamic changes in basal and methamphetamine-induced synaptic mitochondrial function.SIGNIFICANCE STATEMENT Methamphetamine dependence is a significant public health concern with no FDA-approved treatment. We discovered a role for the RNA binding protein hnRNP H in methamphetamine reward and reinforcement. Hnrnph1 mutation also blunted methamphetamine-induced dopamine release in the NAc, a key neurochemical event contributing to methamphetamine addiction liability. Finally, Hnrnph1 mutants showed a marked increase in basal level of synaptosomal hnRNP H and mitochondrial proteins that decreased in response to methamphetamine, whereas WT mice showed a methamphetamine-induced increase in synaptosomal mitochondrial proteins. Thus, we identified a potential role for hnRNP H in basal and dynamic mitochondrial function that informs methamphetamine-induced cellular adaptations associated with reduced addiction liability.

GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine.

Despite escalating methamphetamine use and high relapse rates, pharmacotherapeutics for methamphetamine use disorders are not available. Our iterative drug discovery program had found that R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), a selective vesicular monoamine transporter-2 (VMAT2) inhibitor, specifically decreased methamphetamine's behavioral effects. However, GZ-793A inhibited human-ether-a-go-go-related gene (hERG) channels, suggesting cardiotoxicity and prohibiting clinical development. The current study determined if replacement of GZ-793A's piperidine ring with a phenylalkyl group to yield S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11608) diminished hERG interaction while retaining pharmacological efficacy. VMAT2 inhibition, target selectivity, and mechanism of GZ-11608-induced inhibition of methamphetamine-evoked vesicular dopamine release were determined. We used GZ-11608 doses that decreased methamphetamine-sensitized activity to evaluate the potential exacerbation of methamphetamine-induced dopaminergic neurotoxicity. GZ-11608-induced decreases in methamphetamine reinforcement and abuse liability were determined using self-administration, reinstatement, and substitution assays. Results show that GZ-11608 exhibited high affinity (Ki = 25 nM) and selectivity (92-1180-fold) for VMAT2 over nicotinic receptors, dopamine transporter, and hERG, suggesting low side-effects. GZ-11608 (EC50 = 620 nM) released vesicular dopamine 25-fold less potently than it inhibited VMAT2 dopamine uptake. GZ-11608 competitively inhibited methamphetamine-evoked vesicular dopamine release (Schild regression slope = 0.9 ± 0.13). GZ-11608 decreased methamphetamine sensitization without altering striatal dopamine content or exacerbating methamphetamine-induced dopamine depletion, revealing efficacy without neurotoxicity. GZ-11608 exhibited linear pharmacokinetics and rapid brain penetration. GZ-11608 decreased methamphetamine self-administration, and this effect was not surmounted by increasing methamphetamine unit doses. GZ-11608 reduced cue- and methamphetamine-induced reinstatement, suggesting potential to prevent relapse. GZ-11608 neither served as a reinforcer nor substituted for methamphetamine, suggesting low abuse liability. Thus, GZ-11608, a potent and selective VMAT2 inhibitor, shows promise as a therapeutic for methamphetamine use disorder. SIGNIFICANCE STATEMENT: GZ-11608 is a potent and selective vesicular monoamine transporter-2 inhibitor that decreases methamphetamine-induced dopamine release from isolated synaptic vesicles from brain dopaminergic neurons. Results from behavioral studies show that GZ-11608 specifically decreases methamphetamine-sensitized locomotor activity, methamphetamine self-administration, and reinstatement of methamphetamine-seeking behavior, without exhibiting abuse liability. Tolerance does not develop to the efficacy of GZ-11608 to decrease the behavioral effects of methamphetamine. In conclusion, GZ-11608 is an outstanding lead in our search for a therapeutic to treat methamphetamine use disorder.

Effects of acute treatments with the serotonin 2A antagonist M100907 alone or in combination with the serotonin 2C agonist WAY163909 on methamphetamine self-administration in rhesus monkeys

BackgroundSerotonin 5-HT2A receptor antagonists and 5-HT2C receptor agonists have been proposed as important candidates for the development of pharmacotherapies for psychostimulant abuse, with evidence suggesting that those receptors may act together to control behavior. However, the role of 5-HT2A receptors on the reinforcing effects of psychostimulant drugs has not been fully elucidated. MethodsIn the present study, we investigated the effects of the selective 5HT2A receptor antagonist M100907 alone or in combination with the selective 5HT2C agonist WAY 163909 on intravenous methamphetamine self-administration in rhesus macaques (N = 3). Methamphetamine self-administration (0.01-0.03 mg/kg/inf) was evaluated under a fixed-ratio 20-schedule of reinforcement, and acute pretreatments were conducted 1 h (M100907) or 45 min (WAY 163,909) prior to the beginning of self-administration sessions at the EDMax dose of methamphetamine once stability criteria were met. ResultsPretreatment with M100907 (0.03–0.3 mg/kg, i.m.) dose-dependently attenuated methamphetamine self-administration, with the highest dose significantly decreasing response rates compared to vehicle. Combined administration of ineffective doses of M100907 and WAY 163,909 had no effects on methamphetamine self-administration. ConclusionsOur study indicates that acute selective 5-HT2A receptor blockade decreases peak methamphetamine intake in nonhuman primates. Combination approaches with sub-threshold doses of 5-HT2A receptor antagonists and 5-HT2C receptor agonists, on the other hand, do not seem to be effective in decreasing methamphetamine reinforcement. Further studies are needed in order to investigate the effects of chronic treatments with M100 on complete METH SA dose-response curves.

Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys

BackgroundPreclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. MethodsBehavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0–0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0–10mg/kg/day, intramuscular) treatment periods. ResultsUnder control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2–10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. ConclusionsRepeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction.

A genetic animal model of differential sensitivity to methamphetamine reinforcement

Sensitivity to reinforcement from methamphetamine (MA) likely influences risk for MA addiction, and genetic differences are one source of individual variation. Generation of two sets of selectively bred mouse lines for high and low MA drinking has shown that genetic factors influence MA intake, and pronounced differences in sensitivity to rewarding and aversive effects of MA play a significant role. Further validation of these lines as a unique genetic model relevant to MA addiction was obtained using operant methods to study MA reinforcement. High and low MA drinking line mice were used to test the hypotheses that: 1) oral and intracerebroventricular (ICV) MA serve as behavioral reinforcers, and 2) MA exhibits greater reinforcing efficacy in high than low MA drinking mice. Operant responses resulted in access to an MA or non-MA drinking tube or intracranial delivery of MA. Behavioral activation consequent to orally consumed MA was determined. MA available for consumption maintained higher levels of reinforced instrumental responding in high than low MA drinking line mice, and MA intake in the oral operant procedure was greater in high than low MA drinking line mice. Behavioral activation was associated with amount of MA consumed during operant sessions. High line mice delivered more MA via ICV infusion than did low line mice across a range of doses. Thus, genetic risk factors play a critical role in the reinforcing efficacy of MA and the oral self-administration procedure is suitable for delineating genetic contributions to MA reinforcement.

MGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats.

Addiction to methamphetamine is a significant public health problem, and there are currently no pharmacological agents that are approved for the treatment of addiction to this powerful psychostimulant. Chronic methamphetamine use leads to cognitive dysfunction as well as numerous psychiatric, neurological, and cardiovascular complications. There is a growing body of literature implicating an important role for glutamate neurotransmission in psychostimulant addiction. In the present study, we examined the effects of the selective type 5 metabotropic glutamate receptor (mGluR5) antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) on intravenous self-administration of methamphetamine and reinstatement of methamphetamine-seeking behavior. Adult male Sprague-Dawley rats were trained to respond for intravenous methamphetamine (0.1 or 0.2 mg/kg per infusion) or food pellets and were subsequently administered vehicle or MTEP (0.3-3 mg/kg) before drug or food self-administration on a fixed-ratio 1 (FR1) schedule of reinforcement or a progressive ratio (PR) schedule of reinforcement. We also examined the effects of vehicle or MTEP (0.3-3 mg/kg) on cue- and drug-induced reinstatement of methamphetamine-seeking behavior as well as cue-induced reinstatement of food-seeking behavior. Our results show that MTEP dose dependently reduced the reinforcing effects of methamphetamine under FR1 and PR schedules of reinforcement without altering overall responding for food. MTEP also dose dependently prevented cue- and drug-induced reinstatement of methamphetamine-seeking behavior, but did not alter cue-induced reinstatement of food-seeking behavior. Together, these results indicate that mGluR5 receptors mediate methamphetamine reinforcement and methamphetamine-seeking behavior, and that pharmacological inhibitors of mGluR5 receptor function may represent a novel class of potential therapeutic agents for the treatment of methamphetamine addiction.

Black agouti (ACI) rats show greater drug- and cue-induced reinstatement of methamphetamine-seeking behavior than Fischer 344 and Lewis rats

Fischer 344 (F344) and Lewis (LEW) rats differ in methamphetamine self-administration (SA) and methamphetamine-induced reinstatement of previously extinguished behavior. We sought to determine whether genetic background also influences methamphetamine reinforcement efficacy, conditioned reinstatement, and methamphetamine-primed reinstatement of responding in F344, LEW, and Black Agouti (ACI) rats. We implanted rats with jugular catheters and trained them to self-administer methamphetamine (0.06 mg/kg/infusion) under a progressive ratio (PR) schedule of reinforcement during daily 2-h SA sessions. A compound stimulus (light + tone; LT) was paired with each infusion. Dose-dependent intake was determined for each rat. Rats then entered the extinction phase of the experiment where responding resulted in no programmed consequences. Following extinction sessions, rats underwent conditioned reinstatement testing. For conditioned reinstatement, rats received response-contingent presentations of the LT and no methamphetamine. Last, methamphetamine-primed reinstatement test sessions where conducted where subjects received experimenter delivered infusions of methamphetamine (0.06, 0.12, or 0.24 mg/kg). The strains did not differ in PR responding across the doses tested. The ACI rats demonstrated the highest behavioral output during extinction training, conditioned- and methamphetamine-primed reinstatement of previously extinguished behavior compared to the other strains. These data suggest that genetic background differentially influences extinction, conditioned reinstatement and methamphetamine-primed reinstatement in rats.

Effects of isradipine, a dihydropyridine-class calcium-channel antagonist, on d-methamphetamine's subjective and reinforcing effects

In healthy human volunteers, we have previously shown that isradipine, a dihydropyridine-class calcium-channel antagonist, reduces some methamphetamine-induced positive subjective effects associated with its abuse liability, presumably by antagonizing cortico-mesolimbic dopamine pathways. In the present study, we combined acute immediate-release (IR) isradipine with repeated sustained-release (SR) isradipine pretreatment to determine whether isradipine could antagonize methamphetamine's positive subjective and reinforcing effects in methamphetamine-dependent research subjects. We included 18 non-treatment-seeking, methamphetamine-dependent subjects aged between 18 and 51 years in this double-blind, within-subject, cross-over study, which was done in a human laboratory. Intravenous methamphetamine (0, 15 and 30 mg) was administered on three different days after 5 days of double-blind cross-over treatment with either isradipine or matching placebo. Subjects received oral isradipine 30 mg SR at bedtime, plus 15 mg IR administered 2 h before methamphetamine infusion. Self-report questionnaires measured drug liking, euphoria, craving, stimulation, and methamphetamine preference. Methamphetamine reinforcement was measured by a behavioural procedure involving choices between methamphetamine and money. For those who received isradipine second and placebo first as the pretreatment paradigm but not vice versa, methamphetamine-induced drug liking, elation, and preference were reduced significantly by isradipine. Depending upon conditioning status, isradipine can reduce some methamphetamine-induced positive subjective and reinforcing effects associated with its abuse liability in methamphetamine addicts.

Methamphetamine self-administration in the cat.

A procedure for studing intravenous drug self-administration in the cat is described. Ten cats were given 24-h access to methamphetamine reinforcement (0.04 mg/kg/inj). The subjects maintained a significantly higher response rate for drug reinforcement than for saline. The pattern of self-administration over days alternated between periods of high and low drug intake. Six additional cats were used to study the effect of dose per injection on methamphetamine self-administration under conditions of limited access. When methamphetamine was subtituted at various doses per infusion in animals maintained on cocaine reinforcement, response rate was shown to be an inverted U-shaped function of dose. These studies demonstrate that methamphetamine is a reinforcer in the cat and its patterns of intake under conditions of 24-h and limited access resemble other species.

Chemical interactions in methamphetamine reinforcement.

Responding by rats was reinforced by intravenous infusions of 0.5 mg/kg methamphetamine hydrochloride. The effects of intraperitoneal injections of various doses of methamphetamine, alpha-methyl-para-tyrosine (AMPT) and 3, 4-dihydroxyphenylalanine (1-DOPA) were determined on this baseline. Intraperitoneally-administered methamphetamine produced a dose-related pause in responding, apparently indicating drug satiation. Injections of AMPT caused responding either to increase at low doses, or, at intermediate and high doses, to increase, then cease altogether, and finally return at a high rate which decreases to baseline. Injections of 1-DOPA had no noticeable effect on drug responding. Some biochemical implications of these data were discussed.

Methamphetamine reinforcement in rats

Methamphetamine was found to serve as a reinforcer for the rat. Long-term drug self-administration was characterized by periods of responding and not responding for drug injection. Response rate varied as a function of drug dosage and value of a fixed-ratio reinforcement schedule.