Evidence for behavioral sensitization to cocaine in preweanling rat pups

While chronic intermittent administration of stimulants often induces behavioral sensitization in adulthood, stimulant sensitization has rarely been reported prior to weaning [around postnatal day (P) 21]. Consistent pairing of drug administration with the test context often facilitates sensitization in adults, yet young animals have been typically returned to the home cage immediately post-injection. To determine whether promoting context-dependent sensitization might facilitate expression of sensitization in preweanlings, Sprague-Dawley rats were injected daily from P14 to P20 with 0, 5, 15, or 30 mg/kg cocaine HC1 and placed for 30 min in either the experimental chamber or home cage. On P21 (test day), subjects were challenged with either 15 mg/kg cocaine or saline prior to placement in the experimental chamber. Significant sensitization of cocaine-induced stereotyped head movements was evident in animals given 15 or 30 mg/kg chronically in the experimental chamber, but not when these same doses were given in the home cage. Less consistent evidence for cocaine-induced sensitization was seen when examining locomotion, although trends for sensitization of this behavior were seen in animals chronically injected in either the test chamber or home cage. Thus, preweanlings can exhibit cocaine sensitization, particularly in terms of stereotypy, when tested shortly after the chronic exposure period, with expression of this sensitization being facilitated by pairing the chronic injections with the test context. Received: 19 November 1996/Final version: 10 December 1997     

Morphine-induced antinociception in the formalin test: sensitization and interactions with D1 and D2 dopamine receptors and nitric oxide agents

In this study, the effects of dopamine receptor antagonists and nitric oxide agents on morphine-induced sensitization in the formalin test in mice have been investigated. Repeated daily intraperitoneal administration of morphine (30 mg/kg for 3 days) followed by a 11-day wash out period increased morphine-induced antinociception in the formalin test, which may be due to sensitization. The antinociceptive response to higher doses of morphine (6 and 9 mg/kg) but not 3 mg/kg was significantly increased in sensitized animals compared with control groups. Pretreatment of animals with an opioid receptor antagonist, naloxone (4 mg/kg), during repeated administration of morphine, attenuated the morphine-induced sensitization. In the second part of the study, the animals received SCH23390 (D1 receptor antagonist), sulpiride (D2 receptor antagonist), L-Arg (nitric oxide precursor) and NG-nitro-L-Arg methylester (nitric oxide synthase inhibitor) during repeated morphine administration, to evaluate the role of dopamine receptor antagonists and nitric oxide agents in this phenomenon. Pretreatment of animals with NG-nitro-L-Arg methylester (20 mg/kg) and sulpiride (100 mg/kg) during morphine sensitization decreased the antinociceptive response to higher doses of morphine in the formalin test. It is concluded that D2 dopamine receptor and nitric oxide mechanisms may be involved at least partly in morphine-induced sensitization in the formalin test.     

Blockade of Sensitization to the Toxic Effects of Cocaine in Mice by Nitric Oxide Synthase Inhibitors

Repeated administration of cocaine to animals results in sensitization to several reactions to the drug, including seizures and mortality. These consequences are thought to be related to the pathology that develops in humans abusing cocaine. Previous studies implied the involvement of the N-methyl-D-aspartate (NMDA) type of glutamate receptors in cocaine-induced toxicity, and recent studies documented a role for nitric oxide in NMDA-receptor mediated neurotoxicity. The present study was undertaken to determine whether nitric oxide synthase inhibitors block the development of sensitization to the toxic effects of cocaine in mice. Repeated administration of cocaine (45 mg/kg/day; intraperitoneally) to Swiss Webster mice, for 7 days, resulted in a progressive increase in the duration of the convulsive response to cocaine, an increase in the number of animals that had seizures, and augmentation in lethality rate. Pretreatment with N^G–nitro-L-arginine methyl ester (L-NAME; 100 mg/kg/day; intraperitoneally) or N^G–nitro-L-arginine (NO-Arg; 25 mg/kg/day; intraperitoneally) completely abolished the sensitization to the convulsive and lethal responses to cocaine. Receptor binding assays indicated first, that pretreatment with L-NAME apparently diminished cocaine-induced upregulation of cortical NMDA receptors, and second, that the effects of the nitric oxide synthase inhibitors tested are not mediated via a direct interaction of the drugs with the phencyclidine/NMDA receptor complex. Taken together, the present study suggests an important role for nitric oxide in the development of sensitization to the toxic effects of cocaine, and further supports the relationship between NMDA-receptor mediated neurotoxicity and nitric oxide.     

Guinea pig maximization test assessment of hydrocortisone and tixocortol pivalate

The anti-inflammatory properties of topical corticosteroids are well documented; additionally, their sensitization potential is also known. We aimed to assess the relative sensitization potential of hydrocortisone and tixocortol pivalate in an animal assay as it relates to potential for sensitization in humans. Using the guinea pig maximization test (GPMT), animals were sensitized intradermally on d0, and again topically on d7. On d21 the animals were challenged topically with a closed patch for 24 h and readings were taken 24 h and 48 h post-challenge. A sham control group received the same induction and challenge applications excluding the test agent. Animals were subsequently rechallenged with open application; the tixocortol pivalate group was further retested at different test agent concentrations to determine threshold concentration that elicited response. Tixocortol pivalate resulted in sensitization rates of 42% (24 h) and 80% (48 h); hydrocortisone exhibited 0% (24 h) and 5% (48 h). Scores ranged from 0% (sham group) to 2.4 (48 h tixocortol pivalate). Open rechallenge also resulted in greater tixocortol pivalate sensitization rates compared to hydrocortisone, 82% verse 16% at 48 h, respectively. All tested concentrations of tixocortol pivalate induced sensitization, albeit at differing rates dependant on concentration and timepoint. We conclude that the GPMT remains largely for hazard identification, as it was originally designed, and requires further data sets regarding quantitative induction and elicitation for risk assessment of various compounds in clinical implications.     

Effect of sensitization and aerosol antigen challenge in guinea-pigs—studies of airway receptor function and characteristics

Immunological sensitization of guinea-pigs and subsequent antigen inhalation challenge has provided an animal model which has several features in common with human asthma. Impairment of β-adrenoceptor-mediated function and mechanisms have been postulated to contribute to the hyperreactivity to contractile agonists demonstrated in vivo and in vitro in these animals. Functional and receptor radioligand binding studies were carried out on airway tissue from: non-sensitized; sensitized; sensitized saline challenged; sensitized antigen challenged guinea-pigs. Sensitization did not alter responsiveness of airway tissue to carbachol, although subsequent antigen challenge did increase carbachol sensitivity of peripheral airway tissue six-fold. Neither sensitization itself nor subsequent antigen challenge altered binding characteristics of the muscarinic cholinoceptor ligand [³H]quinuclidi-nyl benzilate ([³H]QNB) to peripheral airway tissue, suggesting that mechanisms responsible for increases in carbachol sensitivity are distal to these receptors. Relaxation of airway preparations to isoprenaline was not altered by sensitization or further antigen challenge of the animals. However, sensitization significantly reduced affinity but not the total number of binding sites in peripheral airway tissue for the β-adrenoceptor ligand [³H]dihydroalpreno-lol ([³H]DHA). Antigen challenge of the animals did not further alter β-adrenoceptor ligand binding characteristics. These results suggest that airway hyperreactivity in this model is not a function of alteration in receptor characteristics, or impairment of relaxation mechanisms.     

Skin toxicity of propranolol in guinea pigs.

The skin toxicities of propranolol were studied in guinea pigs. In the primary and cumulative skin irritation studies, the skin reactions and the histopathological changes were observed in all animals treated with propranolol, and those tended to increase with the increase of propranolol dosage. The skin reactions increased with the application times of propranolol up to 7 days in the cumulative skin irritation study. In the skin sensitization, the phototoxicity and the skin photosensitization studies, no skin reactions were observed in any animals used in the studies. These results indicate that propranolol caused skin irritation, but was negative for skin sensitization, phototoxicity and skin photosensitization in guinea pigs.     

The development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment

Two experiments were designed to assess the effect of a novel environment on the development of sensitization to the psychomotor activating effects ofd-amphetamine. In the first experiment, rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopamine system received ten daily injections of amphetamine (2 mg/kg), either in their home cages or in novel test cages. The home and novel cages were physically identical (cylindrical transparent buckets), but one group lived and were tested in these cages, whereas the other group was transported from the stainless steel hanging cages where they lived to these novel test cages, for each test session. The first injection of amphetamine produced significantly more rotational behavior in animals tested in a novel environment than in animals tested at home. In addition, animals tested in a novel environment showed greater sensitization than animals tested at home, so the difference between the two groups was even more pronounced following the last injection. In a second experiment, locomotor activity was quantified in rats that received ten injections of either saline or 1.5 mg/kg amphetamine, in their home cages or in a physically identical novel environment. Again, there was a significantly greater locomotor response to the first injection of amphetamine, and greater sensitization, in animals tested in a novel environment than in animals tested at home. These data indicate that environmental factors can exert a large effect on the susceptibility to sensitization, and mechanisms by which this may occur are discussed.     

Extinction procedures abolish conditioned stimulus control but spare sensitized responding to amphetamine

The effect of extinction on previously established environment-specific sensitization of the locomotor activating effects of 1.0mg/kg d-amphetamine sulfate was studied in an attempt to investigate the relation between sensitization and conditioning of the drug effect. During the conditioning phase, groups of eight rats each were administered drug, i.p., prior to being placed in activity boxes and saline in their home cages (paired group), drug in the home cages and saline in the activity boxes (unpaired group), or saline in both environments. Evidence for conditioning and environment-specific sensitization was found following the conditioning phase in tests during which animals were administered saline or amphetamine, respectively. On a final test for environment-specific sensitization that followed the extinction phase (during which all animals received saline injections in both the activity boxes and the home cages), sensitized responding to amphetamine was found in both the paired and unpaired groups, suggesting that prior to extinction the expression of sensitization in the unpaired group had been under inhibitory control.     

Withdrawal from continuous amphetamine administration abolishes latent inhibition but leaves prepulse inhibition intact

Rationale Schizophrenia has been associated with dysregulation of dopamine (DA) transmission and impairment in a number of experimental tasks, including sensorimotor gating assessed using prepulse inhibition (PPI) and selective attention assessed using latent inhibition (LI). We have demonstrated in previous studies that after withdrawal from escalating (ESC) dosages of amphetamine (AMPH), animals exhibited disruption of LI but no alteration of PPI. Moreover, these animals always showed behavioural sensitization to an AMPH challenge. Objective In this study, we were interested in testing whether a different administration schedule would elicit disruption of both LI and PPI. Methods Animals were treated with continuous AMPH release (via osmotic mini-pumps at a dosage of 10 mg kg⁻¹ day⁻¹ for 7 days) and tested for their performance in L and PPI during withdrawal in a drug free state. Rats received AMPH treatment during the induction phase in their home cages or in the activity chambers. Following withdrawal, the expression of behavioural sensitization to an AMPH challenge was tested in both cases in the activity chambers. Results Animals pretreated with AMPH from both groups did not exhibit behavioural sensitization. Withdrawal from continuous administration induced LI attenuation with no effect on PPI. Conclusions These findings are similar to what was previously found with respect to an ESC AMPH regime. The only difference between the schedules was that the ESC AMPH schedule led to behavioural sensitization whereas the continuous AMPH did not. It is suggested that the expression of sensitization may not be a prerequisite for observed LI disruption.     

A differentiated approach to testing skin sensitization

The present EEC and OECD Guidelines for testing skin sensitization have been reviewed in light of scientific evidence demonstrating that those methods which use Freund's Complete Adjuvant (FCA) are likely to be more accurate in predicting a probable skin-sensitizing effect of a new substance in humans than those methods not employing Freund's Complete Adjuvant. In this new test guideline, therefore, the primary testing of a substance should be carried out using one of the recommended Adjuvant methods. In special cases a non-adjuvant method may be performed in addition. Not all of the seven methods in the EEC Guideline or eight methods in the OECD Guideline have been included, but in a proposal for an updated test protocol two Adjuvant tests (Maximization test by Magnusson and Kligman and Optimization test by Maurer), and two non-Adjuvant tests (Open Epicutaneous test by Klecak and Buehler test) are suggested. The criteria for selecting these methods are based on the fact that they are well validated and widely used on a broad basis by the scientific community. Furthermore, it is considered appropriate to permit the use of a lower number of animals than presently recommended for the testing of skin sensitization. This is also in agreement with aspects of animal welfare.     

Dose-Response Relationships and Threshold Levels in Skin and Respiratory Allergy

A literature study was performed to evaluate dose-response relationships and no-effect levels for sensitization and elicitation in skin- and respiratory allergy. With respect to the skin, dose-response relationships and no-effect levels were found for both intradermal and topical induction, as well as for intradermal and topical elicitation of allergenic responses in epidemiological, clinical, and animal studies. Skin damage or irritation may result in a significant reduction of the no-effect level for a specific compound. With respect to the respiratory tract, dose-response relationships and no-effect levels for induction were found in several human as well as animal studies. Although dose-response relationships for elicitation were found in some epidemiological studies, concentration-response relationships were present only in a limited number of animal studies. Reported results suggest that especially relatively high peak concentrations can induce sensitization, and that prevention of such concentrations will prevent workers from developing respiratory allergy. Moreover, induction of skin sensitization may result in subsequent heightened respiratory responsiveness following inhalation exposure. The threshold concentration for the elicitation of allergic airway reactions in sensitized subjects is generally lower than the threshold to induce sensitization. Therefore, it is important to consider the low threshold levels for elicitation for recommendation of health-based occupational exposure limits, and to avoid high peak concentrations. Notwithstanding the observation of dose-response relationships and no-effect levels, due to a number of uncertainties, no definite conclusions can be drawn about absolute threshold values for allergens with respect to sensitization of and elicitation reactions in the skin and respiratory tract. Most predictive tests are generally meant to detect the potential of a chemical to induce skin and/or respiratory allergy at relatively high doses. Consequently, these tests do not provide information of dose-response relationships at lower doses such as found in, for example, occupational situations. In addition, the observed dose-response relationships and threshold values have been obtained by a wide variety of test methods using different techniques, such as intradermal exposure versus topical or inhalation exposure at the workplace, or using different endpoints, which all appear important for the outcome of the test. Therefore, especially with regard to respiratory allergy, standardized and validated dose-response test methods are urgently required in order to be able to recommend safe exposure levels for allergens at the workplace.     

Dose-response relationships and threshold levels in skin and respiratory allergy

A literature study was performed to evaluate dose-response relationships and no-effect levels for sensitization and elicitation in skin- and respiratory allergy. With respect to the skin, dose-response relationships and no-effect levels were found for both intradermal and topical induction, as well as for intradermal and topical elicitation of allergenic responses in epidemiological, clinical, and animal studies. Skin damage or irritation may result in a significant reduction of the no-effect level for a specific compound. With respect to the respiratory tract, dose-response relationships and no-effect levels for induction were found in several human as well as animal studies. Although dose-response relationships for elicitation were found in some epidemiological studies, concentration-response relationships were present only in a limited number of animal studies. Reported results suggest that especially relatively high peak concentrations can induce sensitization, and that prevention of such concentrations will prevent workers from developing respiratory allergy. Moreover, induction of skin sensitization may result in subsequent heightened respiratory responsiveness following inhalation exposure. The threshold concentration for the elicitation of allergic airway reactions in sensitized subjects is generally lower than the threshold to induce sensitization. Therefore, it is important to consider the low threshold levels for elicitation for recommendation of health-based occupational exposure limits, and to avoid high peak concentrations. Notwithstanding the observation of dose-response relationships and no-effect levels, due to a number of uncertainties, no definite conclusions can be drawn about absolute threshold values for allergens with respect to sensitization of and elicitation reactions in the skin and respiratory tract. Most predictive tests are generally meant to detect the potential of a chemical to induce skin and/or respiratory allergy at relatively high doses. Consequently, these tests do not provide information of dose-response relationships at lower doses such as found in, for example, occupational situations. In addition, the observed dose-response relationships and threshold values have been obtained by a wide variety of test methods using different techniques, such as intradermal exposure versus topical or inhalation exposure at the workplace, or using different endpoints, which all appear important for the outcome of the test. Therefore, especially with regard to respiratory allergy, standardized and validated dose-response test methods are urgently required in order to be able to recommend safe exposure levels for allergens at the workplace.     

Potentiation of the behavioral and convulsant effects of cocaine by chronic administration in the rat

The effect of chronic administration on the behavioral response to cocaine was studied in male Sprague-Dawley rats. In experiment 1 five groups of rats received daily intraperitoneal injections of either saline, 20 mg/kg, or 40 mg/kg cocaine hydrochloride for 10 days, or of higher doses of cocaine until either one or three convulsions occured. Following this initial treatment, all animals were left untreated for seven days, and then sensitivity to cocaine was assessed in all animals by a test injection series (daily injections of increasing doses of cocaine). Animals which had received 40 mg/kg cocaine during the initial treatment exhibited a greater behavioral response (stereotyped behavior) to cocaine during the test injection series than did animals treated with saline; both the 40 mg/kg and one — convulsion treatments during the initial stage of the experiment resulted in greater sensitivity to the convulsant effect of cocaine during the test injection series. In experiment 2 animals were injected intraperitoneally with either saline or 40 mg/kg cocaine for 10 days and then tested with a series of daily cocaine injections of increasing dosage after remaining untreated for 4, 8, 16 or 32 days. The results indicated that the initial treatment with 40 mg/kg cocaine augmented both the behavioral and convulsant effects of cocaine during the subsequent test injection series. The sensitization to the convulsant effect of cocaine was significant at all intervals after initial treatment except 16 days, while the duration of sensitization to the behavioral effects of cocaine could not be determined due to apparent age-related changes in the response of control animals to cocaine. The sensitization which was observed was attributed to the effects of cocaine per se rather than to convulsions produced by the drug.     

Enhanced self-stimulation responding from the substantia nigra after chronic amphetamine treatment: A role for conditioning factors

Rats treated with 2 mg/kg of d-amphetamine and tested for self-stimulation responding supported from the substantia nigra (pre-trial group), showed a progressive augmentation in rates of self-stimulation responding relative to control animals following repeated drug/test pairings for 10 days. A similar behavioral profile was not observed among animals that received behavioral testing followed by drug administration (post-trial group) during the chronic phase. On test day (Day 11), rats that received repeated drug/test pairings during the chronic phase exhibited a facilitated self-stimulation response to a low test dosage of d-amphetamine (0.5 mg/kg) which otherwise had no behavioral effect, whereas rats exposed to chronic test/drug pairings during the chronic phase did not show enhaced self-stimulation rates to the test dosage of d-amphetamine. Animals chronically treated with pre-trial injections of amphetamine also showed facilitated self-stimulation responding when tested with saline, relative to animals that were chronically treated with post-trial injections of amphetamine and tested with saline. These findings were not parallelled by drug-induced changes in locomotor activity. Response sensitization after chronic amphetamine treatment does not appear to involve the accumulation of the drug in adipose tissue. A role for conditioning factors in the development of the response sensitization is discussed.     

Locomotor sensitization to quinpirole: environment-modulated increase in efficacy and context-dependent increase in potency

 This study examines whether behavioural sensitization to the dopamine agonist, quinpirole, reflects an increase in the drug’s potency and/or efficacy to induce locomotion, and how these parameters are influenced by environmental context. Three experiments were conducted in which animals received either chronic quinpirole (10×0.5 mg/kg, twice weekly) or saline injections in either the home cage environment, an alternate environment or the testing environment (activity monitors), followed by a dose-response test for the expression of sensitization in the activity monitors. Compared to the acute dose-response relationship, chronic quinpirole increased the maximum response. This increase in efficacy was significantly higher in animals treated with quinpirole in a non-home cage environment compared to those that received chronic treatment in the home cage. A leftward shift in the dose-effect function was observed only in animals with prior drug experience in the testing environment. Results indicate that locomotor sensitization to quinpirole reflects an environment-modulated increase in the drug’s efficacy, and an environment-dependent increase in drug potency. Efficacy and potency may be subject to sensitization by non-associational and associational mechanisms, respectively. Received: 11 April 1997 / Final version: 7 June 1997     

Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK-801 (dizocilpine)

Rationale: It has been inferred from indirect tests that MK-801, an NMDA receptor antagonist, blocks sensitization to amphetamine and to morphine. These inferences were made from studies where behavioral scores were not recorded after each drug treatment in the sensitization protocol. Objectives: We reinvestigated the role of NMDA receptors in sensitization to amphetamine or morphine more directly by taking locomotor and stereotypy scores after each of several treatments with MK-801 and amphetamine or morphine. Methods: Each male Long Evans rat was administered intraperitoneal injections of MK-801 (0.1 or 0.25 mg/kg) or saline followed 30 minutes later by amphetamine (0.75 mg/kg), morphine (1.25 mg/kg) or saline and placed immediately in a photocell chamber. Locomotion and stereotypy were measured simultaneously by photobeam breaks and direct observation, respectively. This procedure was repeated on days 1, 2, 3, 4, 5, 8, 11 and 27 for rats receiving amphetamine or saline as the second injection and on days 1–10, 13, 16 and 32 for rats receiving morphine or saline as their second injection (with no testing or treatment on intervening days). Results: The animals treated in the amphetamine condition and animals treated in the morphine condition all showed progressively greater locomotion and stereotypy over the first 5 (amphetamine) or 10 (morphine) test days; the sensitized response was seen regardless of whether the animals were pretreated with saline or with MK-801. Thus MK-801 failed to block the development of psychomotor sensitization seen with these treatment regimens. When, following initial sensitization, amphetamine or morphine was given in the absence of MK-801 (days 8 and 13 for amphetamine and morphine rats, respectively), there was no expression of the sensitized response; the sensitized response of animals previously treated in the MK-801 drug state was expressed only when the animal was tested in the MK-801 drug state. The sensitized response was still expressed, in animals tested in the appropriate drug condition, after a 2-week period in which no drugs were given, confirming that the changes underlying this form of sensitization were long-lasting and thus probably a consequence of some form of synaptic plasticity. Conclusions: Our data provide evidence that behavioral sensitization to amphetamine and to morphine can occur despite the presence of NMDA receptor blockade. These and previous findings suggest that the failure of expression of sensitization seen when MK-801 is withdrawn from a given psychomotor stimulant treatment regimen reflects, at least in part, the dependency of sensitization on the various conditions of training rather than dependency on some essential function of NMDA receptor activation. Received: 14 October 1999 / Accepted: 7 March 2000     

Suxamethonium-induced histamine release from the heart of na?ve and suxamethonium-sensitized guinea-pigs: evidence suggesting spontaneous sensitization in na?ve animals, and relevance to anaphylactoid reactions in man

A guinea-pig model for anaphylactic and anaphylactoid reactions to suxamethonium was evaluated. 'Sensitization' to that drug was demonstrated both by cardiac anaphylaxis in the Langendorff preparation, and by serum antibody studies. Spontaneous sensitization to cross-reacting chemicals in a proportion of control animals is strongly suggested, somewhat akin to spontaneous sensitization in patients with anaphylactoid reactions to neuromuscular blockers on first exposure, and in whom IgE antibodies are detected.     

Importance of environmental context in the development of amphetamine- or apomorphine-induced stereotyped behavior after single and multiple doses

The present study was designed to determine whether single and repeated pretreatment regimens with amphetamine or apomorphine differ in the context-dependency of sensitization of stereotyped behavior. Male CF-1 mice that were pretreated with a single high dose of amphetamine (14 mg/kg intraperitoneally [IP]) or apomorphine (40 mg/kg subcutaneously [SC]) only became sensitized to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was the same as the pretreatment environment. However, animals pretreated with 3 high doses (24-h apart) of amphetamine (14 mg/kg IP) or apomorphine (40 mg/kg SC) did demonstrate sensitization to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was different from the pretreatment environment. Context-dependent sensitization, but not context-independent sensitization, was extinguished by pairing the test environment with saline injections instead of drug injections. In addition, it was determined that neither sensitization model could be related to pharmacokinetic factors. Therefore, the results indicate that repeated exposure to amphetamine or apomorphine overcomes the context-dependent component of sensitization of amphetamine- or apomorphine-induced stereotyped behavior.     

Behavioral sensitization in humans.

Behavioral sensitization is the process whereby repeated, intermittent stimulant administration produces a progressively greater and enduring behavioral response. For over two decades, behavioral sensitization has been reliably demonstrated in a number of different animal species and has been proposed as a model for the development of stimulant dependence. However, the application of this model to humans is limited since there have been relatively few studies of sensitization in human subjects. Nonetheless, results from these studies suggest that, similar to animal studies, enhanced behavioral responses do occur following repeated stimulant administration that resemble sensitization. Further research is necessary to examine characteristics of sensitization in humans, including the neurobiological systems involved.