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Gender Differences in Cocaine

Self-Administration in Rats:

Relevance to Human

Drug-Taking Behavior

David C.S. Roberts, Ph.D., and Rachel Phelan, M.Sc.

INTRODUCTION

Recent data indicate that there is an interaction between psychostimulant drugs and gonadal hormones. Mello and colleagues (1994) have

collected convincing evidence suggesting that psychomotor drugs can

disrupt or alter ovarian and hypophysial hormonal function. The reverse

of this also appears to be true; that is, these hormones can affect the

physiological and behavioral response to cocaine (Glick et al. 1983; Van

Haaren and Anderson 1994) as well as to other drugs of abuse such as

amphetamine (Beatty and Holzer 1978; Brass and Glick 1981; Camp et al.

1986) and alcohol (Sutker et al. 1983). This chapter presents data

suggesting that ovarian hormones also can influence the reinforcing effects

of cocaine in laboratory animals as well as a discussion of whether these

data have clinical relevance to drug addiction in women.

PHYSIOLOGICAL AND BEHAVIORAL

INFLUENCE OF HORMONES

Although the precise mechanisms through which hormonal systems

affect physiological responses remain unclear, there are several possibilities. One way that ovarian hormones could influence the response

to psychomotor stimulants is through alterations in drug metabolism.

Some degradative enzymes in the liver are steroid sensitive, and hormonal

fluctuations across the estrous cycle may lead to alterations in the half-life

of various drugs. Some evidence demonstrates that estrogen may even

protect female rats against cocaine toxicity, possibly through alterations

in drug metabolism (Morishima et al. 1993).

The peripheral effects of gonadal hormones are well recognized, and

increasing evidence suggests that hormonal systems may influence the
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behavioral response to psychomotor stimulants via central nervous

system mechanisms as well (Camp et al. 1986; Morse et al. 1986; Wilson

1992; Diaz-Veliz et al. 1994). Cocaine and amphetamine act as indirect

agonists at dopamine terminals by causing the release or inhibition of

dopamine reuptake into the presynaptic terminal. The reinforcing

action of psychostimulant drugs is a result of the augmentation of

dopamine transmission in the nucleus accumbens and possibly other

forebrain structures (Roberts 1992, pp. 73-90). These dopamine

systems, which are essential to the reinforcing action of drugs, also are

modulated by ovarian hormones. Receptors for both estrogen and

progesterone are widespread throughout the central nervous system and

appear to be particularly dense within the mesostriatal and mesolimbic

dopamine pathways (see Maggi and Perez 1985 for a review). Estrogen

reportedly potentiates amphetamine-induced dopamine release and

reduces striatal dopamine concentrations; at the same time, it appears to

initiate increases in dopamine turnover and receptor binding (see Maggi

and Perez 1985 for a review). In summary, the biochemical response to

amphetamine is altered by estrogen, and dopamine turnover varies

across the estrous cycle. In addition, evidence indicates that the brain is

one of the primary sites of hormonal interaction, and it is conceivable

that ovarian hormones directly alter dopamine function, which, in turn,

regulates hormonal cycles to influence observed behavioral responses.

Given that ovarian hormones exert a physiological influence on

dopaminergic systems, it is not surprising that hormone levels can

modulate the behavioral response to dopaminergic drugs (Beatty and

Holzer 1978; Brass and Glick 1981; Glick et al. 1983; Camp et al. 1986;

Van Haaren and Anderson 1994). Estrogen also has been reported to

increase the stereotyped behaviors produced by the administration of

dopamine agonists in rats. For example, Beatty and Holzer (1978) found

that female rats demonstrated more intense and prolonged stereotypies

in response to high doses (i.e., 5 mg/kg) and greater stimulant effects

in response to low doses (1.5 mg/kg) of d-amphetamine than their

male counterparts. Similarly, Camp and colleagues (1986) found that

ovariectomies attenuated amphetamine-induced rotational behavior,

although castration had no effect. From these and other observations,

it was suggested that endogenous hormonal systems facilitate activity

within the mesostriatal dopamine system.
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Other evidence suggests that the differential sensitivities to both

cocaine (Glick et al. 1983) and amphetamine (Brass and Glick 1981)

may be related to gender-specific asymmetrical distributions in brain

levels of dopamine and norepinephrine (Dark et al. 1984) and that such

asymmetries may vary with the strain of animal employed (Brass and

Glick 1981; Haney et al. 1994). Furthermore, apomorphine and amphetamine have significant effects on the performance of animals in

learning situations, and these responses are modified by the estrous cycle

and by estradiol (Diaz-Veliz et al. 1994).

EFFECTS OF GENDER AND STEROID LEVELS

Despite the considerable evidence for physiological and behavioral

interactions of ovarian hormones with psychostimulant drugs, few

studies have examined whether the reinforcing effects of psychostimulant drugs might be affected also by gender or by steroid levels.

The authors and colleagues have addressed this question in several

self-administration experiments (e.g., Bennett et al. 1988; Roberts

et al. 1987, 1989). Animals were implanted with chronically indwelling

intravenous cannulae. During initial training, the intravenous delivery

of cocaine was made contingent on a single lever response (FR 1).

After animals had demonstrated a stable pattern of cocaine selfadministration, a progressive ratio (PR) schedule was imposed. Under

this schedule, the first response of the daily session resulted in the

delivery of a single drug infusion. Thereafter, the response requirements

increased through an exponential function (i.e., 2, 4, 6, 9, 12, 15, 20,

etc.) until self-administration behavior ceased. The final ratio achieved

during the session was defined as the “breaking point,” which provided

an indication of the motivational state of the animal. This PR schedule

has been used to examine how the motivation to self-administer cocaine

is influenced by pharmacological treatments or neurotoxic lesions.

The breaking point has been shown to be sensitive to alterations in

unit injection dose of cocaine and to pretreatment with dopaminergic

antagonists.

Female rats responded to much higher breaking points than male

rats. More interesting, however, was that the motivation to selfadminister cocaine fluctuated across the estrous cycle. Female rats

responded to dramatically higher final ratios during the day of estrus

compared with the days of metestrus, diestrus, and proestrus (Roberts
168

et al. 1989). Figure 1 shows examples of the cumulative records for a

female rat during various stages of the estrous cycle. The results show

that cocaine has a higher reinforcing efficacy during the day of estrus.

These data have been replicated and extended by Grimm and See

(1994), who reported that breaking points fluctuate across the estrous

cycle and, furthermore, that injections of 17- estradiol increase the

reinforcing efficacy of cocaine. Because the alterations in cocaine

self-administration in the laboratory were not observed for the FR 1

schedule, the hormonal influence appears to be specific to the motivational state of the animal but has no influence on the response rate.

SUMMARY

The results of this study suggest that ovarian hormones influence

the motivation of rats to self-administer cocaine. The obvious and

important question is whether these data have any clinical implications

for drug abuse in humans. The self-administration paradigm is an

animal model for the study of drug reinforcement and has been used

in several different applications—as a tool to investigate the specific

brain regions and neurochemical mechanisms involved in the rewarding

properties of drugs of abuse and as a model to evaluate the relative

reinforcing value of novel compounds and offer predictions about

the potential abuse liability in humans. However, like all models, the

self-administration paradigm offers predictions rather than definitive

answers. The value of any model must be evaluated ultimately by the

accuracy of its predictions, for example, how well it predicts abuse

liability or patterns of drug use.

Through use of the self-administration paradigm as a model of

human drug-taking behavior, it was demonstrated that steroid function

affected the reinforcing properties associated with cocaine use in rats.

However, it also should be emphasized that the estrous cycle of the rat is

very different from the menstrual cycle in women. Estrus is a behavioral

term that denotes “sexual receptivity,” which is confined to a few hours

during the 4-day rodent estrous cycle. Because there are vast differences

between the species with respect to sexual motivation, one also might

expect different hormonal interactions in the brain.

The main objective of the self-administration experiments was to

identify possible estrogen-dopamine interactions in the rat brain as
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FIGURE 1. Cocaine self-administration during various stages of the

estrous cycle in the rat. Each line represents a cumulative

record of a female rat responding on a progressive ratio

schedule. Vertical increments indicate lever responses.

Arrows indicate the time of each cocaine injection. The

first response during the daily 5-hour session was reinforced.

The response requirements for each subsequent injection

escalated exponentially (Roberts et al. 1989). Group data

showed that female rats responded to significantly higher

breaking points during estrus.
170

indicated by observed behavioral responses. Such effects might serve

as a model for neuroscientists interested in brain-hormone interactions.

In this respect, these experiments were highly relevant. They were

not intended to “model” cocaine effects in women, although the

experiments do offer an interesting prediction and suggest that gender

and menstrual cycle changes could have an important influence on

cocaine reinforcement. Preliminary clinical evidence indicates that

male human subjects displayed significantly higher plasma cocaine levels

than female volunteers who were given identical intranasal dosages of

cocaine (Lukas et al. 1996). Furthermore, differences in plasma levels

also were seen between women in the follicular phase and women in

the luteal phase of the menstrual cycle. Physiological and psychological

measures of the cocaine response paralleled these plasma differences

(Lukas et al. 1996). Clearly, gender and hormonal influences must

be explored as factors in human drug abuse.

REFERENCES

Beatty, W.W., and Holzer, G.A. Sex differences in stereotyped behaviour in the

rat. Pharmacol Biochem Behav 9:777-783, 1978.

Bennett, S.A.L.; Roberts, D.C.S.; and Vickers, G.J. Gender and estrous cycle

affect cocaine self-administration on a progressive ratio schedule. Soc

Neurosci Abstr 14(1):659, 1988.

Brass, C.A., and Glick, S.D. Sex differences in drug-induced rotation in two

strains of rats. Brain Res 223:229-234, 1981.

Camp, D.M.; Becker, J.B.; and Robinson, T.E. Sex differences in the effects of

gonadectomy on amphetamine-induced rotational behavior in rats. Behav

Neural Biol 46:491, 1986.

Dark, K.A.; Ellman, G.; Peeke, H.V.; Galin, D.; and Reus, V.I. Sex differences

and asymmetries of catecholamines: Relation to turning preferences.

Pharmacol Biochem Behav 20:327-330, 1984.

Diaz-Veliz, G.; Baeza, R.; Benavente, F.; Dussaubat, N.; and Mora, S. Influence

of the estrous cycle and estradiol on the behavioral effects of amphetamine

and apomorphine in rats. Pharmacol Biochem Behav 49:819-825, 1994.

Glick, S.D.; Hinds, P.A.; and Shapiro, R.M. Cocaine-induced rotation: Sexdependent differences between left- and right-sided rats. Science 221:775-

776, 1983.

Grimm, J.W., and See, R.E. Effects of 17-estradiol on intravenous cocaine selfadministration by castrated female rats. Soc Neurosci Abstr 20(2):1633, 1994.
171

Haney, M.; Catanon, N.; Cador, M.; Le Moal, M.; and Mormede, P. Cocaine

sensitivity in roman high and low avoidance rats is modulated by sex and

gonadal hormone status. Brain Res 645:179-185, 1994.

Lukas, S.E.; Sholar, M.B.; Lundahl, L.H.; Lamas, X; Kouri, E.; Wines, J.D.;

Kragie, L; and Mendelson, J.H. Sex differences in plasma cocaine levels and

subjective effects after acute cocaine administration in human volunteers.

Psychopharmacology (Berl) 125:346-354, 1996.

Maggi, A., and Perez, J. Role of female gonadal hormones in the CNS: Clinical

and experimental aspects. Life Sci 37:893-906, 1985.

Mello, N.K.; Mendelson, J.H.; Drieze, J.M.; Teoh, S.K.; Kelly, M.L.; and Sholar,

J.W. Effects of dopamine on prolactin: Interactions with cocaine selfadministration by female rhesus monkeys. J Pharm Exp Ther 270:1110-1120,

1994.

Morishima, H.O.; Abe, Y.; Matsuo, M.; Akiba, K.; Masaoko, T.; and Cooper,

T.B. Gender-related differences in cocaine toxicity in the rat. J Lab Clin

Med 122:157-163, 1993.

Morse, J.K.; Scheff, S.W.; and DeKosky, S.T. Gonadal steroids influence axon

sprouting in the hippocampal dentate gyrus: A sexually dimorphic

response. Exp Neurol 94:649-659, 1986.

Roberts, D.C.S. Neural substrates mediating cocaine reinforcement: The role of

monoamine systems. In: Lakowski, J.M.; Galloway, M.P.; and White, F.J.,

eds. Cocaine Pharmacology, Physiology and Clinical Strategies. Boca Raton, FL:

CRC Press, 1992.

Roberts, D.C.S.; Bennett, S.A.L.; and Vickers, G.J. The estrous cycle affects

cocaine self-administration on a progressive ratio schedule in rats.

Psychopharmacology (Berl) 98:408-411, 1989.

Roberts, D.C.S.; Dalton, J.C.H.; and Vickers, G.J. Increased self-administration

of cocaine following haloperidol: Effect of ovariectomy, estrogen

replacement and estrous cycle. Pharmacol Biochem Behav 26:37-43, 1987.

Sutker, P.B.; Tabakoff, B.; Goist, K.C., Jr.; and Randall, C.L. Acute alcohol

intoxication, mood states and alcohol metabolism in women and men.

Pharmacol Biochem Behav 18:349-354, 1983.

Van Haaren, F., and Anderson, K. Effects of cocaine on fixed interval behavior

and schedule-induced alcohol consumption in male and female rats.

Pharmacol Biochem Behav 47:997-1002, 1994.

Wilson, M.A. Influences of gender, gonadectomy and estrous cycle on GABA/

BZ receptors and benzodiazepine responses in rats. Brain Res Bull 29:165-

172, 1992.
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ACKNOWLEDGMENT

This chapter was prepared with support from National Institute on

Drug Abuse contract no. N01DA-3-7302.

AUTHORS

David C.S. Roberts, Ph.D.

Professor

(613) 520-2600, ext. 7495 (Tel)

(613) 520-4052 (Fax)

droberts@ccs.carleton.ca (E-mail)

Rachel Phelan, M.Sc.

Research Assistant

(613) 520-2600, ext. 1995 (Tel)

(613) 520-4052 (Fax)

Department of Psychology

Life Sciences Research Centre

Carleton University

1125 Colonel By Drive

Ottawa, Ontario K1S 5B6

CANADA