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Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS--mainly those located in limbic and basal forebrain structures--are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism. Dopaminergic neurotransmission--primarily in basal forebrain structures--is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT.
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Psychoneuroendocrinology, Vol. 23, No. 8, pp. 945– 962, 1998
© 1998 Elsevier Science Ltd. All rights reserved
Printed in Great Britain
0306-4530/98 $ - see front matter
PII: S0306-4530(98)00064-X
Ga´bor L. Kova´cs
, Zolta´n Sarnyai
and Gyula Szabo´
Central Laboratory, Markusovszky Teaching Hospital, Szombathely, H-9701, Markusovszky u.
3, Hungary
Laboratory of Neuroendocrinology and Laboratory of Biology of Addictive Diseases, The
Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
Department of Pathophysiology, Albert Szent-Gyo¨ rgyi University Szeged, Semmelweis u.1,
Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine
addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released
at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the
CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate
various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin
was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently
decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic
cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly
inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT.
OXT receptors in the CNS—mainly those located in limbic and basal forebrain structures —are
responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism.
Dopaminergic neurotransmission—primarily in basal forebrain structures —is another important
biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g.
hypothermia-inducing effect of ethanol) also was inhibited by OXT. © 1998 Elsevier Science Ltd. All
rights reserved.
Keywords—Neuropeptides; Oxytocin; Opiate; Cocaine; Ethanol; Rapid tolerance; Addiction;
In the last 25 years there has been a great increase in interest in central nervous system
(CNS) functions of neuroactive peptides (Ho¨kfelt, 1991). Neuropeptides may function as
neurotransmitters as well as neuromodulators. Neurotransmitters are localized in nerve
terminals, preferentially in synaptic vesicles. They are released upon nerve stimulation,
interact with receptor molecules on the postsynaptic cell membrane, and are subsequently
inactivated by enzymatic degradation and re-uptake mechanisms. The response to classic
neurotransmitters is rapid and short lasting. Neuromodulation includes a slow time course
of action, a more diffuse site of action and an ability to change responses to neurotrans-
mitters (Kow and Pfaff, 1988). In view of these characteristics, neuropeptides may indeed
influence a variety of biological functions by acting as neuromodulators.
Address correspondence and reprint requests to: Ga´ bor L. Kova´cs, Central Laboratory,
Markusovszky Teaching Hospital, H-9701, Szombathely, Markusovszky u.3., Hungary (Tel: 36 94
312172; Fax: 36 94 327873; E-mail:
G. L. Kova´csetal.946
Repeated administration of drugs such as ethanol, opiates or barbiturates leads to the
development of tolerance and physical dependence. Tolerance is described as a diminished
response to a drug upon repeated exposures. Physical dependence is demonstrated by the
occurrence of withdrawal symptoms when drug administration is stopped. Some aspects of
functional tolerance to opiates have been considered to be a form of learning (Colbern et
al., 1986). The same may hold for tolerance to other compounds such as ethanol. Abused
drugs are known to enhance brain reward mechanisms. The mesolimbic dopaminergic
projections form a crucial drug-sensitive component of the reward circuitry, which is
preferentially activated neurochemically by abusable substances to enhance brain reward.
The mesolimbic dopaminergic fibers terminating in the nucleus accumbens appear to be
the most crucial reward-relevant components of the ascending mesotelecephalic dopamine
system (Koob, 1992; Lowinson et al., 1992). The drug-sensitive dopaminergic components
of the reward circuitry are under the modulatory control of a wide variety of other
neuronal and hormonal systems. In the present paper we consider the hypothesis that a
specific neuropeptide, oxytocin (OXT), acting within the CNS, may modulate the role of
dopamine in the reward circuitry. Evidence regarding this hypothesis comes primarily from
studies of the role of neuropeptides, and in particular of OXT, on experimental drug
addiction in rodents. These studies are reviewed here.
The Effects of Oxytocin on Opiate Tolerance
In recent years it has become increasingly evident that neurohypophyseal neuropeptides
(OXT and vasopressin, VP) might play a role in drug addiction processes (Kova´cs, 1986;
Kova´cs and Telegdy, 1987b; Krivoy et al., 1974; Van Ree, 1983). For example,
-vasopressin (DG-LVP) facilitated the rate at which tolerance to
morphine-induced analgesia developed in mice (Krivoy et al., 1974). Van Ree and De
Wied (1977a,b) found that the hormonally active VP and a variety of hormonally inactive
vasopressin-like peptide fragments increased the rate of tolerance (the analgesic action of
opiates was investigated in these studies).
OXT, on the other hand, dose-dependently attenuated the development of rapid and
chronic morphine tolerance in mice. For example, in animals treated with OXT and then
with a high, tolerance inducing dose of morphine (Fig. 1), the analgesic effect of a second
morphine injection was greater than in the control animals which did not receive OXT.
Interestingly, OXT did not modify the magnitude or the duration of the analgesic effect of
the first morphine challenge in drug-naive animals (Kova´cs and Telegdy, 1987a; Kova´cs et
al., 1985).
Of physiological interest might be the finding that tolerance to the antinociceptive effect
of b-endorphin was also attenuated by graded doses of OXT. The dose-response effect of
OXT was U-shaped, because medium-high doses of this neuropeptide were more effective
than high peptide doses. Since b-endorphin is an endogenous substance in the central
nervous system, the results indicate the possibility of a physiological interaction between
two different neuronal peptides (OXT and b-endorphin) in the organization of opiate
tolerance (Kova´cs and Telegdy, 1987a).
Intracerebroventricular (ICV) injections of OXT were considerably more potent than
were systemic peptide injections in attenuating analgesic morphine tolerance (Fig. 1). This
Oxytocin and Addiction 947
finding suggests that CNS, and not peripheral mechanisms are involved in this effect of the
neurohypophyseal neuropeptide. Local intracerebral microinjections of OXT were even
more potent than ICV injections (Ibragimov et al., 1987; Kova´cs et al., 1984; Sarnyai et
al., 1988). The most sensitive brain sites were the hippocampus and the basal forebrain
(including the nucleus accumbens and the posterior olfactory nuclei). Oxytocinergic nerve
terminals (Buijs, 1983; Sawchenko and Swanson, 1985) and binding sites (De Kloet et al.,
1985; Ferrier et al., 1983) are present in these brain nuclei.
It is remarkable that the interaction of OXT with morphine tolerance could also be
observed in non-analgesic effects of the opiate alkaloid. Accordingly, in mice OXT
treatment inhibited the development of tolerance in the locomotor hyperactivity that
follows the administration of high doses of morphine (Kova´cs and Telegdy, 1987b). Since
brain structures involved in the control of pain perception and those responsible for
hyperlocomotion are not identical, these data suggest that the effect of OXT on morphine
tolerance was not specifically related to the effector (output) mechanisms of these
behavioral processes, but rather to more fundamental neuronal mechanisms responsible
for the organization of tolerance.
Oxytocin and Morphine Withdrawal
The degree of physical dependence to a given narcotic drug is characterized by the
severity of withdrawal reactions (e.g. stereotyped jumping due to extrapyramidal incoordi-
nation, salivation, loss of body weight as a consequence of intensive diarrhea and
urination, decrease in colonic temperature, irritability, etc.). Injections of OXT in graded
doses, given prior to the first morphine challenge, attenuated various signs of the
Fig. 1. The effect of OXT on the development of morphine tolerance. Mice were rendered tolerant
to/dependent on morphine by the subcutaneous implantation of a morphine pellet (Kova´ cs et al.,
1981). A single injection of OXT in graded doses was given 2 h prior to the pellet implantation; 48
h later, a test dose of 5 mg/kg morphine was injected and the analgesic effect was measured 30 min
later by the heat irradiant tail-flick method. Left curve: ICV OXT treatment; right curve: SC OXT
treatment. ICV injections were administered via chronically implanted plastic cannulae. Each point
represents the mean (9SE) of eight experimental animals. The horizontal dotted area represents the
analgesic effect of 5 mg/kg morphine in the tolerant control animals (
pB.001 vs. tolerant control animals).
G. L. Kova´csetal.948
naloxone-precipitated withdrawal reaction. Low doses of OXT were needed to attenuate
the withdrawal-induced hypothermia, while higher doses of the neuropeptide were required
to antagonize the withdrawal-induced loss in body weight and the latency of the onset of
stereotyped jumping. It is therefore likely that OXT interfered with the development of
physical dependence and a lower degree of physical dependence resulted in a secondary
manner in the appearance of less severe withdrawal signs.
Heroin Self-administration and Neurohypophyseal Peptides
Since neurohypophyseal neuropeptides deeply affected the development of tolerance to,
and dependence on narcotic drugs (Kova´cs and Telegdy, 1985, 1987b; Van Ree, 1983),
their roles in drug-induced reinforcement process also have been studied. Van Ree and De
Wied (1977a,b) found that desglycinamide
-vasopressin, a behaviorally active
fragment of VP, reduced intravenous self-administration of heroin in non-tolerant rats.
OXT exerted a different effect in this study: rats treated with this neuropeptide self-admin-
istered significantly more heroin (Van Ree and De Wied, 1977a) than did VP-treated
animals, but not more than the non-treated control animals. Basically different findings
were published more recently (Ibragimov et al., 1987; Kova´cs and Van Ree, 1985; Kova´cs
et al., 1985), when the effect of OXT treatment on the development of heroin self-admin-
istration was investigated in heroin tolerant rats. OXT dose-dependently reduced the
self-injected heroin dose. In non-tolerant rats, on the other hand, systemic injections of
OXT did not modify the rate of heroin self-administration. Taken together, these findings
suggest that OXT reduced the higher self-administration rate of the heroin-tolerant/depen-
dent rats to a level of self-injection, similar to that of non-tolerant rats (Kova´cs and Van
Ree, 1985). These data suggest the hypothesis that the primary action of OXT is not on
the reinforcing efficacy of heroin, but rather on the degree of tolerance to, and dependence
on heroin.
The In6ol6ement of Central Ner6ous Oxytocinergic Receptors
Earlier results indicated that endogenous OXT, which is present in oxytocinergic nerve
fibres and terminals in the brain (Buijs, 1983; Sawchenko and Swanson, 1985) may have
a physiological role in adaptive components of narcotic addiction (Kova´cs, 1986). The
description of saturable oxytocinergic binding sites in the limbic system (De Kloet et al.,
1985; Ferrier et al., 1983) stimulated research investigating whether receptor antagonists of
OXT could effectively block the action of OXT on morphine tolerance (Kova´cs et al.,
1987). ICV injections of N-a-acetyl-[2-O-methyltyrosine]-OXT, an antagonist of oxytocin-
ergic receptors (Jost and Sorm, 1971), dose-dependently antagonized the inhibitory effect
of OXT on the development of rapid-morphine tolerance in mice. It also has been
demonstrated that local microinjections of minute amounts of this receptor antagonist into
limbic brain areas is highly effective in inhibiting the effects of OXT on morphine
tolerance in mice (Sarnyai et al., 1988), or heroin self-administration in rats (Ibragimov et
al., 1987). It is, therefore, likely that endogenous OXT acts on OXT receptors in limbic
brain areas to inhibit adaptive mechanisms underlying experimental drug addiction
(Kova´cs et al., 1986a).
However, it cannot be ruled out that OXT may exert some of its effects on drug
addiction through central nervous VP receptors. Receptors in the brain, selective for VP,
are presumably of the V
type (Kira´ly et al., 1986; Shewey and Dorsa, 1988). There is no
firm evidence for central V
or V
receptors. V
receptors have been found in various
Oxytocin and Addiction 949
brain areas, including the limbic system (e.g. the anterior olfactory nucleus, lateral septum,
nucleus accumbens, central amygdaloid nucleus, and dentate gyrus (Tribollet et al., 1988).
Also two types of OXT binding sites have been detected in the central nervous system. One
widely distributed throughout the CNS is comparable to the uterus type receptor and a
sexually dimorphic slightly different type in the nucleus ventromedialis. Elands et al.
(1988), using a highly specific tritiated OXT agonist, showed that the OXT receptor in the
ventral hippocampus exhibits properties similar to the OXT receptors in the rat uterus and
lactating mammary gland. This receptor also has a high affinity for VP, as does the
peripheral OXT receptor, although the bioleogical potency of VP in uterus and mammary
gland is low. In the brain, this receptor may mediate central effects of VP and OXT and
may thus be regarded as a ‘non-selective’ receptor.
The Role of Forebrain Dopamine in Mediating the Effect of OXT
Forebrain dopamine plays an important, presumably causal, role in drug addiction
processes (Acquas and Di Chiara, 1992; Koob, 1992; Redmond and Krystal, 1984). It was,
therefore, of interest to investigate whether OXT could alter dopaminergic neurotransmis-
sion in the basal forebrain. In rats the effect of OXT was more pronounced on the
nigrostriatal, than on the mesolimbic, dopamine system (Kova´cs and Telegdy, 1983; Van
Heuven-Nolsen et al., 1984; Versteeg, 1983). In mice, on the other hand, chronic OXT
treatment decreased the utilization and the receptor binding (Kova´cs et al., 1986b) of
dopamine in the mesolimbic dopamine system. In the basal forebrain structures, also
involving the nucleus accumbens and the posterior olfactory nuclei, chronic treatment with
OXT significantly inhibited the high potassium-induced stimulated in vitro release of
dopamine in these brain structures (Fig. 2). The basal (low potassium-induced) release of
dopamine, on the other hand, was not affected by the same treatment schedule. OXT also
interferes with the effect of apomorphine on locomotor activity and modulates the
development of receptor supersensitivity following haloperidol treatment (Kova´cs et al.,
1986b). These and other findings support the idea that the effect of OXT on narcotic
addiction is—at least partly mediated by dopamine receptors in the basal forebrain.
Cocaine is a psychostimulant, which acts primarily through the brain dopaminergic
system as an inhibitor of the dopamine transporter, thus resulting in an increase in
synaptic dopamine content (Galloway, 1988; Koob et al., 1997). Locomotor hyperactivity,
exploratory hyperactivity and stereotyped behavior were investigated as acute behavioral
responses to cocaine. Two types of behavioral adaptation to repeated cocaine administra-
tion, sensitization and tolerance were chosen to study the interactions of OXT with
chronic cocaine exposure. Intracerebroventricular and local intracerebral microinjections
of OXT and OXT receptor antagonists were utilized to localize the site/s of action of OXT
on cocaine-induced behavioral responses and adaptations. The roles of nigrostriatal and
mesolimbic dopaminergic neurotransmission in the mediation of the effects of OXT were
studied by neurochemical means.
Acute Effects of Cocaine
Locomotor Hyperacti6ity and Stereotyped Beha6ior
Locomotor hyperactivity elicited by psychostimulants has been considered to develop
through the mesolimbic dopaminergic system. The nigrostriatal dopamine system, on the
G. L. Kova´csetal.950
Fig. 2. The effect of OXT treatment on dopamine release in the mouse forebrain. The release of
H]dopamine was measured in vitro in brain slices of the basal forebrain. The experiments were
carried out with low potassium (4.2 mmol/l, control values are indicated by the lower horizontal
dotted area) as well as high potassium (30 mmol/l, control values are indicated by the upper
horizontal dotted area) concentrations (Kova´ cs et al., 1986b) (the former gives information about
the basal, the latter about stimulated release of dopamine). Columns A, B, C: low potassium release
groups; columns D, E, F: high potassium release groups. Column A: in vitro OXT treatment. The
peptide was added to the incubation medium in a concentration of 1 nmol/l. Column B: acute in
vivo OXT treatment (0.2 mg/kg OXT SC). Mice were decapitated 1 h after peptide treatment.
Column C: chronic in vivo OXT treatment. The peptide was injected for 8 consecutive days in a dose
of 0.2 mg/kg SC mice were decapitated 1 h after the last peptide injection. Column D: identical to
group A, but the potassium concentration of the incubation medium was high. Column E: identical
to group B, but the concentration of potassium was high. Column F: identical to group C, but the
concentration of potassium was high. The y-axis indicates the ratio of the DPM of [
H]dopamine in
the supernatant, and that of the pellet fraction of the homogenate prepared from forebrain slices
pB.05 vs. group D). High ratio indicates increased in vitro release.
other hand, is widely accepted as the neuronal basis of stereotyped behavior (Johanson
and Fischman, 1989). However, the situation may be more complex, since the most typical
element of stereotyped behavior induced by moderate doses of cocaine, sniffing behavior,
could be equally elicited by the local microinjection of cocaine into the mesolimbic
dopamine terminals located in the nucleus accumbens and tuberculum olfactorium, as well
as by local intrastriatal administration of the drug (Sarnyai, 1993). Grooming behavior,
another component of the cocaine-induced behavioral repertoire, on the other hand, could
only be elicited by local cocaine microinjection into the caudate nucleus (Sarnyai, 1993).
Cocaine produced a long-lasting (:120 min) locomotor hyperactivity in a familiar
environment (measured by an automated, microprocessor-controlled, six-channel motime-
ter (Kova´cs et al., 1990)). Different doses of OXT (0.2, 1.0 and 5 mg/animal) were given
SC 60 min before cocaine (30 mg/kg) administration. OXT (1.0 and 5 mg) dose depen-
dently decreased the cocaine-induced locomotor hyperactivity during both the first and
second hour after cocaine treatment. Cocaine-induced hyperlocomotion was not altered by
0.2 mg of OXT.
The effect of cocaine in a stressful environment was studied by measuring novel
environment-induced exploratory hyperactivity in mice (Sarnyai et al., 1990). Animals
were tested in an unfamiliar open-field apparatus. Exposure to the novel environment
resulted in an exploratory hyperactivity characterized by increased locomotion interrupted
by rearing/sniffing episodes. Cocaine administration (7.5 mg/kg) 10 min prior to exposure
to the novel open-field situation produced a 3-fold increase in crossing behavior. Pretreat-
Oxytocin and Addiction 951
ment with graded doses of OXT (0.005–5.0 mg) attenuated the cocaine-induced ex-
ploratory hyperactivity with a U-shaped dose-response relationship, an effect rather
typical for neuropeptides. OXT was found to be ineffective in altering the behavior of
cocaine-naive (saline-treated) control animals in both paradigms.
A higher dose of cocaine (15 mg/kg) produced a long lasting, characteristic stereotyped
behavioral pattern dominated by sniffing behavior. Peripheral pretreatment with OXT
(0.05, 0.5 and 5.0 mg/animal; SC), resulted in a dose-dependent decrease in cocaine-in-
duced stereotyped behavior (Fig. 4(A)) (Sarnyai et al., 1991). Grooming behavior, which
was not a prominent behavioral pattern after this dose of cocaine (15 mg/kg), remained
unchanged by OXT. It is interesting to note that two neuropeptides structurally related to
OXT, arginine-vasopressin and lysine-vasopressin, failed to alter this behavioral response.
Chronic Effects of Cocaine
Tolerance and Sensitization
Chronic cocaine administration could lead to either tolerance or sensitization, depending
on the dose and route of administration, treatment schedule or environmental effects
(Hammer et al., 1997; Johanson and Fischman, 1989). The effects of OXT on the
development of both tolerance and sensitization to cocaine have been studied in rats and
mice (Sarnyai et al., 1992a,b). Repeated administration of cocaine (7.5 mg/kg, 2×a day,
for 4 days) produced a behavioral tolerance to the sniffing-inducing effects of cocaine
(Sarnyai et al., 1992a) (Fig. 3). This was indicated by a parallel shift to the right of
dose–response and time effect curves of the test doses (1.875, 3.25 and 7.5 mg/kg)
injected on the fifth day of chronic cocaine administration (Fig. 3(A)). The relative potency
of cocaine to induce sniffing was 6.42×greater in the cocaine-tolerant than in cocaine-
naive rats, therefore a 6.42×larger dose was required to produce the same effect in
cocaine-tolerant rats as in cocaine-naive control animals. The development of tolerance
was inhibited by pretreatment with OXT (0.05 mg but not 0.005 mg, SC, and administered
60 min before each daily injection of cocaine). OXT pretreatment in these cocaine-tolerant
rats shifted the dose-response curve of a test dose of cocaine back to the level of the
non-tolerant control rats. The relative potency of cocaine between the OXT-pretreated
cocaine-tolerant versus the peptide-naive cocaine-tolerant groups was 5.3. This effect can
be interpreted as an inhibition of the development of tolerance to cocaine.
Subchronic administration of cocaine (7.5 mg/kg, SC, and 2×a day for 5 days)
induced behavioral sensitization (gradually increasing hypermotility to a challenge dose of
cocaine) (Sarnyai et al., 1992b). It was investigated whether repeated administration of
OXT would affect cocaine sensitization. Different doses of OXT (0.005, 0.05 and 0.5
mg/animal) were injected 60 min prior to daily cocaine administration, except on the test
day. A higher dose of OXT (0.5 mg) significantly facilitated the development of cocaine-in-
duced behavioral sensitization. Interestingly, arginine-vasopressin (0.005, 0.05 and 0.5 mg)
pretreatment inhibited the development of sensitization to cocaine in the same paradigm.
Site of Action of OXT
Brain Versus Periphery
Inhibitory effects of peripherally administered OXT on acute and chronic behavioral
actions of cocaine have been demonstrated. One of the major concerns interpreting the
CNS effects of peripherally administered neuropeptides is that peptide molecules do not
readily penetrate the blood–brain barrier making difficult to reach a brain target for their
actions. Three different approaches were applied to study the site(s) of action of OXT.
G. L. Kova´csetal.952
Central Pretreatment with a Specific Oxytocin-receptor Antagonist Followed by Periph-
eral Oxytocin Administration. If target sites of OXT’s actions are in the brain, an ICV
administered OXT antagonist should inhibit the effects of peripheral OXT treatment. It
has been hypothesized that a minor amount of subcutaneously (SC) injected peptide (or
behaviorally active fragments thereof that can interact with cerebral OXT binding sites)
can pass the blood–brain barrier and reach brain target sites. To test this hypothesis, a
strategy of central OXT-antagonist/peripheral OXT has been utilized. Cocaine-induced
sniffing behavior (Sarnyai et al., 1991) was selected as a test model. N-a-(2-O-methyl-
paratyrosine)-OXT, an OXT-receptor antagonist, was administered ICV at a dose of 50
pg, 15 min prior to SC OXT injection. OXT was administered SC 60 min before acute
cocaine injection. The development of cocaine-induced sniffing behavior was inhibited by
peripheral pretreatment with OXT in a dose of 0.5 mg. ICV administration of the
OXT-receptor antagonist (50 pg) completely abolished the effect of peripherally injected
Fig. 3. Role of hippocampal OXT in cocaine tolerance. (A) Tolerance to sniffing-inducing effect of
cocaine and its reversal by SC OXT (0.05 mg/rat) administration; (B) decreased hippocampal OXT
content in cocaine-tolerant (TOL) rats; (C) tolerance to sniffing-inducing effect of cocaine and its
reversal by intrahippocampal OXT (100 pg/rat) administration.
pB.05 versus CTR (non-toler-
ant); * pB.05 versus TOL (7.5 mg/kg of cocaine, SC, 2 ×a day, for 4 days) (Sarnyai et al., 1992a).
Oxytocin and Addiction 953
Fig. 4. Peripheral (A) and central (B) OXT administration attenuate the cocaine-induced stereo-
typed sniffing behavior in rats. cocaine: 15 mg/kg of cocaine, SC; saline: 0.9% NaCl; * pB.05 versus
cocaine-treated animals (Sarnyai et al., 1991).
OXT in this paradigm. This result could be explained by assuming that a minor, but
sufficient amount of OXT (or one of its active fragments) administered peripherally might
have passed the blood–brain barrier and acted on central nervous system target sites. The
OXT-receptor antagonist used in these studies was tested on mammary gland myoepithe-
lial tissue to demonstrate its antagonistic property (Krejci et al., 1973a,b). The same
OXT-receptor antagonist injected into the nucleus accumbens potently blocked the effect
of ICV administered OXT on novelty-induced grooming behavior (Drago et al., 1991).
Caldwell et al. (1986) showed that a structurally different OXT antagonist (having activity
on peripheral OXT receptors of the myoepithelial cells), administered into the lateral
ventricle, altered novelty-induced grooming behavior modulated by OXT. These data
support the hypothesis that central and peripheral OXT receptors may have structural
functional similarities.
Intracerebro6entricular Administration of Minute Amounts of Oxytocin. If a very small
amount of OXT, which is ineffective when administered to the periphery, were able to act
on drug-induced processes after central (ICV) injection, this would suggest that the site of
action of OXT be in the brain. Peripheral administration of 0.5 and 5.0 mg OXT
effectively attenuated cocaine-induced stereotyped behavior. Lateral ventricular injection
of graded doses of OXT (1–100 ng) caused a dose-related attenuation in cocaine-induced
sniffing (Sarnyai et al., 1991). The effective ICV doses of OXT (10 and 50 ng) were
approximately one tenth of the effective peripheral doses (Fig. 4(B)).
Local Administration of OXT in a Physiological Dose Range. To investigate brain target
sites of OXT’s action on cocaine-induced stereotyped sniffing behavior, OXT was microin-
jected into basal forebrain regions (nucleus accumbens, tuberculum olfactorium and
nucleus olfactorius) and into the caudate nucleus; these brain regions have been implicated
in the mediation of sniffing behavior in rats (Sarnyai et al., 1991). The microinjection of
OXT (100 pg, 60 min prior to cocaine administration) into the nucleus accumbens resulted
in a more than 50% decrease in cocaine-induced sniffing behavior. Cocaine-induced
G. L. Kova´csetal.954
sniffing also was significantly attenuated by OXT microinjection into the olfactory
tubercle. The dose of OXT used for the local microinjection was 10
×lower than the
lowest effective dose injected ICV. In contrast to the active brain sites, microinjections of
OXT into some other—occasionally adjacent brain areas, such as the olfactory nucleus,
central amygdaloid nucleus, or caudate nucleus did not alter cocaine-induced stereotyped
behavior. The nucleus accumbens and the olfactory tubercle are the site of the termination
of the mesolimbic dopaminergic projections (Lindvall and Bjo¨rklund, 1978). The mesolim-
bic dopaminergic terminals in the nucleus accumbens also are critically involved in
cocaine-related behavioral processes (Koob, 1992; Koob and Bloom, 1988). Dopamine-re-
ceptors in the tuberculum olfactorium are thought to be responsible for the manifestation
of sniffing behavior induced by dopaminergic drugs (Madras, 1984). These data strongly
suggest that OXT receptors located in basal forebrain areas mediate the effect of OXT on
cocaine-induced stereotyped behavior.
Behavioral tolerance to chronic cocaine administration was inhibited by low doses of
OXT injected SC Furthermore, chronic cocaine administration resulted in a decrease in
immunoreactive OXT content (Fig. 3(B)) in the hippocampus (Sarnyai et al., 1992a). To
study the target site of exogenous OXT and the role of hippocampal (endogenous) OXT
in the development of cocaine tolerance, OXT was administered into the ventral
hippocampus (Fig. 3(C)) (Sarnyai et al., 1992b). Sniffing activity, induced by a test dose of
cocaine, was gradually decreased by repeated cocaine treatments, demonstrating the
development of behavioral tolerance to cocaine (Fig. 3(A)). Intrahippocampal administra-
tion of 100 pg of OXT—given 60 min before each tolerance-inducing cocaine injection
almost completely prevented the development of cocaine tolerance (Fig. 3(C)). This
conclusion also is supported by the finding that a test dose of cocaine on the OXT treated
cocaine-tolerant animals elicited the same sniffing activity as in saline-treated, non-tolerant
controls. On the other hand, chronic intrahippocampal OXT treatment did not alter the
sniffing activity induced by a single test dose of cocaine. These data showed that the
ventral hippocampus plays a critical role in both the mediation of the effect of OXT and
the regulation of adaptive CNS processes related to cocaine tolerance.
In conclusion, basal forebrain and limbic structures, such as the olfactory tubercle,
nucleus accumbens and the hippocampus are important in the mediation of the effects of
OXT on psychostimulant-induced adaptive behavioral changes.
Cocaine and Brain Oxytocin Content. In order to determine the adaptive changes of the
endogenous brain OXT to cocaine challenge, it is of interest to study the effects of acute
and chronic cocaine administration on the levels of OXT in different brain regions. Acute
administration of behaviorally effective doses of cocaine (7.5–30 mg/kg) increased the
levels of OXT in the hypothalamus and in the hippocampus in rats. On the contrary, OXT
levels were decreased in the basal forebrain regions in response to acute cocaine treatment.
No change was found in the amygdala (Sarnyai et al., 1992c). The data on the increased
hypothalamic OXT level in response to acute cocaine administration is also supported by
the in vitro results of Sim and Morris (1992). These authors demonstrated that cocaine
and dopamine increased the c-fos activity of OXT cells from a neonatal paraventricular
nucleus cell culture. Chronic cocaine administration (7.5 mg/kg, 2×a day, for 4 days), a
treatment schedule that can produce behavioral tolerance in rats (Sarnyai et al., 1992a),
resulted in a significant decrease in OXT levels in the peripheral blood and in the
hypothalamus, indicating an OXT depletion in the hypothalamo–neurohypophyseal sys-
tem. OXT also was depleted from the hippocampus by chronic cocaine administration
Oxytocin and Addiction 955
(Fig. 3(B)). OXT contents in the basal forebrain and in the amygdala were not different
from control values after chronic cocaine administration. These data suggest the plasticity
of brain OXT systems in response to cocaine. Furthermore, the decreased OXT levels in
the hippocampus in cocaine-tolerant animals together with the inhibitory effects of
intrahippocampal OXT injection on cocaine tolerance might indicate a functional role of
hippocampal OXT in the regulation of adaptive behavioral processes in response to
repeated cocaine administration.
Mechanisms of Action
Oxytocin,Cocaine and Dopaminergic Neurotransmis-
sion. Dopaminergic neurotransmission in the brain has been considered as a major target
system for cocaine. Reinforcing and psychostimulant actions of cocaine are mainly
mediated through the mesolimbic dopaminergic system (Koob, 1992; Kuhar et al., 1991).
Two characteristic acute effects of cocaine, the locomotor hyperactivity and the stereo-
typed sniffing behavior, were both inhibited by OXT administration (Kova´cs et al., 1990;
Sarnyai et al., 1990, 1991). Locomotor activation by cocaine is mediated through the
mesolimbic dopamine structures (nucleus accumbens), but both the nigrostriatal (caudate
nucleus) and the mesolimbic (nucleus accumbens and tuberculum olfactorium) structures
are responsible for cocaine-induced sniffing (Sarnyai, 1993). Cocaine administration facili-
tated a-MPT-induced dopamine disappearance in both the nucleus accumbens and the
striatum (Kova´cs et al., 1990; Sarnyai et al., 1990). SC administration of OXT, in a dose
which effectively antagonized the behavioral effects of cocaine, inhibited the effect of
cocaine on dopamine utilization in nucleus accumbens, but not in the striatum (Kova´cs et
al., 1990; Sarnyai et al., 1990). Interestingly, although cocaine microinjection (15 and 30
mg) into the nucleus accumbens, tuberculum olfactorium as well as into the caudate
nucleus elicited the stereotyped sniffing behavior (Sarnyai, 1993), OXT inhibited this effect
of cocaine when it was microinjected into the nucleus accumbens and tuberculum
olfactorium, but not into the caudate nucleus (Sarnyai et al., 1991). One possible
explanation of the lack of effect of OXT in caudate nucleus might be the relatively low
density of OXT binding sites in this structure. This surprisingly close correlation between
behavioral and neurochemical data suggest that the mesolimbic dopamine system pays a
role in the mediation of the effects of OXT on the acute behavioral actions of cocaine.
Chronic cocaine administration produced behavioral symptoms such as tolerance or
sensitization. Changes of dopamine neurotransmission as a possible neurochemical basis of
chronic cocaine abuse have been extensively studied (Johanson and Fischman, 1989).
Chronic inhibitory effects of OXT on dopamine utilization, release and on postsynaptic
dopamine receptors in the basal forebrain structures might explain the inhibitory and
stimulatory effects of OXT on cocaine tolerance and sensitization, respectively.
Oxytocin and Ethanol Tolerance
In the CNS, ethanol tolerance appears to be a combined process with both behavioral
and cellular components. Tolerance to ethanol has been shown to involve learning. Some
forms of tolerance are dependent on learning. The animals display tolerance only in the
environment where ethanol was initially presented and not in a novel environment.
G. L. Kova´csetal.956
Development of rapid tolerance to the hypothermic effect of ethanol has been proposed
as a reliable model for investigating the above phenomenon. Peripheral administration of
OXT (1.5–6.0 mg/animal) prevented the development (Fig. 5) of tolerance to ethanol in
mice (Szabo´ et al., 1985, 1987b). Central administration of OXT was found to be at least
500×more potent than peripheral injection at blocking the development of rapid
tolerance to ethanol (Szabo´ et al., 1989), which lends support to the theory that OXT acts
on CNS mechanisms to influence adaptive responses to drugs.
Using other techniques, where ethanol was presented covertly and continuously as a
liquid diet or by using inhalation chambers, tolerance developed independent of environ-
mental clues. OXT given peripherally at a high dose (10 mg/animal) either during the
induction or dissipation of tolerance was without effect (Hoffman et al., 1978).
The Role of Brain Monoamines in Mediating the Effect of Oxytocin on the De6elopment
of Rapid Tolerance to Ethanol
Central administration of OXT in doses which inhibit the development of rapid
tolerance to ethanol increased norepinephrine levels in the hypothalamus, dopamine levels
in the striatum and medulla oblongata, and serotonin levels in the hippocampus and
striatum (Szabo´ et al., 1988). From measuring steady-state levels of monoamines in the
CNS one cannot draw conclusion regarding the effects of OXT on synaptic events (e.g.
changes in transmitter uptake release, turnover and/or metabolism). The results, however,
can be used as a correlative measure for demonstrating the effect of OXT on neurotrans-
mission as the animals were subjected to biochemical investigation at the conclusion of the
behavioral observations. The mechanism of ethanol’s action on CNS neurotransmission is
unclear. It appears that primarily serotonergic and dopaminergic neurotransmissions are
altered during the inhibition of tolerance development by OXT (Szabo´ et al., 1988).
Fig. 5. Effect of OXT on ethanol-induced hypothermia. Mice were injected with OXT 2 h before
injection of ethanol. Rectal temperature was monitored 45 min after ethanol administration. Values
represent mean9SEM for 10– 19 animals per group.
Oxytocin and Addiction 957
Table I. Effects of OXT on addiction
Effects of OXT on Route of adminis- ReferenceDose of OXT
tration (mg/kg)addiction
Kova´ cs et al. (1981)10
SCMorphine tolerance
ICV Kova´ cs et al. (1981)10
Morphine tolerance
ICMorphine tolerance 10
Ibragimov et al. (1987)
Kova´ cs et al. (1987)
Sarnyai et al. (1988)
Kova´ cs et al. (1981)SCMorphine with- 10
Kova´ cs et al. (1981)Morphine with- ICV 10
IC Kova´ cs et al. (1987)Morphine tolerance
Sarnyai et al. (1988)
SC Kova´ cs and Telegdy (1987a)10
b-Endorphin toler-
Heroin self-admin- 10
SC Kova´ cs and Van Ree (1985)
Heroin self-administra- IC Ibragimov et al. (1987)
SC Szabo´ et al. (1985, 1987a,b)Ethanol tolerance 10
ICV 10
Szabo´ et al. (1989)Ethanol tolerance
SC Sarnyai et al. (1991)Cocaine sensitiza-
Sarnyai et al. (1991)Cocaine sensitiza- 10
Effect of Oxytocin on Ethanol Withdrawal Symptoms
During ethanol withdrawal, OXT-treated mice displayed milder withdrawal convul-
sions. This effect is increased in response to increasing doses of the peptide (0.6–6
mg/animal SC) and the rate of lethality also were decreased (Szabo´ et al., 1987a). At a
lower dose of OXT (0.06 mg/animal) the animals displayed severe withdrawal signs and
increase in mortality.
Recent results from our laboratories (Kova´cs, 1986; Sarnyai and Kova´cs 1994), and
other laboratories (Krivoy et al., 1974; Van Ree, 1983; Van Ree and De Wied, 1977a,b)
suggest that neurohypophyseal neuropeptides modulate the response to drugs of abuse.
In the case of OXT, adaptive components of drug addiction are affected primarily: the
neuropeptide inhibits the development of tolerance to, and physical dependence on,
morphine and reduces the self-administration of another frequently abused opiate drug,
heroin. Development of ethanol tolerance and that of cocaine sensitization also is
inhibited by OXT treatment.
G. L. Kova´csetal.958
Fig. 6. Effects of OXT on opiate, cocaine and ethanol addiction: a summary OXT may modulate
adaptive CNS processes related to opiates, cocaine and ethanol through an interconnected neural
circuit, which contains the hypothalamus, ventral hippocampus and ventral striatum.
Peripheral injections of OXT were considerably less potent than ICV or local intracere-
bral administration of the peptide (Table I), suggesting that the primary site of action of
the neuropeptide was in the CNS. It is somewhat striking that peripheral injections of the
neuropeptide were not completely ineffective, since the blood–brain barrier is largely
impermeable to neurohypophyseal peptides. However, peripheral injections with OXT may
also increase the OXT content in the cerebrospinal fluid (Mens, 1982) in drug-naive rats.
It has been suggested, that 1% of OXT or OXT-antagonists may pass the blood brain
barrier following peripheral injections (Kastin et al., 1976). In addicted animals, however,
the permeability of the blood-brain barrier may also be damaged (Lange et al., 1983),
leading to an increased leakage of the peptide from the blood stream to the cerebrospinal
fluid. It cannot be ruled out either that peripheral OXT treatment modulates the release of
central OXT by nervous or humoral mechanisms.
Opiates, cocaine and alcohol act on the CNS through different mechanisms (Lowinson
et al., 1992). These differences in neuroanatomical, biochemical, neurochemical and
molecular mechanisms are particularly significant between stimulant and depressant drugs.
And yet, the neuropeptide OXT inhibits adaptive CNS processes in response to all of these
addictive drugs. Since oxytocinergic neuronal transmission and CNS OXT receptors are
supposedly involved in these effects, one can hypothesize that central nervous oxytociner-
gic neurons—primarily those located in basal forebrain and limbic structures are
integral elements of the adaptive response of the brain to addictive drugs. The adaptive
response of the CNS to repeated administration of addictive drugs leads to drug tolerance,
physical and psychological dependence. Activation of brain oxytocinergic neurotransmis-
sion under these circumstances may represent a physiological counterbalance mechanism,
Oxytocin and Addiction 959
which may be of functional significance, especially in early neuronal adaptation, and may
prevent the rapid onset of drug tolerance and dependence (Fig. 6).
These observations might provide useful insights into the way in which an endogenous
neuronal peptide modulates adaptive functions of the CNS by acting through its own
receptors and also by modifying the efficacy of a ‘classical’ neuronal transmitter system
(e.g. dopamine) in the forebrain. Endogenous neuropeptides following their synthesis and
release, similarly to the biological half-life of exogenously administered neuropeptides, are
present in the brain and body fluids only for minutes. Their effects on addiction, however,
can be detected long after peptide release/administration. Thus neuropeptides set into
motion various secondary events in the CNS, that keeps all these changes viable. Further
studies may shed light on molecular mechanisms involved in these alterations, i.e. on
changes in gene expression involved in mediating adaptive processes of the CNS during
drug addiction. Since individual sensitivity of human patients towards addictive drugs
largely depends on yet unknown parameters, understanding the role of neuronal peptides
in human drug and ethanol addiction would be of outstanding theoretical and practical
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... Oxytocin is best known for its role in lactation and partus, but it has many other effects in the periphery, as well as particularly in the central nervous system [17][18][19][20][21]. This includes an important role for oxytocin in addiction to alcohol (and other drugs) [22][23][24][25][26], supporting theories invariably paying close attention to the interaction of oxytocin with dopaminergic neurotransmission [22,23,26]. However, we would like to point out that the role of dopamine in the mechanism of addiction is less certain, partly because oxytocin has recently been shown to decrease alcohol drinking in alcohol dependence, but not in nondependent drinking when dopamine may have a more prominent role [27]. ...
... Oxytocin is best known for its role in lactation and partus, but it has many other effects in the periphery, as well as particularly in the central nervous system [17][18][19][20][21]. This includes an important role for oxytocin in addiction to alcohol (and other drugs) [22][23][24][25][26], supporting theories invariably paying close attention to the interaction of oxytocin with dopaminergic neurotransmission [22,23,26]. However, we would like to point out that the role of dopamine in the mechanism of addiction is less certain, partly because oxytocin has recently been shown to decrease alcohol drinking in alcohol dependence, but not in nondependent drinking when dopamine may have a more prominent role [27]. ...
Full-text available
Background: The neuropeptides β-endorphin and oxytocin are released into the bloodstream as hormones from the pituitary gland but also have an important function as neuroregulators in the forebrain. The blood levels of both polypeptides have been shown to reflect depressive symptoms. β-Endorphin, in particular, is also involved in abstinence from alcohol. Methods: The serum levels of β-endorphin and oxytocin were measured during the early withdrawal phase in patients with alcohol use disorder (AUD) with (N = 35) or without (N = 45) depressive comorbidity and compared with those in healthy volunteers (N = 23). In addition to comparing the groups, the study examined whether serum levels correlated with various psychometric measures of dependence, depression and aggression, as well as with clinical characteristics of dependence. Results: Both serum levels of beta-endorphin and oxytocin were significantly lower in patients than those in healthy controls (p = 0.011 for β-endorphin and p = 0.005 for oxytocin, Kruskal-Wallis test). In patients with depressive comorbidity, the significance was greatest (p = 0.005 for β-endorphin and p = 0.004 for oxytocin, U-test). There was no correlation with clinical or psychometric parameters (p > 0.05, Spearman test), but beta-endorphin levels did correlate significantly with physical aggression (p = 0.026, Spearman test). Conclusions: Serum levels of β-endorphin and oxytocin are lower in patients with AUD, particularly in those with depressive comorbidity. β-Endorphin levels correlated with physical aggression according to the Buss-Durkee (BDHI) estimates.
... Oxytocin also seems to modify the addictive behaviour (Sarnyai Z, 1994). This was proved by Opiat and Cocaine abuse (Kovacs GL, 1998). In some cases an extreme compulsive behaviour (Obsessive compulsive disorder) was ascribed in a dysfunction in the balance of oxytocin (Leckman JF, 1994). ...
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Oxytocin is a body-own hormone which is released in the posterior pituitary gland and controls a number of bodily functions. However, since the 90ies, its psychoactive component is being investigated and is becoming very meaningful in diagnosis and therapy of both Psychiatry and Psychology. Since the 60's Oxytocin is used in Gynaecology to induce labour. This contribution has emerged from over a decade of working with newborn babies. In this contribution, the thesis is set up that the use of Oxytocin under birth can have consequences on the psyche of the child, for the important time after the birth and in addition for the remainder of life. Its use should therefore be strictly carefully considered. As an example, in the USA almost 80where the application could be consequential in social importance. Through the course of the years, the author has set up a treatment for the concerned children and adults, and consequently clarifies its principles.
... All of these regions are relevant to drug-seeking behaviour [2]. Other research has found that OXT modulates the response to alcohol through interaction with neural sites implicated in the development of substance-use disorders and craving [2][3][4]. ...
... In heroin-tolerant rats, a single dose of OXT (0.05, 0.5, and 5 µg; s.c.) was all that was required to reduce heroin selfadministration and block the expression of heroin tolerance. However, this effect was not found in heroin-naive rats [67,68]. The acute intracerebroventricular administration of OXT (1 µg/5 µL) reduced alcohol self-administration and prevented the ethanol-induced release of DA in the NAc in rats both chronically exposed and naive to ethanol [69]. ...
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Recently, oxytocin (OXT) has been investigated for its potential therapeutic role in addiction. OXT has been found to diminish various drug-seeking and drug-induced behaviors. Although its behavioral effects are well-established, there is not much consensus on how this neuropeptide exerts its effects. Previous research has given thought to how dopamine (DA) may be involved in oxytocinergic mechanisms, but there has not been as strong of a focus on the role that glutamate (Glu) has. The glutamatergic system is critical for the processing of rewards and the disruption of glutamatergic projections produces the behaviors seen in drug addicts. We introduce the idea that OXT has direct effects on Glu transmission within the reward processing pathway. Thus, OXT may reduce addictive behaviors by restoring abnormal drug-induced changes in the glutamatergic system and in its interactions with other neurotransmitters. This review offers insight into the mechanisms through which a potentially viable therapeutic target, OXT, could be used to reduce addiction-related behaviors.
The prefrontal cortex plays a critical role in regulating substance use disorder and is strongly implicated in inhibition of and relapse to drug-seeking. Within the prefrontal cortex, inhibitory interneurons make up tightly regulated microcircuits that moderate activity of pyramidal neurons and hence control output to downstream circuits including those important for addiction-related behaviours. These interneurons can be classed into subpopulations based on peptide expression, however the complexity of these subclasses is only beginning to be understood. In this review we focus on four peptides that have receptor expression on interneurons and pyramidal neurons in the PFC. All four peptides have well-known roles in mediating drug-seeking behaviours, however their function within the prefrontal cortex is less well defined. We will review evidence from preclinical animal models that cells expressing these receptors are recruited during addiction-related behaviours, and that direct pharmacological manipulation of these systems within the prefrontal cortex may lead to altered drug-seeking behaviours. In our view, a deeper understanding of activity of specific microcircuits within this region, and their effect on pyramidal neuronal output are critical for understanding and remediating specific behaviours relevant to substance use disorder. Uncovering function of cells populations that express these neuropeptides and their receptors may help to define these microcircuits, and hence to understand how and why these behaviours are altered following drug exposure.
It is well established that the damaging effects of drugs of abuse, such as cocaine, can extend beyond the user to their offspring. While most preclinical models of the generational effects of cocaine abuse have focused on maternal effects, we, and others, report distinct effects on offspring sired by fathers treated with cocaine prior to breeding. However, little is known about the effects of paternal cocaine use on first generation (F1) offspring’s social behaviors. Here, we expand upon our model of oral self-administered paternal cocaine use to address the idea that paternal cocaine alters first generation offspring social behaviors through modulation of the oxytocin system. F1 cocaine-sired males displayed unaltered social recognition vs. non-cocaine sired controls but showed increased investigation times that were not related to altered olfaction. Paternal cocaine did not alter F1 male-aggression behavior or depression-like behaviors, but cocaine-sired males did display decreased anxiety-like behaviors. Female F1 behavior was similarly examined, but there were no effects of paternal cocaine. Cocaine-sired male mice also exhibited localized oxytocin receptor expression differences vs. controls in several brain regions regulating social behavior. These results provide evidence for effects of paternal cocaine exposure on social behaviors in male offspring with associated alterations in central oxytocin transmission.
The initial enthusiasm towards oxytocin (OXT) as a potential treatment for alcohol use disorder has been recently tempered by recognizing existing gaps in literature and the recent appearance of a relatively small number of clinical studies with negative outcomes. On the other hand, several new studies continue to support the OXT system’s potential for such treatment. In this review, we thoroughly analyze existing literature assessing both alcohol’s effects on the OXT system and OXT’s effects on alcohol-related behaviors. Both rodent and clinical research is discussed. We identify areas that have been studied extensively and those that have been undeservingly understudied. OXT’s potential effects on tolerance, withdrawal, craving, anxiety and social behaviors, and how these processes ultimately affect alcohol consumption, are critically explored. We conclude that while OXT can affect alcohol consumption in males and females, more comprehensive studies on OXT’s effects on alcohol-related tolerance, withdrawal, craving, anxiety and social affiliations in subjects of both sexes and across several levels of analyses are needed.
Oxycodone is one of the most commonly used analgesics in the clinic. However, long‐term use can contribute to drug dependence. Accumulating evidence of changes in DNA methylation after opioid relapse has provided insight into mechanisms underlying drug‐associated memory. The neuropeptide oxytocin is reported to be a potential treatment for addiction. The present study sought to identify changes in global and synaptic gene methylation after cue‐induced reinstatement of oxycodone conditioned place preference (CPP) and the effect of oxytocin. We analyzed hippocampal mRNA of synaptic genes and also synaptic density in response to oxycodone CPP. We determined the mRNA levels of DNA methyltransferases (Dnmts) and ten‐eleven translocations (Tets), observed global 5‐methylcytosine (5‐mC) and 5‐hydroxymethylcytosine (5‐hmC) levels, and measured DNA methylation status of four synaptic genes implicated in learning and memory (Arc, Dlg1, Dlg4, and Syn1). Both synaptic density and the transcription of 15 hippocampal synaptic genes significantly increased following cue‐induced reinstatement of oxycodone CPP. Oxycodone relapse was also related to markedly decreased 5‐mC levels and decreased transcription of Dnmt1, Dnmt3a, and Dnmt3b; in contrast, 5‐hmC levels and the transcription of Tet1 and Tet3 were increased. Oxycodone exposure induced DNA hypomethylation at the exons of the Arc, Dlg1, Dlg4, and Syn1 genes. Intracerebroventricular (ICV) administration of oxytocin (2.5 μg/μl) specifically blocked oxycodone relapse, possibly by inhibition of Arc, Dlg1, Dlg4, and Syn1 hypomethylation in oxycodone‐treated rats. Together, these data indicate the occurrence of epigenetic changes in the hippocampus following oxycodone relapse and the potential role of oxytocin in oxycodone addiction.
Social rewards are fundamental to survival and overall health. Several studies suggest that adequate social stimuli during early life are critical for developing appropriate socio‐emotional and cognitive skills, while adverse social experiences negatively affect the proper development of brain and behavior, by increasing the susceptibility to develop neuropsychiatric conditions. Therefore, a better understanding of the neural mechanisms underlying social interactions, and their rewarding components in particular, is an important challenge of current neuroscience research. In this context, preclinical research has a crucial role: animal models allow to investigate the neurobiological aspects of social reward in order to shed light on possible neurochemical alterations causing aberrant social reward processing in neuropsychiatric diseases, and they allow to test the validity and safety of innovative therapeutic strategies. Here, we discuss preclinical research that has investigated the rewarding properties of two forms of social interaction that occur in different phases of the lifespan of mammals, i.e., mother‐infant interaction and social interactions with peers, by focusing on the main neurotransmitter systems mediating their rewarding components. Together, the research performed so far helped to elucidate the mechanisms of social reward and its psychobiological components throughout development, thus increasing our understanding of the neurobiological substrates sustaining social functioning in health conditions and social dysfunction in major psychiatric disorders.
Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development. SIGNIFICANCE STATEMENT: The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.
The past 10 years have witnessed the growth of the view that neuropeptides are essential to the functional integrity of the central nervous system. Oxytocin (OXT), which was long considered to be implicated in milk ejection only, is a neuropeptide with potent behavioral effects. Since the original discovery by Sterba (1974), a great number of morphological (for reviews, see Buijs 1983; Swanson and Sawchenko 1983; Sofroniew 1983; Palkovits and Brownstein 1983; Kozlowski et al. 1983) and biochemical (Dogterom et al. 1978; Mens et al. 1983; Kovács et al. 1985d; Hawthorn et al. 1984) results indicate that the biologically active OXT is present in various extrahypothalamic (mainly limbic and brainstem) brain regions. The release of extrahypothalamic OXT by depolarizing stimuli has been demonstrated (Buijs and Van Heerikhuize 1982), and the existence of specific binding sites for OXT (putative OXT receptors) has been described in limbic brain structures (Ferrier et al. 1983; Brinton et al. 1984). However, the biological significance of OXT in the brain is not clear. The neuropeptide has been implicated in the regulation of behavioral reactions. Evidence has accumulated that OXT attenuates learning and memory processes (for review, see Kovács and Telegdy 1982), regulates the adaptive response to narcotic analgesics (Kovács et al. 1984 b, c), and alters the efficacy of addictive drugs (Van Ree and De Wied 1977 a; Kovács and Telegdy 1984; Kovács et al. 1985 a).
A common denominator for the occurrence of abuse with various drugs is their reinforcing action, which can be analysed reliably in experimental animals by drug self-administration. This behaviour is influenced by external factors, drug-induced alterations of homeostatic mechanisms in the body and by internal factors. These internal factors are directly related to reinforcement or could modulate the drug-induced reinforcing activity. Experimental data show that the opioid peptide β-endorphin acts as a positive reinforcer in rats and that desglycinamide9-arginine8-vasopressin decreases acquisition of heroin self-administration in these animals. It is concluded that brain neuropeptide systems are operative in the reward mechanism and may be implicated in the acquisition of drug seeking behaviour; this may be of relevance to the underlying mechanisms of drug addiction.
The effects of oxytocin, administered intracerebroventricularly in doses of 1, 10, 100 and 1000 pmol, were studied on the disappearance of catecholamines induced by α-methyl-p-tyrosine in microdissected nuclei of the rat brain. Oxytocin dose-dependently decreased the utilization of noradrenaline in the lateral and medial septal nuclei and anterior hypothalamic area, whereas an enhanced utilization was observed in the nucleus supraopticus. Tendency towards a change in utilization of noradrenaline was found in the dorsal septal nucleus and the lateral amygdala. Utilization of dopamine was not significantly affected in any of the nuclei of the brain studied. Tendency towards a decrease in utilization of dopamine was observed in the nucleus caudatus, globus pallidus and medial septal nucleus. It thus appears that oxytocin elicited changes in only a restricted number of brain nuclei. Interestingly, these nuclei contain cell bodies (nucleus supraopticus) and terminals (other nuclei) of the oxytocin system in the brain. Though the effects of oxytocin were not as widespread as those previously seen after administration of vasopressin, it is worthy of note that, in general, the effects of oxytocin were opposite to those seen after vasopressin. The opposite effecs of vasopressin and oxytocin on catecholamine metabolism could be related to the opposite effects of the two peptides on behaviour, neuroendocrine and autonomie regulation.